Адам ағзасындағы интерлейкин-2 ақуызы

Mammalian protein found in Homo sapiens

Interleukin 2 (IL 2) 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. The IL 2 receptor (IL 2R) α subunit binds IL 2 with low affinity (Kd~ 10−8 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. IL 2 can signalize either via intermediate affinity dimeric CD122/CD132 IL 2R (Kd~ 10−9 M) or high affinity trimeric CD25/CD122/CD132 IL 2R (Kd~ 10−11 M). with an "express other proteins" signal. The proteins expressed by means of 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 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 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 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 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 increases the cell killing activity of both natural killer cells and cytotoxic T cells.

IL 2 has been discovered in all classes of jawed vertebrates, including sharks, at 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 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. 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. and appears to preferentially stimulate regulatory T cells. Fish IL 2 induces 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.

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. 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 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 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 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.

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 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, 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 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. 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. This drug binds to IL 2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing 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 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 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 the clone of IL 2 mAb, IL 2 ic can selectively stimulate either CD25high (IL 2/JES6 1 complexes), or CD122high 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. In the mid 1970s, it was discovered that T cells could be selectively proliferated when normal human bone marrow cells were cultured in conditioned medium obtained from phytohemagglutinin stimulated normal human lymphocytes. The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980. The gene for human IL 2 was cloned in 1982 after an intense competition. Commercial activity to bring an IL 2 drug to market was intense in the 1980s and '90s. By 1983, Cetus Corporation had created a proprietary recombinant version of IL 2 (Aldesleukin, later branded as Proleukin), with the alanine removed from its N terminal and residue 125 replaced with serine. The failure led to the collapse of Cetus, and in 1991 the company was sold to Chiron Corporation. Chiron continued the development of IL 2, which was finally approved by the FDA as Proleukin for metastatic renal carcinoma in 1992. By 1993 aldesleukin was the only approved version of IL 2, but Roche was also developing a proprietary, modified, recombinant IL 2 called teceleukin, with a methionine added at is N terminal, and Glaxo was developing a version called bioleukin, with a methionine added at is N terminal and residue 125 replaced with alanine. Dozens of clinical trials had been conducted of recombinant or purified IL 2, alone, in combination with other drugs, or using cell therapies, in which cells were taken from patients, activated with IL 2, then reinfused. Novartis acquired Chiron in 2006 and licensed the US aldesleukin business to Prometheus Laboratories in 2010 before global rights to Proleukin were subsequently acquired by Clinigen in 2018 and 2019.