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175-665: Cancer immunotherapy ( immuno-oncotherapy ) is the stimulation of the immune system to treat cancer , improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology ( immuno-oncology ) and a growing subspecialty of oncology . Cancer immunotherapy exploits the fact that cancer cells often have tumor antigens , molecules on their surface that can bind to antibody proteins or T-cell receptors , triggering an immune system response. The tumor antigens are often proteins or other macromolecules (e.g., carbohydrates ). Normal antibodies bind to external pathogens, but

350-564: A lysosome to form a phagolysosome . The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome. Phagocytosis evolved as a means of acquiring nutrients , but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism. Phagocytosis probably represents the oldest form of host defense, as phagocytes have been identified in both vertebrate and invertebrate animals. Neutrophils and macrophages are phagocytes that travel throughout

525-465: A "self" receptor called a major histocompatibility complex (MHC) molecule. There are two major subtypes of T cells: the killer T cell and the helper T cell . In addition there are regulatory T cells which have a role in modulating immune response. Killer T cells are a sub-group of T cells that kill cells that are infected with viruses (and other pathogens), or are otherwise damaged or dysfunctional. As with B cells, each type of T cell recognizes

700-490: A Fab region that binds PD-1 but also an Fc region. Experimental work indicates that the Fc portion of cancer immunotherapy drugs can affect the outcome of treatment. For example, anti-PD-1 drugs with Fc regions that bind inhibitory Fc receptors can have decreased therapeutic efficacy. Imaging studies have further shown that the Fc region of anti-PD-1 drugs can bind Fc receptors expressed by tumor-associated macrophages. This process removes

875-510: A T cell response. A number of cytokines are produced by NKs, including tumor necrosis factor α ( TNFα ), IFNγ , and interleukin ( IL-10 ). TNFα and IL-10 act as proinflammatory and immunosuppressors, respectively. The activation of NK cells and subsequent production of cytolytic effector cells impacts macrophages , dendritic cells , and neutrophils , which subsequently enables antigen-specific T and B cell responses. Instead of acting via antigen-specific receptors, lysis of tumor cells by NK cells

1050-517: A binding region (Fab) and the Fc region that can be detected by immune system cells via their Fc surface receptors . Fc receptors are found on many immune system cells, including NK cells. When NK cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasing perforin and granzyme B to kill the tumor cell. Examples include rituximab , ofatumumab , elotuzumab , and alemtuzumab . Antibodies under development have altered Fc regions that have higher affinity for

1225-404: A cancer-targeting gene (as with CAR T). The mixture is then added to a MASTER (scaffold), which absorbs them. The MASTER contains antibodies that activate the T cells and interleukins that trigger cell proliferation. The MASTER is then implanted into the patient. The activated T cells interact with the viruses to become CAR T cells. The interleukins stimulate these CAR T cells to proliferate, and

1400-426: A cell slated for killing, perforin forms pores in the cell membrane of the target cell, creating an aqueous channel through which the granzymes and associated molecules can enter, inducing either apoptosis or osmotic cell lysis. The distinction between apoptosis and cell lysis is important in immunology : lysing a virus-infected cell could potentially release the virions , whereas apoptosis leads to destruction of

1575-423: A chemical barrier following menarche , when they become slightly acidic , while semen contains defensins and zinc to kill pathogens. In the stomach , gastric acid serves as a chemical defense against ingested pathogens. Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with pathogenic bacteria for food and space and, in some cases, changing

1750-538: A chimeric antigen receptor (CAR) that specifically recognizes cancer cells, then infuse the resulting CAR-T cells into patients to attack their tumors. Tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR-T) therapy, was approved by the FDA in 2017 to treat acute lymphoblastic leukemia (ALL). This treatment removes CD19 positive cells (B-cells) from the body (including the diseased cells, but also normal antibody-producing cells). Axicabtagene ciloleucel (Yescarta)

1925-422: A condition known as "missing self". This term describes cells with low levels of a cell-surface marker called MHC I ( major histocompatibility complex )—a situation that can arise in viral infections of host cells. Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors, which essentially put

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2100-584: A different antigen. Killer T cells are activated when their T-cell receptor binds to this specific antigen in a complex with the MHC Class I receptor of another cell. Recognition of this MHC:antigen complex is aided by a co-receptor on the T cell, called CD8 . The T cell then travels throughout the body in search of cells where the MHC I receptors bear this antigen. When an activated T cell contacts such cells, it releases cytotoxins , such as perforin , which form pores in

2275-533: A diminished effect and may result in lower antibody production, and a lower immune response, than would be noted in a well-rested individual. Additionally, proteins such as NFIL3 , which have been shown to be closely intertwined with both T-cell differentiation and circadian rhythms , can be affected through the disturbance of natural light and dark cycles through instances of sleep deprivation. These disruptions can lead to an increase in chronic conditions such as heart disease, chronic pain, and asthma. In addition to

2450-641: A false NK response and consequently creating competition for the receptor site. This method of evasion occurs in prostate cancer . In addition, prostate cancer tumors can evade CD8 cell recognition due to their ability to downregulate expression of MHC class 1 molecules. This example of immune evasion actually highlights NK cells' importance in tumor surveillance and response, as CD8 cells can consequently only act on tumor cells in response to NK-initiated cytokine production (adaptive immune response). Experimental treatments with NK cells have resulted in excessive cytokine production, and even septic shock . Depletion of

2625-647: A firm conclusion has not yet been drawn as to what combination provides decreased HIV and AIDS susceptibility. NK cells can impose immune pressure on HIV, which had previously been described only for T cells and antibodies. HIV mutates to avoid NK cell detection. Most of our current knowledge is derived from investigations of mouse splenic and human peripheral blood NK cells. However, in recent years tissue-resident NK cell populations have been described. These tissue-resident NK cells share transcriptional similarity to tissue-resident memory T cells described previously. However, tissue-resident NK cells are not necessarily of

2800-510: A form of immunological memory, characterized by a more potent response upon secondary challenge with the same antigen. In mice, the majority of research was carried out with murine cytomegalovirus (MCMV) and in models of hapten-hypersensitivity reactions. Especially, in the MCMV model, protective memory functions of MCMV-induced NK cells were discovered and direct recognition of the MCMV-ligand m157 by

2975-549: A high level of cytokines which help mediate their function. NK cells interact with HLA-C to produce cytokines necessary for trophoblastic proliferation. Some important cytokines they secrete include TNF-α , IL-10 , IFN-γ , GM-CSF and TGF-β , among others. For example, IFN-γ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site. By shedding decoy NKG2D soluble ligands, tumor cells may avoid immune responses. These soluble NKG2D ligands bind to NK cell NKG2D receptors, activating

3150-399: A link between the bodily tissues and the innate and adaptive immune systems, as they present antigens to T cells , one of the key cell types of the adaptive immune system. Granulocytes are leukocytes that have granules in their cytoplasm. In this category are neutrophils, mast cells, basophils, and eosinophils. Mast cells reside in connective tissues and mucous membranes and regulate

3325-416: A lower level than peripheral NK cells, despite containing perforin . Lack of cytotoxicity in vivo may be due to the presence of ligands for their inhibitory receptors. Trophoblast cells downregulate HLA-A and HLA-B to defend against cytotoxic T cell -mediated death. This would normally trigger NK cells by missing self recognition; however, these cells survive. The selective retention of HLA-E (which

3500-463: A mechanism of responding to virus infections that was previously only known for T cells of the adaptive immune system . As the majority of pregnancies involve two parents who are not tissue-matched, successful pregnancy requires the mother's immune system to be suppressed . NK cells are thought to be an important cell type in this process. These cells are known as " uterine NK cells " (uNK cells) and they differ from peripheral NK cells. They are in

3675-549: A natural immunity to tumors was performed by Dr. Henry Smith at the University of Leeds School of Medicine in 1966, leading to the conclusion that the "phenomenon appear[ed] to be an expression of defense mechanisms to tumor growth present in normal mice." Other researchers had also made similar observations, but as these discoveries were inconsistent with the established model at the time, many initially considered these observations to be artifacts. By 1973, 'natural killing' activity

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3850-497: A number of patients with solid tumors in a phase I/II study, which is underway. In a study at Boston Children's Hospital, in coordination with Dana–Farber Cancer Institute , in which immunocompromised mice had contracted lymphomas from EBV infection, an NK-activating receptor called NKG2D was fused with a stimulatory Fc portion of the EBV antibody. The NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of

4025-486: A patient with lymphoma, they must be irradiated prior to infusion. Efforts, however, are being made to engineer the cells to eliminate the need for irradiation. The irradiated cells maintain full cytotoxicity. NK-92 are allogeneic (from a donor different from the recipient), but in clinical studies have not been shown to elicit significant host reaction. Unmodified NK-92 cells lack CD-16, making them unable to perform antibody-dependent cellular cytotoxicity (ADCC); however,

4200-460: A pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12 , TNF-alpha and IFN-gamma . These cytokines then stimulate immune functions such as immune cell activation, proliferation, and differentiation . During this time of a slowly evolving adaptive immune response, there is a peak in undifferentiated or less differentiated cells, like naïve and central memory T cells. In addition to these effects,

4375-491: A reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency . AIDS and some types of cancer cause acquired immunodeficiency. Overactive immune responses form the other end of immune dysfunction, particularly the autoimmune diseases . Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides. One of

4550-416: A rudimentary immune system in the form of enzymes that protect against viral infections. Other basic immune mechanisms evolved in ancient plants and animals and remain in their modern descendants. These mechanisms include phagocytosis , antimicrobial peptides called defensins , and the complement system . Jawed vertebrates , including humans, have even more sophisticated defense mechanisms, including

4725-471: A single MHC:antigen molecule. Helper T cell activation also requires longer duration of engagement with an antigen-presenting cell. The activation of a resting helper T cell causes it to release cytokines that influence the activity of many cell types. Cytokine signals produced by helper T cells enhance the microbicidal function of macrophages and the activity of killer T cells. In addition, helper T cell activation causes an upregulation of molecules expressed on

4900-460: A specific foreign antigen. This antigen/antibody complex is taken up by the B cell and processed by proteolysis into peptides . The B cell then displays these antigenic peptides on its surface MHC class II molecules. This combination of MHC and antigen attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide , its offspring ( plasma cells ) secrete millions of copies of

5075-406: A specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness. Many tumor cells overexpress CD47 to escape immunosurveilance of host immune system. CD47 binds to its receptor signal-regulatory protein alpha (SIRPα) and downregulate phagocytosis of tumor cell. Therefore, anti-CD47 therapy aims to restore clearance of tumor cells. Additionally, growing evidence supports

5250-681: A therapeutic monoclonal antibody targeting tumor cells and an IL-15/IL-15 receptor fusion protein (IL-15RF) promoting cytokine-independent persistence. A more efficient way to obtain high numbers of NK cells is to expand NK-92 cells , an NK cell line with all the characteristics of highly active blood Natural Killer (NK) cells but with much broader and higher cytotoxicity. NK-92 cells grow continuously in culture and can be expanded to clinical-grade numbers in bags or bioreactors. Clinical studies have shown NK-92 cells to be safe and to exhibit anti-tumor activity in patients with lung or pancreatic cancer, melanoma, and lymphoma. When NK-92 cells originate from

5425-452: A tumor, culturing but not modifying them, and infusing the result back into the tumour. The first therapy of this type, Lifileucel , achieved US Food and Drug Administration (FDA) approval in February 2024. The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to target and destroy them. Scientists harvest T cells from people, genetically alter them to add

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5600-508: A tumor-escape strategy on tumor cells, ligand expression for the CAR receptor is downregulated. NK cells derived from umbilical cord blood have been used to generate CAR.CD19 NK cells. These cells are capable of self-producing the cytokine IL-15 , thereby enhancing autocrine/paracrine expression and persistence in vivo . Administration of these modified NK cells is not associated with the development of CSR, neurotoxicity, or GvHD. The FT596 product

5775-428: A valuable approach to enhance effector cell efficacy. CARs induce high-affinity binding of effector cells carrying these receptors to cells expressing the target antigen, thereby lowering the threshold for cellular activation and inducing effector functions. CAR T cells are now a fairly well-known cell therapy . However, wider use is limited by several fundamental problems: The high cost of CAR T cell therapy, which

5950-524: A variety of sources, including human cells, mice, and a combination of the two (chimeric antibodies). Different sources of antibodies can provoke different kinds of immune responses. For example, the human immune system can recognize mouse antibodies (also known as murine antibodies) and trigger an immune response against them. This could reduce the effectiveness of the antibodies as a treatment and cause an immune reaction. Chimeric antibodies attempt to reduce murine antibodies' immunogenicity by replacing part of

6125-528: Is a fixed-dose combination medication used for the treatment of non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. It contains atezolizumab , a programmed death-ligand 1 (PD-L1) blocking monoclonal antibody; and hyaluronidase (human recombinant), an endoglycosidase . It is taken by subcutaneous injection . The most common adverse reactions include fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. Avelumab , sold under

6300-555: Is a ganglioside found on the surface of many types of cancer cell including neuroblastoma , retinoblastoma , melanoma , small cell lung cancer , brain tumors , osteosarcoma , rhabdomyosarcoma , Ewing's sarcoma , liposarcoma , fibrosarcoma , leiomyosarcoma and other soft tissue sarcomas . It is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy. As of 2014, clinical trials were underway. The complement system includes blood proteins that can cause cell death after an antibody binds to

6475-463: Is a monoclonal anti-HER2 antibody that is used as a treatment of the HER2+ breast cancer . NK cells are an important part of the therapeutical effect of trastzumab as NK cells recognize the antibody coated cancer cells which induces ADCC (antibody-dependent cellular cytotoxicity) reaction. TLR ligand is used in addition to trastuzumab as a means to enhance its effect. The polysaccharide krestin , which

6650-454: Is a ligand for NK cell inhibitory receptor NKG2A ) and HLA-G (which is a ligand for NK cell inhibitory receptor KIR2DL4 ) by the trophoblast is thought to defend it against NK cell-mediated death. Uterine NK cells have shown no significant difference in women with recurrent miscarriage compared with controls. However, higher peripheral NK cell percentages occur in women with recurrent miscarriages than in control groups. NK cells secrete

6825-449: Is a major killing mechanism of some monoclonal antibodies like rituximab (Rituxan) , ofatumumab (Azzera) , and others. The contribution of antibody-dependent cell-mediated cytotoxicity to tumor cell killing can be measured with a specific test that uses NK-92 , an immortal line of NK-like cells licensed to NantKwest, Inc. : the response of NK-92 cells that have been transfected with a high-affinity Fc receptor are compared to that of

7000-409: Is a transient immunodepression, where the number of circulating lymphocytes decreases and antibody production declines. This may give rise to a window of opportunity for infection and reactivation of latent virus infections, but the evidence is inconclusive. During exercise there is an increase in circulating white blood cells of all types. This is caused by the frictional force of blood flowing on

7175-483: Is a type of adoptive T-cell therapy that targets some cancers. TCR-T therapies use heterodimers made of alpha and beta peptide chains to recognize MHC -presented polypeptide fragment molecules. Unlike CAR-T, which uses cell surface antigens, TCR-T can recognize MHC's larger set of intracellular antigen fragments. However, TCR-T cell therapy depends on MHC molecules, limiting its usefulness. Two types are used in cancer treatments: Fc's ability to bind Fc receptors

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7350-446: Is activated by complement binding to antibodies that have attached to these microbes or the binding of complement proteins to carbohydrates on the surfaces of microbes . This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs after sequential proteolytic activation of complement molecules, which are also proteases. After complement proteins initially bind to

7525-527: Is affected by sleep and rest, and sleep deprivation is detrimental to immune function. Complex feedback loops involving cytokines , such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement ( REM ) sleep. Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep. In people with sleep deprivation, active immunizations may have

7700-502: Is also recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (such as Lck ) that are responsible for the T cell's activation. Helper T cells have a weaker association with the MHC:antigen complex than observed for killer T cells, meaning many receptors (around 200–300) on the helper T cell must be bound by an MHC:antigen to activate the helper cell, while killer T cells can be activated by engagement of

7875-518: Is an NK-92 derived cell engineered with both a CD16 and an anti-PD-L1 CAR; currently in clinical development for oncology indications. A clinical grade NK-92 variant that expresses a CAR for HER2 (ErbB2) has been generated and is in a clinical study in patients with HER2 positive glioblastoma . Several other clinical grade clones have been generated expressing the CARs for PD-L1, CD19, HER-2, and EGFR. PD-L1 targeted high affinity NK cells have been given to

8050-549: Is an immune response that damages the body's own tissues. It is divided into four classes (Type I – IV) based on the mechanisms involved and the time course of the hypersensitive reaction. Type I hypersensitivity is an immediate or anaphylactic reaction, often associated with allergy. Symptoms can range from mild discomfort to death. Type I hypersensitivity is mediated by IgE , which triggers degranulation of mast cells and basophils when cross-linked by antigen. Type II hypersensitivity occurs when antibodies bind to antigens on

8225-415: Is an important feature of cellular innate immunity performed by cells called phagocytes that engulf pathogens or particles. Phagocytes generally patrol the body searching for pathogens, but can be called to specific locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome , which subsequently fuses with another vesicle called

8400-429: Is another CAR-T therapeutic, approved in 2017 for treatment of diffuse large B-cell lymphoma (DLBCL). Multifunctional alginate scaffolds for T cell engineering and release (MASTER) is a technique for in situ engineering, replication and release of genetically engineered T cells. It is an evolution of CAR T cell therapy. T cells are extracted from the patient and mixed with a genetically engineered virus that contains

8575-537: Is becoming increasingly important in research using NK cell activity as a potential cancer therapy and HIV therapy. In early experiments on cell-mediated cytotoxicity against tumor target cells, both in cancer patients and animal models, investigators consistently observed what was termed a "natural" reactivity; that is, a certain population of cells seemed to be able to destroy tumor cells without having been previously sensitized to them. The first published study to assert that untreated lymphoid cells were able to confer

8750-561: Is critical to systematically incorporate NK cells monitoring as an outcome in antitumor DC-based clinical trials. Sipuleucel-T (Provenge) was approved for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer in 2010. The treatment consists of removal of antigen-presenting cells from blood by leukapheresis and growing them with the fusion protein PA2024 made from GM-CSF and prostate-specific prostatic acid phosphatase (PAP) and reinfused. This process

8925-594: Is determined by the balance of inhibitory and activating receptor stimulation. For example, if the inhibitory receptor signaling is more prominent, then NK cell activity will be inhibited; similarly, if the activating signal is dominant, then NK cell activation will result. NK cell receptor types (with inhibitory, as well as some activating members) are differentiated by structure, with a few examples to follow: NK cells are cytotoxic ; small granules in their cytoplasm contain proteins such as perforin and proteases known as granzymes . Upon release in close proximity to

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9100-615: Is done intravenously. Each intravenous injection of elotuzumab should be premedicated with dexamethasone , diphenhydramine , ranitidine and acetaminophen . It is being developed by Bristol Myers Squibb and AbbVie . Common side effects of elotuzumab with lenalidomide and dexamethasone includes fatigue , diarrhea , pyrexia , constipation , cough , peripheral neuropathy , nasopharyngitis , upper respiratory tract infection , decreased appetite, and pneumonia . The most common side effects of elotuzumab with pomalidomide and dexamethasone includes constipation and hyperglycemia . There

9275-466: Is due to the need to generate specific CAR T cells for each patient; the necessity to use only autologous T cells, due to the high risk of GvHD if allogeneic T cells are used; the inability to reinfuse CAR T cells if the patient relapses or low CAR T cell survival is observed; CAR T therapy also has a high toxicity, mainly due to IFN-γ production and subsequent induction of CRS ( cytokine release syndrome ) and/or neurotoxicity . The use of CAR NK cells

9450-721: Is encountered. Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules . In immunology, self molecules are components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self molecules are those recognized as foreign molecules. One class of non-self molecules are called antigens (originally named for being anti body gen erators) and are defined as substances that bind to specific immune receptors and elicit an immune response. Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of most leaves,

9625-480: Is extracted from Trametes versicolor , is a potent ligand of TLR-2 and so activates NK cells, induces the production of IFNg and enhances the ADCC caused by recognition of trastuzumab-coated cells. Stimulation of TLR-7 induces the expression of IFN type I and other pro-inflammatory cytokines like IL-1b , IL-6 and IL-12 . Mice suffering with NK cell-sensitive lymphoma RMA-S were treated with SC1 molecule. SC1

9800-415: Is found on >95% of peripheral blood lymphocytes (both T-cells and B-cells) and monocytes , but its function in lymphocytes is unknown. It binds to CD52 and initiates its cytotoxic effect by complement fixation and ADCC mechanisms. Due to the antibody target (cells of the immune system), common complications of alemtuzumab therapy are infection, toxicity and myelosuppression . Atezolizumab , sold under

9975-649: Is important because it allows antibodies to activate the immune system. Fc regions are varied: they exist in numerous subtypes and can be further modified, for example with the addition of sugars in a process called glycosylation . Changes in the Fc region can alter an antibody's ability to engage Fc receptors and, by extension, will determine the type of immune response that the antibody triggers. For example, immune checkpoint blockers targeting PD-1 are antibodies designed to bind PD-1 expressed by T cells and reactivate these cells to eliminate tumors . Anti-PD-1 drugs contain not only

10150-543: Is known as "missing-self recognition", a term coined by Klas Kärre and co-workers in the late 90s. MHC class I molecules are the main mechanism by which cells display viral or tumor antigens to cytotoxic T cells. A common evolutionary adaptation to this is seen in both intracellular microbes and tumors: the chronic down-regulation of MHC I molecules, which makes affected cells invisible to T cells, allowing them to evade T cell-mediated immunity. NK cells apparently evolved as an evolutionary response to this adaptation (the loss of

10325-530: Is mediated by transmembrane proteins known as toll-like receptors (TLRs). TLRs share a typical structural motif, the leucine rich repeats (LRRs) , which give them a curved shape. Toll-like receptors were first discovered in Drosophila and trigger the synthesis and secretion of cytokines and activation of other host defense programs that are necessary for both innate or adaptive immune responses. Ten toll-like receptors have been described in humans. Cells in

10500-475: Is mediated by alternative receptors, including NKG2D , NKp44, NKp46, NKp30, and DNAM. NKG2D is a disulfide -linked homodimer which recognizes a number of ligands, including ULBP and MICA , which are typically expressed on tumor cells. The role of dendritic cell—NK cell interface in immunobiology have been studied and defined as critical for the comprehension of the complex immune system. NK cells, along with macrophages and several other cell types, express

10675-739: Is no available information for the use of elotuzumab in pregnant women . Elotuzumab is an immunostimulatory antibody that targets the Signaling Lymphocytic Activation Molecule Family member 7 ( SLAMF7 ) through two mechanisms. Ipilimumab (Yervoy) is a human IgG1 antibody that binds the surface protein CTLA4 . In normal physiology T-cells are activated by two signals: the T-cell receptor binding to an antigen - MHC complex and T-cell surface receptor CD28 binding to CD80 or CD86 proteins. CTLA4 binds to CD80 or CD86, preventing

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10850-499: Is not limited by the need to generate patient-specific cells, and at the same time, GvHD is not caused by NK cells, thus obviating the need for autologous cells. Toxic effects of CAR T therapy, such as CSR, have not been observed with the use of CAR NK cells. Thus, NK cells are considered an interesting "off-the-shelf" product option. Compared to CAR T cells, CAR NK cells retain unchanged expression of NK cell activating receptors. Thus, NK cells recognize and kill tumor cells even if, due to

11025-528: Is novel small-molecule TLR-7 agonist and its repeated administration reportedly activated NK cells in TLR-7- and IFN type I- dependent manner thus reversing the NK cell anergy which ultimately lead to lysis of the tumor. VTX-2337 is a selective TLR-8 agonist and together with monoclonal antibody cetuximab it was used as a potential therapy for the treatment of recurrent or metastatic SCCHN . Results have shown that

11200-465: Is one of the first responses of the immune system to infection, but it can appear without known cause. Natural killer cell NK cells can be identified by the presence of CD56 and the absence of CD3 (CD56 , CD3 ). NK cells differentiate from CD127 common innate lymphoid progenitor, which is downstream of the common lymphoid progenitor from which B and T lymphocytes are also derived. NK cells are known to differentiate and mature in

11375-408: Is only depleted in patients with severe COVID-19. NK cell receptors can also be differentiated based on function. Natural cytotoxicity receptors directly induce apoptosis (cell death) after binding to Fas ligand that directly indicate infection of a cell. The MHC-independent receptors (described above) use an alternate pathway to induce apoptosis in infected cells. Natural killer cell activation

11550-640: Is repeated three times. Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells. They are found in blood and tissue and typically activate when they find foreign pathogens . Activation occurs when the T-cell's surface receptors encounter cells that display parts of foreign proteins (either on their surface or intracellularly). These can be either infected cells or other antigen-presenting cells (APCs). The latter are found in normal tissue and in tumor tissue, where they are known as tumor-infiltrating lymphocytes (TILs). They are activated by

11725-653: Is the first "Off-the-Shelf", universal, and allogenic CAR NK cellular product derived from iPSCs to be authorized for use in clinical studies in the USA. It consists of an anti-CD19 CAR optimized for NK cells with a transmembrane domain for the NKG2D activation receptor, a 2B4 costimulatory domain and a CD3ζ signaling domain. Two additional key components were added: 1) a high-affinity, non-cleavable Fc receptor CD16 (hnCD16) that enables tumor targeting and enhanced antibody-dependent cell cytotoxicity without negative regulation, combined with 2)

11900-504: Is to generate active forms of the inflammatory cytokines IL-1β and IL-18. The complement system is a biochemical cascade that attacks the surfaces of foreign cells. It contains over 20 different proteins and is named for its ability to "complement" the killing of pathogens by antibodies . Complement is the major humoral component of the innate immune response. Many species have complement systems, including non- mammals like plants, fish, and some invertebrates . In humans, this response

12075-445: Is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken-down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response. Dendritic cell therapies include the use of antibodies that bind to receptors on

12250-402: The "professional" phagocytes ( macrophages , neutrophils , and dendritic cells ). These cells identify and eliminate pathogens, either by attacking larger pathogens through contact or by engulfing and then killing microorganisms. The other cells involved in the innate response include innate lymphoid cells , mast cells , eosinophils , basophils , and natural killer cells . Phagocytosis

12425-503: The CD56 NK cell subset, potent at cytokine secretion, but with low cytotoxic ability and relatively similar to peripheral CD56 NK cells, with a slightly different receptor profile. These uNK cells are the most abundant leukocytes present in utero in early pregnancy, representing about 70% of leukocytes here, but from where they originate remains controversial. These NK cells have the ability to elicit cell cytotoxicity in vitro , but at

12600-580: The Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation. "During the 17th and 18th centuries, various forms of immunotherapy in cancer became widespread... In the 18th and 19th centuries, septic dressings enclosing ulcerative tumours were used for the treatment of cancer. Surgical wounds were left open to facilitate the development of infection, and purulent sores were created deliberately... One of

12775-498: The bone marrow , lymph nodes , spleen , tonsils , and thymus , where they then enter into the circulation. NK cells differ from natural killer T cells (NKTs) phenotypically, by origin and by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting interferon gamma . In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors , but they usually express

12950-573: The endothelial cell surface and catecholamines affecting β-adrenergic receptors (βARs). The number of neutrophils in the blood increases and remains raised for up to six hours and immature forms are present. Although the increase in neutrophils (" neutrophilia ") is similar to that seen during bacterial infections, after exercise the cell population returns to normal by around 24 hours. The number of circulating lymphocytes (mainly natural killer cells ) decreases during intense exercise but returns to normal after 4 to 6 hours. Although up to 2% of

13125-449: The exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of mechanical barriers that are the first line of defense against infection. Organisms cannot be completely sealed from their environments, so systems act to protect body openings such as the lungs , intestines , and the genitourinary tract . In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from

13300-458: The innate immune system , such as dendritic cells, macrophages, monocytes, neutrophils, and epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens , and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or cell death. Recognition of extracellular or endosomal PAMPs

13475-492: The lymphoid lineage . These cells are defined by the absence of antigen-specific B- or T-cell receptor (TCR) because of the lack of recombination activating gene . ILCs do not express myeloid or dendritic cell markers. Natural killer cells (NK cells) are lymphocytes and a component of the innate immune system that does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by

13650-627: The nervous systems. The immune system also plays a crucial role in embryogenesis (development of the embryo), as well as in tissue repair and regeneration . Hormones can act as immunomodulators , altering the sensitivity of the immune system. For example, female sex hormones are known immunostimulators of both adaptive and innate immune responses. Some autoimmune diseases such as lupus erythematosus strike women preferentially, and their onset often coincides with puberty . By contrast, male sex hormones such as testosterone seem to be immunosuppressive . Other hormones appear to regulate

13825-417: The peripheral blood , and are characterized by their cell killing ability. CD56 NK cells are always CD16 positive (CD16 is the key mediator of antibody-dependent cellular cytotoxicity , or ADCC). CD56 can transition into CD56 by acquiring CD16. NK cells can eliminate virus-infected cells via CD16-mediated ADCC. All coronavirus disease 2019 (COVID-19) patients show depleted CD56 NK cells, but CD56

14000-514: The respiratory tract . The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms . Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such as the β- defensins . Enzymes such as lysozyme and phospholipase A2 in saliva , tears, and breast milk are also antibacterials . Vaginal secretions serve as

14175-502: The "wild type" NK-92 which does not express the Fc receptor. Cytokines play a crucial role in NK cell activation. As these are stress molecules released by cells upon viral infection, they serve to signal to the NK cell the presence of viral pathogens in the affected area. Cytokines involved in NK activation include IL-12 , IL-15 , IL-18 , IL-2 , and CCL5 . NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while

14350-399: The B cell surface and recognizes native (unprocessed) antigen without any need for antigen processing . Such antigens may be large molecules found on the surfaces of pathogens, but can also be small haptens (such as penicillin) attached to carrier molecule. Each lineage of B cell expresses a different antibody, so the complete set of B cell antigen receptors represent all the antibodies that

14525-455: The CAR T cells exit the MASTER to attack the cancer. The technique takes hours instead of weeks. And because the cells are younger, they last longer in the body, show stronger potency against cancer, and display fewer markers of exhaustion. These features were demonstrated in mouse models. The treatment was more effective and longer-lasting against lymphoma . T cell receptor T cell therapy (TCR-T)

14700-430: The Fc portion of the antibody. This affinity is determined by the amino acid in position 158 of the protein, which can be phenylalanine (F allele) or valine (V allele). Individuals with high-affinity FcRgammRIII (158 V/V allele) respond better to antibody therapy. This has been shown for lymphoma patients who received the antibody Rituxan. Patients who express the 158 V/V allele had a better antitumor response. Only 15–25% of

14875-437: The Fc receptor (FcR) molecule (FC-gamma-RIII = CD16), an activating biochemical receptor that binds the Fc portion of IgG class antibodies . This allows NK cells to target cells against which there has been a humoral response and to lyse cells through antibody-dependant cytotoxicity (ADCC). This response depends on the affinity of the Fc receptor expressed on NK cells, which can have high, intermediate, and low affinity for

15050-456: The MHC eliminates CD4/CD8 action, so another immune cell evolved to fulfill the function). Natural killer cells often lack antigen-specific cell surface receptors, so are part of innate immunity, i.e. able to react immediately with no prior exposure to the pathogen. In both mice and humans, NKs can be seen to play a role in tumor immunosurveillance by directly inducing the death of tumor cells (NKs act as cytolytic effector lymphocytes), even in

15225-681: The NK cells had become more reactive to the treatment with cetuximab antibody upon pretreatment with VTX-2337. This indicates that the stimulation of TLR-8 and subsequent activation of inflammasome enhances the CD-16 mediated ADCC reaction in patients treated with cetuximab antibody. NK cells play a role in controlling HIV-1 infection. TLR are potent enhancers of innate antiviral immunity and potentially can reverse HIV-1 latency. Incubation of peripheral blood mononuclear cells with novel potent TLR-9 ligand MGN1703 have resulted in enhancement of NK cell effector functions, thus significantly inhibiting

15400-587: The T cell's surface, such as CD40 ligand (also called CD154 ), which provide extra stimulatory signals typically required to activate antibody-producing B cells. Gamma delta T cells (γδ T cells) possess an alternative T-cell receptor (TCR) as opposed to CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T cells, cytotoxic T cells and NK cells. The conditions that produce responses from γδ T cells are not fully understood. Like other 'unconventional' T cell subsets bearing invariant TCRs, such as CD1d -restricted natural killer T cells , γδ T cells straddle

15575-459: The T cells to tumor antigens in a non-immunosuppressive environment, that they recognize as foreign and learn to attack. Another approach is transfer of haploidentical γδ T cells or natural killer cells from a healthy donor. The major advantage of this approach is that these cells do not cause graft-versus-host disease . The disadvantage is that transferred cells frequently have impaired function. The simplest example involves removing TILs from

15750-411: The ability to adapt to recognize pathogens more efficiently. Adaptive (or acquired) immunity creates an immunological memory leading to an enhanced response to subsequent encounters with that same pathogen. This process of acquired immunity is the basis of vaccination . Dysfunction of the immune system can cause autoimmune diseases , inflammatory diseases and cancer . Immunodeficiency occurs when

15925-420: The absence of surface adhesion molecules and antigenic peptides. This role of NK cells is critical to immune success particularly because T cells are unable to recognize pathogens in the absence of surface antigens. Tumor cell detection results in activation of NK cells and consequent cytokine production and release. If tumor cells do not cause inflammation, they will also be regarded as self and will not induce

16100-438: The adaptive immune response generates antigen-specific cytotoxic T cells that can clear the infection. NK cells work to control viral infections by secreting IFNγ and TNFα . IFNγ activates macrophages for phagocytosis and lysis, and TNFα acts to promote direct NK tumor cell killing. Patients deficient in NK cells prove to be highly susceptible to early phases of herpes virus infection. [Citation needed] For NK cells to defend

16275-425: The anti-tumor response. Regulatory T-cells inhibit other T-cells, which may benefit the tumor. Immune system The immune system is a network of biological systems that protects an organism from diseases . It detects and responds to a wide variety of pathogens , from viruses to bacteria , as well as cancer cells , parasitic worms , and also objects such as wood splinters , distinguishing them from

16450-565: The antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph , bind to pathogens expressing the antigen and mark them for destruction by complement activation or for uptake and destruction by phagocytes . Antibodies can also neutralize challenges directly, by binding to bacterial toxins or by interfering with the receptors that viruses and bacteria use to infect cells. Newborn infants have no prior exposure to microbes and are particularly vulnerable to infection. Several layers of passive protection are provided by

16625-409: The antibody with the corresponding human counterpart. Humanized antibodies are almost completely human; only the complementarity determining regions of the variable regions are derived from murine sources. Human antibodies have been produced using unmodified human DNA. Antibody-dependent cell-mediated cytotoxicity (ADCC) requires antibodies to bind to target cell surfaces. Antibodies are formed of

16800-420: The antigen. Dendritic cells are antigen-presenting cells (APCs) in the mammalian immune system. In cancer treatment, they aid cancer antigen targeting. The only approved cellular cancer therapy based on dendritic cells is sipuleucel-T . One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides (small parts of the protein that correspond to

16975-404: The binding of CD28 to these surface proteins and therefore negatively regulates the activation of T-cells. Active cytotoxic T-cells are required for the immune system to attack melanoma cells. Normally inhibited active melanoma-specific cytotoxic T-cells can produce an effective anti-tumor response. Ipilimumab can cause a shift in the ratio of regulatory T-cells to cytotoxic T-cells to increase

17150-784: The body against viruses and other pathogens , they require mechanisms that enable the determination of whether a cell is infected or not. The exact mechanisms remain the subject of current investigation, but recognition of an "altered self" state is thought to be involved. To control their cytotoxic activity, NK cells possess two types of surface receptors : activating receptors and inhibitory receptors, including killer-cell immunoglobulin-like receptors . Most of these receptors are not unique to NK cells and can be present in some T cell subsets, as well. The inhibitory receptors recognize MHC class I alleles , which could explain why NK cells preferentially kill cells that possess low levels of MHC class I molecules. This mode of NK cell target interaction

17325-453: The body can manufacture. When B or T cells encounter their related antigens they multiply and many "clones" of the cells are produced that target the same antigen. This is called clonal selection . Both B cells and T cells carry receptor molecules that recognize specific targets. T cells recognize a "non-self" target, such as a pathogen, only after antigens (small fragments of the pathogen) have been processed and presented in combination with

17500-585: The body in pursuit of invading pathogens. Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, representing 50% to 60% of total circulating leukocytes. During the acute phase of inflammation , neutrophils migrate toward the site of inflammation in a process called chemotaxis and are usually the first cells to arrive at the scene of infection. Macrophages are versatile cells that reside within tissues and produce an array of chemicals including enzymes, complement proteins , and cytokines. They can also act as scavengers that rid

17675-440: The body of worn-out cells and other debris and as antigen-presenting cells (APCs) that activate the adaptive immune system. Dendritic cells are phagocytes in tissues that are in contact with the external environment; therefore, they are located mainly in the skin, nose, lungs, stomach, and intestines. They are named for their resemblance to neuronal dendrites , as both have many spine-like projections. Dendritic cells serve as

17850-654: The border between innate and adaptive immunity. On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes to produce receptor diversity and can also develop a memory phenotype. On the other hand, the various subsets are also part of the innate immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors . For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia respond to stressed epithelial cells. A B cell identifies pathogens when antibodies on its surface bind to

18025-776: The brakes on NK cells. Inflammation is one of the first responses of the immune system to infection. The symptoms of inflammation are redness, swelling, heat, and pain, which are caused by increased blood flow into tissue. Inflammation is produced by eicosanoids and cytokines , which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis ; and interferons that have antiviral effects, such as shutting down protein synthesis in

18200-495: The brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma , urothelial carcinoma , and renal cell carcinoma . Common side effects include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reactions, rash, decreased appetite and swelling of the limbs (peripheral edema). Durvalumab (Imfinzi) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks

18375-445: The brand name Empliciti, is a humanized IgG1 monoclonal antibody medication used in combination with lenalidomide and dexamethasone , for adults that have received 1 to 3 prior therapies for the treatment of multiple myeloma . It is also indicated for adult patients in combination with pomalidomide and dexamethasone , who have received 2 prior therapies including lenalidomide and a protease inhibitor. Administration of elotuzumab

18550-402: The brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma , non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma , but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized , engineered monoclonal antibody of IgG1 isotype against

18725-497: The cancer cell surface, the C1 complex binds to these antibodies and subsequently, protein pores are formed in cancer cell membrane . Blocking Antibody therapies can also function by binding to proteins and physically blocking them from interacting with other proteins. Checkpoint inhibitors (CTLA-4, PD-1, and PD-L1) operate by this mechanism. Briefly, checkpoint inhibitors are proteins that normally help to slow immune responses and prevent

18900-678: The cell surface (the classical complement pathway , among the ways of complement activation). Generally, the system deals with foreign pathogens but can be activated with therapeutic antibodies in cancer. The system can be triggered if the antibody is chimeric, humanized, or human; as long as it contains the IgG1 Fc region . Complement can lead to cell death by activation of the membrane attack complex , known as complement-dependent cytotoxicity ; enhancement of antibody-dependent cell-mediated cytotoxicity ; and CR3-dependent cellular cytotoxicity. Complement-dependent cytotoxicity occurs when antibodies bind to

19075-520: The cells die most migrate from the blood to the tissues, mainly the intestines and lungs, where pathogens are most likely to be encountered. Some monocytes leave the blood circulation and migrate to the muscles where they differentiate and become macrophages . These cells differentiate into two types: proliferative macrophages, which are responsible for increasing the number of stem cells and restorative macrophages, which are involved their maturing to muscle cells. The immune system, particularly

19250-417: The cells have been engineered to express a high affinity Fc-receptor (CD16A, 158V) genetically linked to IL-2 that is bound to the endoplasmic reticulum (ER). These high affinity NK-92 cells can perform ADCC and have greatly expanded therapeutic utility. NK-92 cells have also been engineered to expressed chimeric antigen receptors (CARs), in an approach similar to that used for T cells. An example of this

19425-653: The components of the immune system are inactive. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly , with immune responses beginning to decline at around 50 years of age due to immunosenescence . In developed countries , obesity , alcoholism , and drug use are common causes of poor immune function, while malnutrition is the most common cause of immunodeficiency in developing countries . Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally,

19600-589: The conditions in their environment, such as pH or available iron. As a result, the probability that pathogens will reach sufficient numbers to cause illness is reduced. Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of the innate immune system. The innate response is usually triggered when microbes are identified by pattern recognition receptors , which recognize components that are conserved among broad groups of microorganisms, or when damaged, injured or stressed cells send out alarm signals, many of which are recognized by

19775-639: The decades, the K562 chromium-release assay has become the most commonly used assay to detect human NK functional activity. Its almost universal use has meant that experimental data can be compared easily by different laboratories around the world. Using discontinuous density centrifugation, and later monoclonal antibodies , natural killing ability was mapped to the subset of large, granular lymphocytes known today as NK cells. The demonstration that density gradient-isolated large granular lymphocytes were responsible for human NK activity, made by Timonen and Saksela in 1980,

19950-404: The different roles of the two types of T cell. A third, minor subtype are the γδ T cells that recognize intact antigens that are not bound to MHC receptors. The double-positive T cells are exposed to a wide variety of self-antigens in the thymus , in which iodine is necessary for its thymus development and activity. In contrast, the B cell antigen-specific receptor is an antibody molecule on

20125-473: The drugs from their intended targets (i.e. PD-1 molecules expressed on the surface of T cells) and limits therapeutic efficacy. Furthermore, antibodies targeting the co-stimulatory protein CD40 require engagement with selective Fc receptors for optimal therapeutic efficacy. Together, these studies underscore the importance of Fc status in antibody-based immune checkpoint targeting strategies. Antibodies can come from

20300-419: The effect of the removal of various receptor-bearing cells on this cytotoxicity. Later that same year, Ronald Herberman published similar data with respect to the unique nature of the mouse effector cell. The human data were confirmed, for the most part, by West et al. using similar techniques and the same erythroleukemic target cell line, K562 . K562 is highly sensitive to lysis by human NK cells and, over

20475-437: The employment of tumor antigen-specific T cell response in response to anti-CD47 therapy. A number of therapeutics are being developed, including anti-CD47 antibodies , engineered decoy receptors , anti-SIRPα antibodies and bispecific agents. As of 2017, wide range of solid and hematologic malignancies were being clinically tested. Carbohydrate antigens on the surface of cells can be used as targets for immunotherapy. GD2

20650-427: The expansion of adaptive NKG2C+ NK cells or whether other infections result in re-activation of latent HCMV (as suggested for hepatitis ), remains a field of study. Notably, recent research suggests that adaptive NK cells can use the activating receptor NKG2C ( KLRC2 ) to directly bind to human cytomegalovirus -derived peptide antigens and respond to peptide recognition with activation, expansion, and differentiation,

20825-431: The formation of a membrane attack complex . The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory , where each pathogen is "remembered" by a signature antigen. The adaptive immune response is antigen-specific and requires the recognition of specific "non-self" antigens during a process called antigen presentation . Antigen specificity allows for

21000-419: The functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens , preventing autoimmunity. Common autoimmune diseases include Hashimoto's thyroiditis , rheumatoid arthritis , diabetes mellitus type 1 , and systemic lupus erythematosus . Hypersensitivity

21175-420: The generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it. The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are

21350-615: The goal is to generate an immune response to these antigens through a vaccine. Currently, only one vaccine ( sipuleucel-T for prostate cancer) has been approved. In cell-mediated therapies like CAR-T cell therapy, immune cells are extracted from the patient, genetically engineered to recognize tumor-specific antigens, and returned to the patient. Cell types that can be used in this way are natural killer (NK) cells , lymphokine-activated killer cells , cytotoxic T cells , and dendritic cells . Finally, specific antibodies can be developed that recognize cancer cells and target them for destruction by

21525-429: The hands and feet), nausea, anemia (low red blood cell counts), neutropenia (low white blood cell counts), thrombocytopenia (low platelet counts), rash, tiredness, constipation, reduced appetite, diarrhea, and cough. Atezolizumab was the first PD-L1 inhibitor approved by the U.S. for bladder cancer. Food and Drug Administration (FDA). Atezolizumab/hyaluronidase , sold under the brand name Tecentriq Hybreza,

21700-527: The host cell. Growth factors and cytotoxic factors may also be released. These cytokines and other chemicals recruit immune cells to the site of infection and promote the healing of any damaged tissue following the removal of pathogens. The pattern-recognition receptors called inflammasomes are multiprotein complexes (consisting of an NLR, the adaptor protein ASC, and the effector molecule pro-caspase-1) that form in response to cytosolic PAMPs and DAMPs, whose function

21875-471: The human. The mouse and human work was carried out under the supervision of professors Eva Klein and Hans Wigzell, respectively, of the Karolinska Institute, Stockholm. Kiessling's research involved the well-characterized ability of T lymphocytes to attack tumor cells which they had been previously immunized against. Pross and Jondal were studying cell-mediated cytotoxicity in normal human blood and

22050-471: The immune response. This enhances the ability of the immune system to attack cancer cells. Current research is identifying new potential targets to enhance immune function. Approved checkpoint inhibitors include antibodies such as ipilimumab , nivolumab , and pembrolizumab . Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present

22225-635: The immune system as well, most notably prolactin , growth hormone and vitamin D . Although cellular studies indicate that vitamin D has receptors and probable functions in the immune system, there is no clinical evidence to prove that vitamin D deficiency increases the risk for immune diseases or vitamin D supplementation lowers immune disease risk. A 2011 United States Institute of Medicine report stated that "outcomes related to ... immune functioning and autoimmune disorders , and infections ... could not be linked reliably with calcium or vitamin D intake and were often conflicting." The immune system

22400-539: The immune system from attacking normal cells. Checkpoint inhibitors bind these proteins and prevent them from functioning normally, which increases the activity of the immune system. Examples include durvalumab , ipilimumab , nivolumab , and pembrolizumab . Alemtuzumab (Campath-1H) is an anti- CD52 humanized IgG1 monoclonal antibody indicated for the treatment of fludarabine -refractory chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma , peripheral T-cell lymphoma and T-cell prolymphocytic leukemia . CD52

22575-588: The immune system is less active than normal, resulting in recurring and life-threatening infections. In humans, immunodeficiency can be the result of a genetic disease such as severe combined immunodeficiency , acquired conditions such as HIV / AIDS , or the use of immunosuppressive medication . Autoimmunity results from a hyperactive immune system attacking normal tissues as if they were foreign organisms. Common autoimmune diseases include Hashimoto's thyroiditis , rheumatoid arthritis , diabetes mellitus type 1 , and systemic lupus erythematosus . Immunology covers

22750-550: The immune system. Examples include therapeutic cancer vaccines (also known as treatment vaccines, which are designed to boost the body's immune system to fight cancer), CAR-T cells , and targeted antibody therapies. In contrast, passive immunotherapy does not directly target tumor cells, but enhances the ability of the immune system to attack cancer cells. Examples include checkpoint inhibitors and cytokines . Active cellular therapies aim to destroy cancer cells by recognition of distinct markers known as antigens . In cancer vaccines,

22925-448: The immune system. Examples of such antibodies include rituximab (targeting CD-20), trastuzumab (targeting HER-2), and cetuximab (targeting EGFR). Passive antibody therapies aim to increase the activity of the immune system without specifically targeting cancer cells. For example, cytokines directly stimulate the immune system and increase immune activity. Checkpoint inhibitors target proteins ( immune checkpoints ) that normally dampen

23100-699: The individual's own cells, marking them for destruction. This is also called antibody-dependent (or cytotoxic) hypersensitivity, and is mediated by IgG and IgM antibodies. Immune complexes (aggregations of antigens, complement proteins, and IgG and IgM antibodies) deposited in various tissues trigger Type III hypersensitivity reactions. Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity ) usually takes between two and three days to develop. Type IV reactions are involved in many autoimmune and infectious diseases, but may also involve contact dermatitis . These reactions are mediated by T cells , monocytes , and macrophages . Inflammation

23275-541: The inflammatory cytokine interferon gamma reversed the effect. Tumor-infiltrating NK cells have been reported to play a critical role in promoting drug-induced cell death in human triple-negative breast cancer. Since NK cells recognize target cells when they express nonself HLA antigens (but not self), autologous (patients' own) NK cell infusions have not shown any antitumor effects. Instead, investigators are working on using allogeneic cells from peripheral blood, which requires that all T cells be removed before infusion into

23450-425: The inflammatory response. They are most often associated with allergy and anaphylaxis . Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma . Innate lymphoid cells (ILCs) are a group of innate immune cells that are derived from common lymphoid progenitor and belong to

23625-497: The initiation of Th1 immune responses. During wake periods, differentiated effector cells, such as cytotoxic natural killer cells and cytotoxic T lymphocytes, peak to elicit an effective response against any intruding pathogens. Anti-inflammatory molecules, such as cortisol and catecholamines , also peak during awake active times. Inflammation would cause serious cognitive and physical impairments if it were to occur during wake times, and inflammation may occur during sleep times due to

23800-437: The innate and adaptive immune responses and help determine which immune responses the body makes to a particular pathogen. These cells have no cytotoxic activity and do not kill infected cells or clear pathogens directly. They instead control the immune response by directing other cells to perform these tasks. Helper T cells express T cell receptors that recognize antigen bound to Class II MHC molecules. The MHC:antigen complex

23975-886: The innate component, plays a decisive role in tissue repair after an insult . Key actors include macrophages and neutrophils , but other cellular actors, including γδ T cells , innate lymphoid cells (ILCs), and regulatory T cells (Tregs), are also important. The plasticity of immune cells and the balance between pro-inflammatory and anti-inflammatory signals are crucial aspects of efficient tissue repair. Immune components and pathways are involved in regeneration as well, for example in amphibians such as in axolotl limb regeneration . According to one hypothesis, organisms that can regenerate ( e.g. , axolotls ) could be less immunocompetent than organisms that cannot regenerate. Failures of host defense occur and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities. Immunodeficiencies occur when one or more of

24150-433: The innate immune system have pattern recognition receptors, which detect infection or cell damage, inside. Three major classes of these "cytosolic" receptors are NOD–like receptors , RIG (retinoic acid-inducible gene)-like receptors , and cytosolic DNA sensors. Some leukocytes (white blood cells) act like independent, single-celled organisms and are the second arm of the innate immune system. The innate leukocytes include

24325-473: The innate response, vertebrates possess a second layer of protection, the adaptive immune system , which is activated by the innate response. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory , and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen

24500-591: The interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules. Durvalumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: On 16 February 2018, the Food and Drug Administration approved durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. Elotuzumab , sold under

24675-423: The lifetime of an animal, these memory cells remember each specific pathogen encountered and can mount a strong response if the pathogen is detected again. T-cells recognize pathogens by small protein-based infection signals, called antigens, that bind to directly to T-cell surface receptors. B-cells use the protein, immunoglobulin, to recognize pathogens by their antigens. This is "adaptive" because it occurs during

24850-415: The lifetime of an individual as an adaptation to infection with that pathogen and prepares the immune system for future challenges. Immunological memory can be in the form of either passive short-term memory or active long-term memory. The immune system is involved in many aspects of physiological regulation in the body. The immune system interacts intimately with other systems, such as the endocrine and

25025-459: The loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection. Immunodeficiencies can also be inherited or ' acquired '. Severe combined immunodeficiency is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations. Chronic granulomatous disease , where phagocytes have

25200-454: The major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow . B cells are involved in the humoral immune response , whereas T cells are involved in cell-mediated immune response . Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells and regulatory T cells only recognize antigens coupled to Class II MHC molecules. These two mechanisms of antigen presentation reflect

25375-973: The memory phenotype, and in fact, the majority of the tissue-resident NK cells are functionally immature. These specialized NK-cell subsets can play a role in organ homeostasis. For example, NK cells are enriched in the human liver with a specific phenotype and take part in the control of liver fibrosis. Tissue-resident NK cells have also been identified in sites like bone marrow, spleen and more recently, in lung, intestines and lymph nodes. In these sites, tissue-resident NK cells may act as reservoir for maintaining immature NK cells in humans throughout life. Natural killer cells are being investigated as an emerging treatment for patients with acute myeloid leukemia (AML), and cytokine-induced memory-like NK cells have shown promise with their enhanced antileukemia functionality. It has been shown that this kind of NK cell has enhanced interferon-γ production and cytotoxicity against leukemia cell lines and primary AML blasts in patients. During

25550-509: The microbe, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback . The cascade results in the production of peptides that attract immune cells, increase vascular permeability , and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting their plasma membrane via

25725-408: The milieu of hormones produced at this time (leptin, pituitary growth hormone, and prolactin) supports the interactions between APCs and T-cells, a shift of the T h 1/T h 2 cytokine balance towards one that supports T h 1, an increase in overall T h cell proliferation, and naïve T cell migration to lymph nodes. This is also thought to support the formation of long-lasting immune memory through

25900-487: The modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill. The clinical success of cancer immunotherapy is highly variable between different forms of cancer; for instance, certain subtypes of gastric cancer react well to the approach whereas immunotherapy is not effective for other subtypes. In 2018, American immunologist James P. Allison and Japanese immunologist Tasuku Honjo received

26075-443: The most well-known effects of microorganisms on ... cancer was reported in 1891, when an American surgeon, William Coley , inoculated patients having inoperable tumours with [ Streptococcus pyogenes ]." "Coley [had] thoroughly reviewed the literature available at that time and found 38 reports of cancer patients with accidental or iatrogenic feverish erysipelas . In 12 patients, the sarcoma or carcinoma had completely disappeared;

26250-412: The mother. During pregnancy, a particular type of antibody, called IgG , is transported from mother to baby directly through the placenta , so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. Breast milk or colostrum also contains antibodies that are transferred to the gut of the infant and protect against bacterial infections until

26425-462: The negative consequences of sleep deprivation, sleep and the intertwined circadian system have been shown to have strong regulatory effects on immunological functions affecting both innate and adaptive immunity. First, during the early slow-wave-sleep stage, a sudden drop in blood levels of cortisol , epinephrine , and norepinephrine causes increased blood levels of the hormones leptin , pituitary growth hormone , and prolactin . These signals induce

26600-655: The neuroinflammation by leukocytes in the central nervous system. The ability to generate memory cells following a primary infection and the consequent rapid immune activation and response to succeeding infections by the same antigen is fundamental to the role that T and B cells play in the adaptive immune response. For many years, NK cells have been considered to be a part of the innate immune system. However, recently increasing evidence suggests that NK cells can display several features that are usually attributed to adaptive immune cells (e.g. T cell responses) such as dynamic expansion and contraction of subsets, increased longevity and

26775-506: The newborn can synthesize its own antibodies. This is passive immunity because the fetus does not actually make any memory cells or antibodies—it only borrows them. This passive immunity is usually short-term, lasting from a few days up to several months. In medicine, protective passive immunity can also be transferred artificially from one individual to another. When B cells and T cells are activated and begin to replicate, some of their offspring become long-lived memory cells. Throughout

26950-475: The organism's own healthy tissue . Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions. Nearly all organisms have some kind of immune system. Bacteria have

27125-531: The others had substantially improved. Coley decided to attempt the therapeutic use of iatrogenic erysipelas..." "Coley developed a toxin that contained heat-killed bacteria [ Streptococcus pyogenes and Serratia marcescens ]. Until 1963, this treatment was used for the treatment of sarcoma." "Coley injected more than 1000 cancer patients with bacteria or bacterial products." 51.9% of [Coley's] patients with inoperable soft-tissue sarcomas showed complete tumour regression and survived for more than 5 years, and 21.2% of

27300-442: The patients had no clinical evidence of tumour at least 20 years after this treatment..." Research continued in the 20th century under Maria O'Connor Hornung at Tulane Medical School . There are several types of immunotherapy used to treat cancer: Immunotherapies can be categorized as active or passive based on their ability to engage the host immune system against cancer. Active immunotherapy specifically targets tumor cells via

27475-478: The patients to remove the risk of graft versus host disease , which can be fatal. This can be achieved using an immunomagnetic column (CliniMACS). In addition, because of the limited number of NK cells in blood (only 10% of lymphocytes are NK cells), their number needs to be expanded in culture. This can take a few weeks and the yield is donor-dependent. Chimeric antigen receptors (CARs) are genetically modified receptors targeting cell surface antigens that provide

27650-944: The population expresses the 158 V/V allele. To determine the ADCC contribution of monoclonal antibodies, NK-92 cells (a "pure" NK cell line) has been transfected with the gene for the high-affinity FcR. Natural killer cells (NK cells) and macrophages play a major role in clearance of senescent cells . Natural killer cells directly kill senescent cells, and produce cytokines which activate macrophages which remove senescent cells. Natural killer cells can use NKG2D receptors to detect senescent cells, and kill those cells using perforin pore-forming cytolytic protein. CD8+ cytotoxic T-lymphocytes also use NKG2D receptors to detect senescent cells, and promote killing similar to NK cells. For example, in patients with Parkinson's disease, levels of Natural killer cells are elevated as they degrade alpha-synuclein aggregates, destroy senescent neurons, and attenuate

27825-434: The presence of melatonin . Inflammation causes a great deal of oxidative stress and the presence of melatonin during sleep times could actively counteract free radical production during this time. Physical exercise has a positive effect on the immune system and depending on the frequency and intensity, the pathogenic effects of diseases caused by bacteria and viruses are moderated. Immediately after intense exercise there

28000-605: The presence of APCs such as dendritic cells that present tumor antigens . Although these cells can attack tumors, the tumor microenvironment is highly immunosuppressive, interfering with immune-mediated tumour death. Multiple ways of producing tumour-destroying T-cells have been developed. Most commonly, T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. The T-cells can optionally be modified in various ways, cultured and infused into patients. T cells can be modified via genetic engineering, producing CAR-T cell or TCR T cells or by exposing

28175-510: The progression of HIV to AIDS; an example is the HLA-B57 and HLA-B27 alleles, which have been found to delay progression from HIV to AIDS. This is evident because patients expressing these HLA alleles are observed to have lower viral loads and a more gradual decline in CD4 T cells numbers. Despite considerable research and data collected measuring the genetic correlation of HLA alleles and KIR allotypes,

28350-422: The protein programmed cell death-ligand 1 (PD-L1). The most common side effects when used on its own include tiredness, reduced appetite, nausea, vomiting, cough, difficulty breathing, diarrhea, rash, fever, pain in the back, joints, muscles and bones, weakness, itching and urinary tract infection . The most common side effects when used with other cancer medicines include peripheral neuropathy (nerve damage in

28525-831: The protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). The most common sources of antigens used for dendritic cell vaccine in glioblastoma (GBM) as an aggressive brain tumor were whole tumor lysate, CMV antigen RNA and tumor-associated peptides like EGFRvIII . Dendritic cells can also be activated in vivo by making tumor cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF. Another strategy

28700-467: The receptor Ly49 was demonstrated to be crucial for the generation of adaptive NK cell responses. In humans, most studies have focused on the expansion of an NK cell subset carrying the activating receptor NKG2C ( KLRC2 ). Such expansions were observed primarily in response to human cytomegalovirus (HCMV), but also in other infections including Hantavirus , Chikungunya virus , HIV , or viral hepatitis . However, whether these virus infections trigger

28875-831: The recipients. In a transplantation model of LMP1-fueled lymphomas, the NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients. In Hodgkin lymphoma, in which the malignant Hodgkin Reed-Sternberg cells are typically HLA class I deficient, immune evasion is in part mediated by skewing towards an exhausted PD-1hi NK cell phenotype, and re-activation of these NK cells appears to be one mechanism of action induced by checkpoint-blockade. Signaling through TLR can effectively activate NK cell effector functions in vitro and in vivo . TLR ligands are then potentially able to enhance NK cell effector functions during NK cell anti-tumor immunotherapy . Trastuzumab

29050-532: The same receptors as those that recognize pathogens. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms, and the only one in plants. Cells in the innate immune system use pattern recognition receptors to recognize molecular structures that are produced by pathogens. They are proteins expressed, mainly, by cells of

29225-681: The spread of HIV-1 in culture of autologous CD4+ T-cells . The stimulation of TLR-9 in NK cells induced a strong antiviral innate immune response, an increase in HIV-1 transcription (indicating the reverse in latency of the virus) and it also boosted the NK cell-mediated suppression of HIV-1 infections in autologous CD4+ T cells. Recent research suggests specific KIR-MHC class I gene interactions might control innate genetic resistance to certain viral infections, including HIV and its consequent development of AIDS . Certain HLA allotypes have been found to determine

29400-447: The study of all aspects of the immune system. The immune system protects its host from infection with layered defenses of increasing specificity. Physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all animals . If pathogens successfully evade

29575-495: The surface markers CD16 (FcγRIII) and CD57 in humans, NK1.1 or NK1.2 in C57BL/6 mice . The NKp46 cell surface marker constitutes, at the moment, another NK cell marker of preference being expressed in both humans, several strains of mice (including BALB/c mice ) and in three common monkey species. Outside of innate immunity , both activating and inhibitory NK cell receptors play important functional roles in self tolerance and

29750-445: The surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3 , TLR7 , TLR8 or CD40 have been used as antibody targets. Dendritic cell-NK cell interface also has an important role in immunotherapy. The design of new dendritic cell-based vaccination strategies should also encompass NK cell-stimulating potency. It

29925-399: The sustaining of NK cell activity. NK cells also play a role in the adaptive immune response : numerous experiments have demonstrated their ability to readily adjust to the immediate environment and formulate antigen-specific immunological memory , fundamental for responding to secondary infections with the same antigen. The role of NK cells in both the innate and adaptive immune responses

30100-503: The target cell's plasma membrane , allowing ions , water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis . T cell killing of host cells is particularly important in preventing the replication of viruses. T cell activation is tightly controlled and generally requires a very strong MHC/antigen activation signal, or additional activation signals provided by "helper" T cells (see below). Helper T cells regulate both

30275-486: The virus inside. α-defensins , antimicrobial molecules, are also secreted by NK cells, and directly kill bacteria by disrupting their cell walls in a manner analogous to that of neutrophils . Infected cells are routinely opsonized with antibodies for detection by immune cells. Antibodies that bind to antigens can be recognised by FcγRIII ( CD16 ) receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis . This

30450-414: Was established across a wide variety of species, and the existence of a separate lineage of cells possessing this ability was postulated. The discovery that a unique type of lymphocyte was responsible for "natural" or spontaneous cytotoxicity was made in the early 1970s by doctoral student Rolf Kiessling and postdoctoral fellow Hugh Pross, in the mouse, and by Hugh Pross and doctoral student Mikael Jondal in

30625-569: Was the first time that NK cells had been visualized microscopically, and was a major breakthrough in the field. NK cells can be classified as CD56 or CD56 . CD56 NK cells are similar to T helper cells in exerting their influence by releasing cytokines . CD56 NK cells constitute the majority of NK cells, being found in bone marrow, secondary lymphoid tissue, liver, and skin. CD56 NK cells are characterized by their preferential killing of highly proliferative cells, and thus might have an immunoregulatory role. CD56 NK cells are primarily found in

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