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69-408: 85480 53603 ENSG00000145777 ENSMUSG00000024379 Q969D9 Q9JIE6 NM_033035 NM_138551 NM_021367 NP_149024 NP_612561 NP_067342 Thymic stromal lymphopoietin ( TSLP ) is an interleukin (IL)-2 -like cytokine , alarmin , and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system . It shares

138-435: A T Cell Receptor (a TCR) and an HLA-peptide complex. As a result of that conjunction a signalling pathway (signalling a cell's protein making machinery to express or 'make' IL-2), a PhosphoLipase-C (PLC) dependent pathway, is set up. PLC activates 3 major transcription factors and their pathways: NFAT , NFkB and AP-1 . In addition and after costimulation from CD28 the optimal activation of expression of IL-2 and these pathways

207-407: A broad range of doses, without serious side effects. Tumour blood vessels are more vulnerable than normal blood vessels to the actions of IL-2. When injected inside a tumor, i.e. local application, a process mechanistically similar to the vascular leakage syndrome, occurs in tumor tissue only. Disruption of the blood flow inside of the tumor effectively destroys tumor tissue. In local application,

276-402: A common ancestor with IL-7 . Originally appreciated for its role in immune cell proliferation and development, and then for its pivotal role in type 2 immune responses , TSLP is now known to be involved in other types of immune responses , autoimmune disease , and certain cancers . TSLP production has been observed in numerous species, including humans and mice . In humans, TSLP

345-549: A free cytokine, mammalian IL-2 that is secreted by activated T cells is important for a negative feedback loop by the stimulation of regulatory T cells, the latter being the cells with the highest constitutive IL-2Rα (aka CD25) expression. Besides this negative feedback loop, mammalian IL-2 also participates in a positive feedback loop because activated T cells enhance their own IL-2Rα expression. As in mammals, fish IL-2 also stimulates T cell proliferation and appears to preferentially stimulate regulatory T cells. Fish IL-2 induces

414-631: A high affinity for antigens. TSLP may play an important role in the formation of GCs, as the depletion of TSPLR in CD 4 T cells prevented their formation in mice, as well as the generation of IgG1 . TSLP signals through a heterodimeric receptor complex composed of the TSLP receptor (TSLPR) and the IL-7Rα chain. Upon binding, Janus kinase (JAK)1 and 2 are activated, leading to the activation of signal transducer and activator of transcription (STAT)5A and 5B and, to

483-409: A high predicted MHC binding affinity. Minor histocompatibility antigens, a conceptually similar antigen class are also correctly identified by MHC binding algorithms. Another potential filter examines whether the mutation is expected to improve MHC binding. The nature of the central TCR-exposed residues of MHC-bound peptides is associated with peptide immunogenicity. A native antigen is an antigen that

552-407: A lesser extent, STAT1 and 3 . These transcription factors upregulate pro-inflammatory cytokines such as IL-4 , 5 , 9 , and 13 . TSLP expression is linked to many disease states including asthma, inflammatory arthritis, atopic dermatitis, eczema, eosinophilic esophagitis and other allergic states. The factors inducing the activation of TSLP release are not clearly defined. Expression of TSLP

621-456: A manner reminiscent of how mammalian IL-15 binds to IL-15Rα. Despite fish IL-2 and IL-15 sharing the same IL-15Rα chain, the stability of fish IL-2 is independent of it whereas IL-15 and especially IL-15L depend on binding to (co-presentation with) IL-15Rα for their stability and function. This suggests that, like in mammals, fish IL-2, in contrast to fish IL-15 and IL-15L, is not relying on "in trans" presentation by its receptor alpha chain. As

690-793: A monoclonal antibody which blocks TSLP, is currently approved for the treatment of severe asthma. Fusion proteins consisting of TSLPR and IL-7Rα which can trap TSLP with excellent affinity have also been designed. Additional approaches towards TSLP/TSLPR inhibition include peptides derived from the TSLP:TSLPR interface, natural products and computational fragment-based screening. Interleukin 2 1IRL , 1M47 , 1M48 , 1M49 , 1M4A , 1M4B , 1M4C , 1NBP , 1PW6 , 1PY2 , 1QVN , 1Z92 , 2B5I , 2ERJ , 3QAZ , 3QB1 , 3INK , 4NEJ , 4NEM 3558 16183 ENSG00000109471 ENSMUSG00000027720 P60568 P04351 NM_000586 NM_008366 NP_000577 NP_032392 Interleukin-2 ( IL-2 )

759-434: A novel vaccine adjuvant and anti-cancer immunotherapy due to its broad and potent alarmin functionality, as is evidenced by numerous animal studies. Germinal centres (GCs) are microstructures that form in secondary lymphoid organs during immune responses. GCs are the sites of the clonal expansion of B lymphocytes and the affinity maturation of their antibodies , thus allowing the immune system to generate antibodies with

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828-406: A point of disagreement. The commercial interest in local IL-2 therapy has been very low. Because only a very low dose IL-2 is used, treatment of a patient would cost about $ 500 commercial value of the patented IL-2. The commercial return on investment is too low to stimulate additional clinical studies for the registration of intratumoral IL-2 therapy. Usually, in the U.S., the higher dosage option

897-400: A promising immunotherapeutic agent due to significant drawbacks which are listed above. Some of the issues can be overcome using IL-2 ic. They are composed of IL-2 and some of its monoclonal antibody (mAb) and can potentiate biologic activity of IL-2 in vivo . The main mechanism of this phenomenon in vivo is due to the prolongation of the cytokine half-life in circulation. Depending on

966-416: A similar genomic location. In fish, IL-2 shares a single receptor alpha chain with its related cytokines IL-15 and IL-15-like (IL-15L). This "IL-15Rα" receptor chain is similar to mammalian IL-15Rα, and in tetrapod evolution a duplication of its coding gene plus further diversification created mammalian IL-2Rα. Sequences, and structural analysis of grass carp IL-2, suggest that fish IL-2 binds IL-15Rα in

1035-465: A similarly acting alarmin, TSLP is usually not constitutively expressed and must be upregulated by transcription factors such as nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) or activator protein (AP)1 following insult. Local dendritic cells (DCs) are among the most important targets of TSPL, as they, among other antigen presenting cells (APCs) , allow the immune system to mount adaptive responses . TSLP signalling grants DCs

1104-457: Is a recombinant IL-2 with a serine at residue 125, sold by Shenzhen Neptunus. Neoleukin 2/15 is a computationally designed mimic of IL-2 that was designed to avoid common side effects. However, clinical trials into this candidate were discontinued. Various dosages of IL-2 across the United States and across the world are used. The efficacy and side effects of different dosages is often

1173-579: Is an interleukin , a type of cytokine signaling molecule in the immune system . It is a 15.5–16  kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes ) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection , and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors , which are expressed by lymphocytes. The major sources of IL-2 are activated CD4 T cells and activated CD8 T cells . Put shortly

1242-465: Is called the antigen-antibody reaction . Antigen can originate either from within the body (" self-protein " or "self antigens") or from the external environment ("non-self"). The immune system identifies and attacks "non-self" external antigens. Antibodies usually do not react with self-antigens due to negative selection of T cells in the thymus and B cells in the bone marrow . The diseases in which antibodies react with self antigens and damage

1311-477: Is commenced by IL-2 binding to its receptor, following which cytoplasmatic domains of CD122 and CD132 heterodimerize . This leads to the activation of Janus kinases JAK1 and JAK3 which subsequently phosphorylate T338 on CD122. This phosphorylation recruits STAT transcription factors , predominantly STAT5 , which dimerize and migrate to the cell nucleus where they bind to DNA . with an "express other proteins" signal. The proteins expressed by means of

1380-539: Is dephosphorylated and therefore translocated to the nucleus. AP-1 is a dimer and is composed of c-Jun and c-Fos proteins. It cooperates with other transcription factors including NFkB and Oct. NFkB is translocated to the nucleus after costimulation through CD28. NFkB is a heterodimer and there are two binding sites on the IL-2 promoter. IL-2 has essential roles in key functions of the immune system, tolerance and immunity , primarily via its direct effects on T cells . In

1449-587: Is encoded by the TSLP gene . Alternative splicing of TSLP results in two transcript variants , a long form (lfTSLP, or just TSLP) consisting of 159 amino acid residues , and a short form (sfTSLP) consisting of 63 amino acid residues. These variants use different initiation methionine codons and share a carboxy terminus . sfTSLP mRNA is constitutively expressed in normal human bronchial epithelial cells (NHBE), normal human lung fibroblasts (NHLF), and bronchial smooth muscle cells (BSMC). sfTSLP mRNA expression

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1518-420: Is enhanced under asthma -like conditions (aka Airway HyperResponsiveness or AHR model in the mouse), conditioning APCs in order to orient the differentiation of T cells coming into the lungs towards a TH2 profile (T helper 2 pathway). The TH2 cells then release factors promoting an inflammatory reaction following the repeated contact with a specific antigen in the airways. TSLP-activated Langerhans cells of

1587-560: Is expressed by memory CD8 T cells and NK cells , whereas regulatory T cells and activated T cells express high levels of trimeric IL-2R. Instructions to express proteins in response to an IL-2 signal (called IL-2 transduction) can take place via 3 different signaling pathways ; they are: (1) the JAK-STAT pathway, (2) the PI3K/Akt/mTOR pathway and (3) the MAPK/ERK pathway. The signalling

1656-419: Is generally well tolerated. This is also the case for intralesional IL-2 in other forms of cancer, like nasopharyngeal carcinoma. Eisai markets a drug called denileukin diftitox (trade name Ontak), which is a recombinant fusion protein of the human IL-2 ligand and the diphtheria toxin . This drug binds to IL-2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing

1725-608: Is induced. In summary therefore before a cell will make IL-2 in accordance with this pathway there have to be two reactions: TCR+HLA and protein complex on the one hand and CD28 costimulation on the other indeed mere IL-2 ligation to its receptor is too low affinity to enable pathway. At the same time Oct-1 is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes and Oct2 is induced after cell activation. NFAT has multiple family members, all of them are located in cytoplasm and signaling goes through calcineurin, NFAT

1794-487: Is insufficient to exclude many false positives from the pool of peptides that may be presented by MHC molecules. Instead, algorithms are used to identify the most likely candidates. These algorithms consider factors such as the likelihood of proteasomal processing, transport into the endoplasmic reticulum , affinity for the relevant MHC class I alleles and gene expression or protein translation levels. The majority of human neoantigens identified in unbiased screens display

1863-552: Is involved in itchy psoriasis . Aldesleukin is a form of recombinant interleukin-2. It is manufactured using recombinant DNA technology and is marketed as a protein therapeutic and branded as Proleukin. It has been approved by the Food and Drug Administration (FDA) with a black box warning and in several European countries for the treatment of cancers ( malignant melanoma , renal cell cancer ) in large intermittent doses and has been extensively used in continuous doses. Interking

1932-665: Is not known whether sfTSLP also signals via the TSLP receptor complex . TSLP's pivotal role in initiating immune responses begins with its release by epithelial or stromal cells of the lungs , skin , or gastrointestinal tract as an alarmin following mechanical cell injury , pattern recognition receptor (PRR) and protease-activated receptor (PAR) activation, stimulation by certain cytokines, chemical irritation, or infection. When local mast cells bind an allergen , they produce TSLP indirectly by releasing tryptase in an FcεRI -dependent manner, activating PARs on epithelial cells and causing them to release TSLP. Unlike IL-33 ,

2001-550: Is not significantly upregulated by inflammation . TSLP mRNA is not constitutively expressed in NHBE and has a low level of constitutive expression in NHLF and BSMC. TSLP mRNA expression is upregulated by certain Toll-like receptor (TLR) ligands such as flagellin and poly(I:C) , but not by lipopolysaccharide (LPS) or macrophage-activating lipopeptide 2 (MALP-2) . As the name suggests, TSLP

2070-403: Is not yet processed by an APC to smaller parts. T cells cannot bind native antigens, but require that they be processed by APCs, whereas B cells can be activated by native ones. Antigenic specificity is the ability of the host cells to recognize an antigen specifically as a unique molecular entity and distinguish it from another with exquisite precision. Antigen specificity is due primarily to

2139-461: Is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to

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2208-643: Is shared by all family members. The IL-2 receptor (IL-2R) α subunit binds IL-2 with low affinity (K d ~ 10 M). Interaction of IL-2 and CD25 alone does not lead to signal transduction due to its short intracellular chain but has the ability (when bound to the β and γ subunit) to increase the IL-2R affinity 100-fold. Heterodimerization of the β and γ subunits of IL-2R is essential for signalling in T cells . IL-2 can signalize either via intermediate-affinity dimeric CD122/CD132 IL-2R (K d ~ 10 M) or high-affinity trimeric CD25/CD122/CD132 IL-2R (K d ~ 10 M). Dimeric IL-2R

2277-449: Is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses. Through its role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity . IL-2 has been discovered in all classes of jawed vertebrates, including sharks, at

2346-421: Is used, affected by cancer type, response to treatment and general patient health. Patients are typically treated for five consecutive days, three times a day, for fifteen minutes. The following approximately 10 days help the patient to recover between treatments. IL-2 is delivered intravenously on an inpatient basis to enable proper monitoring of side effects. A lower dose regimen involves injection of IL-2 under

2415-516: Is usually a self-protein or protein complex (and sometimes DNA or RNA) that is recognized by the immune system of patients with a specific autoimmune disease . Under normal conditions, these self-proteins should not be the target of the immune system, but in autoimmune diseases, their associated T cells are not deleted and instead attack. Neoantigens are those that are entirely absent from the normal human genome. As compared with nonmutated self-proteins, neoantigens are of relevance to tumor control, as

2484-584: Is vascular leak syndrome (VLS; also termed capillary leak syndrome ). It is caused by lung endothelial cells expressing high-affinity IL-2R. These cells, as a result of IL-2 binding, causes increased vascular permeability. Thus, intravascular fluid extravasate into organs, predominantly lungs, which leads to life-threatening pulmonary or brain oedema. Other drawbacks of IL-2 cancer immunotherapy are its short half-life in circulation and its ability to predominantly expand regulatory T cells at high doses. Intralesional IL-2 used to treat in-transit melanoma metastases

2553-424: The epidermis induce the production of pro-inflammatory cytokines like TNF-alpha by T cells potentially causing atopic dermatitis . It is thought that by understanding the mechanism of TSLP production and those potential substances that block the production, one may be able to prevent or treat conditions of asthma and/or eczema. The TSLP signaling axis is an attractive therapeutic target. Amgen's Tezepelumab ,

2622-418: The thymus , where T cells mature, it prevents autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells , which suppress other T cells that are otherwise primed to attack normal healthy cells in the body. IL-2 enhances activation-induced cell death (AICD) . IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when

2691-579: The adjuvant component of vaccines plays an essential role in the activation of the innate immune system. An immunogen is an antigen substance (or adduct ) that is able to trigger a humoral (innate) or cell-mediated immune response. It first initiates an innate immune response, which then causes the activation of the adaptive immune response. An antigen binds the highly variable immunoreceptor products (B-cell receptor or T-cell receptor) once these have been generated. Immunogens are those antigens, termed immunogenic , capable of inducing an immune response. At

2760-406: The antigens; depending on the antigen and the type of the histocompatibility molecule, different types of T cells will be activated. For T-cell receptor (TCR) recognition, the peptide must be processed into small fragments inside the cell and presented by a major histocompatibility complex (MHC). The antigen cannot elicit the immune response without the help of an immunologic adjuvant . Similarly,

2829-451: The body's own cells are called autoimmune diseases . Vaccines are examples of antigens in an immunogenic form, which are intentionally administered to a recipient to induce the memory function of the adaptive immune system towards antigens of the pathogen invading that recipient. The vaccine for seasonal influenza is a common example. Paul Ehrlich coined the term antibody ( German : Antikörper ) in his side-chain theory at

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2898-810: The cells. In some leukemias and lymphomas, malignant cells express the IL-2 receptor, so denileukin diftitox can kill them. In 1999 Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of cutaneous T cell lymphoma (CTCL). IL-2 does not follow the classical dose-response curve of chemotherapeutics. The immunological activity of high and low dose IL-2 show sharp contrast. This might be related to different distribution of IL-2 receptors (CD25, CD122, CD132) on different cell populations, resulting in different cells that are activated by high and low dose IL-2. In general high doses are immune suppressive, while low doses can stimulate type 1 immunity. Low-dose IL-2 has been reported to reduce hepatitis C and B infection. IL-2 has been used in clinical trials for

2967-530: The clone of IL-2 mAb, IL-2 ic can selectively stimulate either CD25 (IL-2/JES6-1 complexes), or CD122 cells (IL-2/S4B6). IL-2/S4B6 immune complexes have high stimulatory activity for NK cells and memory CD8 T cells and they could thus replace the conventional IL-2 in cancer immunotherapy . On the other hand, IL-2/JES6-1 highly selectively stimulate regulatory T cells and they could be potentially useful for transplantations and in treatment of autoimmune diseases . According to an immunology textbook: "IL-2

3036-424: The destruction of the infected cell. Endogenous antigens are generated within normal cells as a result of normal cell metabolism , or because of viral or intracellular bacterial infection . The fragments are then presented on the cell surface in the complex with MHC class I molecules. If activated cytotoxic CD8 T cells recognize them, the T cells secrete various toxins that cause the lysis or apoptosis of

3105-428: The end of the 19th century. In 1899, Ladislas Deutsch (László Detre) named the hypothetical substances halfway between bacterial constituents and antibodies "antigenic or immunogenic substances" ( French : substances immunogènes ou antigènes ). He originally believed those substances to be precursors of antibodies, just as a zymogen is a precursor of an enzyme . But, by 1903, he understood that an antigen induces

3174-759: The exact phenotype needed to prime naive CD 4 T cells into T H 2 pro-inflammatory cells, or producing type 2 cytokines , namely by upregulating OX40L , CD80 , and CD86 . TSLP-stimulated DCs that migrate into draining lymph nodes can prime CD 4 T cells into follicular helper T (T FH ) cells , which in turn can promote immunoglobulin (Ig)G and E production by resident B lymphocytes, thus initiating type 2 immune responses. T H 2 can also facilitate B cell class switching towards IgE. As mentioned, TSLP serves as an alarmin following TLR binding by certain pathogen-associated molecular patterns (PAMPs) , including viral and bacterial ones, rather than just irritation by allergens. Thus, TSLP also plays an early role in

3243-509: The expression of cytokines of both type 1 (Th1) and type 2 (Th2) immunity. As has been found in some studies on mammalian IL-2, data suggest that fish IL-2 can form homodimers and that this is an ancient property of the IL-2/15/15L-family cytokines. Homologues of IL-2 have not been reported for jawless fish (hagfish and lamprey) or invertebrates. While the causes of itchiness are poorly understood, some evidence indicates that IL-2

3312-510: The fragments to T helper cells ( CD4 ) by the use of class II histocompatibility molecules on their surface. Some T cells are specific for the peptide:MHC complex. They become activated and start to secrete cytokines, substances that activate cytotoxic T lymphocytes (CTL), antibody-secreting B cells , macrophages and other particles. Some antigens start out as exogenous and later become endogenous (for example, intracellular viruses). Intracellular antigens can be returned to circulation upon

3381-460: The function of IL-2 is to stimulate the growth of helper, cytotoxic and regulatory T cells. IL-2 is a member of a cytokine family, each member of which has a four alpha helix bundle ; the family also includes IL-4 , IL-7 , IL-9 , IL-15 and IL-21 . IL-2 signals through the IL-2 receptor , a complex consisting of three chains, termed alpha ( CD25 ), beta ( CD122 ) and gamma ( CD132 ). The gamma chain

3450-735: The growth factors being studied by endocrinologists and biochemists". Antigen In immunology , an antigen ( Ag ) is a molecule , moiety , foreign particulate matter , or an allergen , such as pollen , that can bind to a specific antibody or T-cell receptor . The presence of antigens in the body may trigger an immune response . Antigens can be proteins , peptides (amino acid chains), polysaccharides (chains of simple sugars), lipids , or nucleic acids . Antigens exist on normal cells , cancer cells , parasites , viruses , fungi , and bacteria . Antigens are recognized by antigen receptors, including antibodies and T-cell receptors. Diverse antigen receptors are made by cells of

3519-482: The immune system so that each cell has a specificity for a single antigen. Upon exposure to an antigen, only the lymphocytes that recognize that antigen are activated and expanded, a process known as clonal selection . In most cases, antibodies are antigen-specific , meaning that an antibody can only react to and bind one specific antigen; in some instances, however, antibodies may cross-react to bind more than one antigen. The reaction between an antigen and an antibody

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3588-435: The infected cell. In order to keep the cytotoxic cells from killing cells just for presenting self-proteins , the cytotoxic cells (self-reactive T cells) are deleted as a result of tolerance (negative selection). Endogenous antigens include xenogenic (heterologous), autologous and idiotypic or allogenic (homologous) antigens. Sometimes antigens are part of the host itself in an autoimmune disease . An autoantigen

3657-399: The inhalation of house dust mite (HDM) antigens in mice who had been sensitised to HDM, an asthma -like model. Similarly, sfTSLP reduces the severity of dextran sulphate sodium (DSS) -induced colitis in mice, a model of inflammatory bowel disease (IBD) , and prevents endotoxic shock and sepsis resulting from bacterial infections . A receptor for sfTSLP has not been discovered. It

3726-448: The initial T cell is also stimulated by an antigen , thus helping the body fight off infections. Together with other polarizing cytokines, IL-2 stimulates naive CD4 T cell differentiation into T h 1 and T h 2 lymphocytes while it impedes differentiation into T h 17 and folicular T h lymphocytes. IL-2 increases the cell killing activity of both natural killer cells and cytotoxic T cells . Its expression and secretion

3795-484: The initiation of type 1 and 3 immune responses to pathogens. This activity has thus far been best described in the respiratory mucosa. TSLP-activated CD 11 b DCs can promote the proliferation and long-term survival of CD 8 cytotoxic T cells, promoting the development of lasting adaptive cellular immunity. Analogously, TSLP-activated CD 11 c cells are essential for the development of IgA antibodies following pneumococcal infection. TSLP also holds considerable promise as

3864-487: The level of dosing usually determines the severity of the side effects. In the case of local IL-2 application, the therapeutic window spans several orders of magnitude. Some common side effects: More serious and dangerous side effects sometimes are seen, such as breathing problems, serious infections , seizures , allergic reactions , heart problems, kidney failure or a variety of other possible complications. The most common adverse effect of high-dose IL-2 therapy

3933-699: The molecular level, an antigen can be characterized by its ability to bind to an antibody's paratopes . Different antibodies have the potential to discriminate among specific epitopes present on the antigen surface. A hapten is a small molecule that can only induce an immune response when attached to a larger carrier molecule, such as a protein . Antigens can be proteins, polysaccharides, lipids , nucleic acids or other biomolecules. This includes parts (coats, capsules, cell walls, flagella, fimbriae, and toxins) of bacteria , viruses , and other microorganisms . Non-microbial non-self antigens can include pollen, egg white, and proteins from transplanted tissues and organs or on

4002-539: The pool of neoantigens. Tumor antigens are those antigens that are presented by MHC class I or MHC class II molecules on the surface of tumor cells . Antigens found only on such cells are called tumor-specific antigens (TSAs) and generally result from a tumor-specific mutation . More common are antigens that are presented by tumor cells and normal cells, called tumor-associated antigens (TAAs). Cytotoxic T lymphocytes that recognize these antigens may be able to destroy tumor cells. Tumor antigens can appear on

4071-465: The production of immune bodies (antibodies) and wrote that the word antigen is a contraction of antisomatogen ( Immunkörperbildner ). The Oxford English Dictionary indicates that the logical construction should be "anti(body)-gen". The term originally referred to a substance that acts as an antibody generator. Antigen-presenting cells present antigens in the form of peptides on histocompatibility molecules . The T cells selectively recognize

4140-476: The protein-coding part of the genome (the exome ) and predict potential neoantigens. In mice models, for all novel protein sequences, potential MHC-binding peptides were predicted. The resulting set of potential neoantigens was used to assess T cell reactivity. Exome–based analyses were exploited in a clinical setting, to assess reactivity in patients treated by either tumor-infiltrating lymphocyte (TIL) cell therapy or checkpoint blockade. Neoantigen identification

4209-436: The quality of the T cell pool that is available for these antigens is not affected by central T cell tolerance. Technology to systematically analyze T cell reactivity against neoantigens became available only recently. Neoantigens can be directly detected and quantified. For virus-associated tumors, such as cervical cancer and a subset of head and neck cancers , epitopes derived from viral open reading frames contribute to

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4278-477: The skin typically on an outpatient basis. It may alternatively be given on an inpatient basis over 1–3 days, similar to and often including the delivery of chemotherapy . Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate. In preclinical and early clinical studies, local application of IL-2 in the tumor has been shown to be clinically more effective in anticancer therapy than systemic IL-2 therapy, over

4347-454: The surface of the tumor in the form of, for example, a mutated receptor, in which case they are recognized by B cells . For human tumors without a viral etiology, novel peptides (neo-epitopes) are created by tumor-specific DNA alterations. A large fraction of human tumor mutations are effectively patient-specific. Therefore, neoantigens may also be based on individual tumor genomes. Deep-sequencing technologies can identify mutations within

4416-460: The surface of transfused blood cells. Antigens can be classified according to their source. Exogenous antigens are antigens that have entered the body from the outside, for example, by inhalation , ingestion or injection . The immune system's response to exogenous antigens is often subclinical. By endocytosis or phagocytosis , exogenous antigens are taken into the antigen-presenting cells (APCs) and processed into fragments. APCs then present

4485-433: The systemic dose of IL-2 is too low to cause side effects, since the total dose is about 100 to 1000 fold lower. Clinical studies showed painful injections at the site of radiation as the most important side effect, reported by patients. In the case of irradiation of nasopharyngeal carcinoma the five-year disease-free survival increased from 8% to 63% by local IL-2 therapy Systemic IL-2 has a narrow therapeutic window , and

4554-401: The three pathways include bcl-6 (the PI3K/Akt/mTOR pathway), CD25 & prdm-1 (the JAK-STAT pathway) and certain cyclins (the MAPK/ERK pathway). Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints (in other words one of the things which needs to be done before IL-2 is expressed) is that there must be signaling through a conjunction of

4623-626: The treatment of chronic viral infections and as a booster (adjuvant) for vaccines. The use of large doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, was found to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials published in 2009. More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis. There are also promising studies looking to use low dose IL-2 in ischaemic heart disease. IL-2 cannot accomplish its role as

4692-559: Was initially discovered as a growth factor derived from the supernatant of a mouse thymic stromal cell line that was found to promote the survival and proliferation of B lymphocytes . TSLP was initially observed to have both pro-inflammatory and anti-inflammatory activity. It is now clear that this seemingly ambivalent action can actually be divided between the two transcript variants , with TSLP being pro-inflammatory and sfTSLP being anti-inflammatory. sfTSLP inhalation prevents airway epithelial barrier disruption caused by

4761-404: Was successful for multiple experimental model systems and human malignancies. The false-negative rate of cancer exome sequencing is low—i.e.: the majority of neoantigens occur within exonic sequence with sufficient coverage. However, the vast majority of mutations within expressed genes do not produce neoantigens that are recognized by autologous T cells. As of 2015 mass spectrometry resolution

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