n. (Abbr. IL-2)
A lymphokine that is released by helper T cells in response to an antigen and interleukin-1 and stimulates the proliferation of helper T cells. It has been used experimentally to treat cancer.
interleukin-2
Dictionary:
in·ter·leu·kin-2 (ĭn'tər-lū'kĭn-tū')  |
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| Oncology Encyclopedia: Interleukin 2 |
Key Terms: Cytokine, Metastatic, Neutrophil, Subcutaneous.
Definition
Interleukin-2 (IL2) is a protein produced naturally in the body in very small amounts. It is produced by a type of white blood cell called a T-lymphocyte and acts as part of the immune system by helping white blood cells work. Aldesleukin is a biological response modifier, a synthetic form of interleukin-2.
Purpose
Interleukin-2 (IL-2) is a naturally occurring chemical, called a cytokine, produced by certain cells of the immune system. It is also manufactured and administered as a drug to augment immune responses. While it is approved by the U.S. Food and Drug Administration (FDA) only for the treatment of kidney cancer, it is, as of 2005, also used in the treatment of HIV and AIDS. Inhaled interleukin-2 may halt disease progression in patients with kidney cancer that has spread to the lungs. Aldesleukin, a synthetic version of interleukin-2, is used to treat cancer of the kidney and skin cancer that has spread to other parts of the body.
Aldesleukin is approved by the United States Food and Drug Administration (FDA) for treatment of meta-static malignant melanoma (skin cancer that has spread to other parts of the body) and metastatic renal cell carcinoma (kidney cancer that has spread to other parts of the body). It has also been used in combination with other drugs in treatment of AIDS and cutaneous t-cell lymphoma.
Description
The kidneys are a pair of bean-shaped organs, located on the sides of the spine. The kidneys filter the blood and eliminate waste in the urine through a complex system of filtration tubules. All of the blood in the body passes through the kidneys approximately twenty times an hour. Renal cell cancer (RCC) is an uncommon form of cancer that is most often characterized by the presence of cancer cells in the lining of the filtration tubules of the kidney. Advanced (metastatic) RCC refers to cancer that has spread outside the kidneys to other locations in the body. The only agent approved for metastatic RCC is high-dose Proleukin (interleukin-2). One site of cancer spread in metastatic RCC is the lungs, referred to as pulmonary metastasis.
Recommended Dosage
IL-2 is usually administered by injection into a vein but can also be injected under the skin (subcutaneous injection). It can be given in a hospital or clinic setting by a healthcare professional and is sometimes given at home. The dosage depends on the height and weight of the patient. It is given as an infusion for 15 minutes every eight hours for up to five days followed by nine days without the drug and then another five-day cycle of infusion. Up to four subsequent maintenance cycles of IL-2 can be given with four-week intervals without the drug to patients who have responded favorably to the treatment. About 15% of patients respond to treatment. It is difficult to estimate the cost of IL-2 treatment since the dose and number of treatment cycles given varies according to patients' individual responses; however, the cost is quite high, perhaps as much as $2,000 for one cycle. A six-cycle regimen of IL-2 may cost about $14,100. Because of the high cost and low effectiveness of interleukin-2, it is often not covered by insurance plans, especially HMOs. It is covered by Medicare if given in a hospital.
Precautions
IL-2 is highly toxic and usually makes patients feel generally unwell. Any side effects should be reported to a physician, but the course of medicine should continue even though the patient feels ill, unless the physician or healthcare professional tells the patient to stop. While using aldesleukin, IL-2 patients will be more susceptible to infection. They should avoid people with colds, flu, and bronchitis. They should not have any vaccinations without their IL-2 prescriber's approval, and they should avoid anyone who has recently had an oral polio vaccine. Patients should drink several glasses of water a day to help reduce possible kidney problems.
Aldesleukin should not be used by lactating mothers. It should also be avoided in patients with the following conditions:
- acute s-t elevation myocardial infarction
- angina pectoris
- atrial fibrillation
- bacterial infection
- bradycardia
- capillary leak syndrome
- coma
- epilepsy
- fungal infections
- impaired cognition
- intestinal perforation
- ischemic bowel disease
- neoplasm metastatic to the central nervous system
- organ transplantation
- pericardial tamponade
- protozoal infection
- pulmonary disease
- renal failure
- supraventricular tachycardia
- toxic psychosis
- ventricular tachycardia
- viral infection
According to
- arthritis
- bone marrow depression
- bullous pemphigoid
- cerebral arteritis
- cholecystitis
- Crohn's disease
- diabetes mellitus
- disease of liver
- glomerulonephritis
- myasthenia gravis
- psychotic disorder
- renal disease
- scleroderma thyroiditis
- untreated hypothyroidism
According to
- chicken pox (including recent exposure)
- herpes zoster (shingles)
- heart disease
- immune system problems
- liver disease
- lung disease
- psoriasis
- underactive thyroid
- infection
- kidney disease
- mental problems
- history of seizures
Side Effects
When IL-2 is given by intravenous infusion, the most common side effect is called capillary leak syndrome. This condition causes weight gain, swelling, low blood pressure, and other problems. At lower doses, people taking IL-2 get flu-like symptoms, including fever and muscle aches. Because IL-2 stimulates the immune system, it can make some immune disorders get worse, including arthritis, psoriasis, and diabetes. It can also reduce the number of neutrophils, a particular type of infection-fighting cell, and can cause low levels of thyroid.
When IL-2 is given by subcutaneous injection, the side effects are usually milder than with intravenous infusions. There is the added side effect of irritation at the site of the injection. Side effects show up from two to six hours after injection of IL-2 and disappear quickly after the end of each cycle. IL-2 can cause mood changes, including irritability, insomnia, confusion, or depression. These can continue for several days after IL-2 is stopped.
Interleukin-2 has a number of other side effects. More common ones are fever or chills, shortness of breath, agitation, confusion, diarrhea, dizziness, drowsiness, mental depression, nausea and vomiting, sores in the mouth and on the lips, tingling of hands or feet, unusual decrease in urination, unusual tiredness, a weight gain of five to ten pounds or more, anemia, heart problems, kidney problems, liver problems, low blood pressure, low platelet counts in blood, low white blood cell counts, other blood problems, under active thyroid, dry skin, loss of appetite, skin rash or redness with burning or itching followed by peeling, and an unusual feeling of general discomfort or illness.
Less common problems include black and tarry stools, skin blisters, blood in the urine, bloody vomit, chest pain, cough or hoarseness, lower back or side pain, painful or difficult urination, pinpoint red spots on the skin, severe stomach pain, unusual bleeding or bruising, bloating and mild stomach pain, blurred or double vision, faintness, fast or irregular heartbeat, loss of taste, rapid breathing, redness, swelling, and soreness of the tongue, trouble in speaking, yellow eyes and skin, constipation, headache, joint pain, and muscle pain.
Rare problems include changes in menstrual periods, clumsiness, coldness, convulsions, listlessness, muscle aches, pain or redness at site of injection, sudden inability to move, swelling in the front of the neck, swelling of the feet or lower legs, and weakness.
Interactions
Interleukin-2 can adversely interact with the anticancer drug dacarbazine and hormones such as prednisone or cortisone.
—Ken R. Wells
| Dental Dictionary: interleukin-2 |
n
A hormone produced by T helper and suppressor lymphocytes that functions to control the expansion and reactivity of T lymphocytes. Used to boost the immune system in HIV-positive patients.
| Wikipedia: Interleukin 2 |
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| Interleukin 2 | ||||||||||||||
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| Human Interleukin 2 crystal structure | ||||||||||||||
| Available structures | ||||||||||||||
| 1irl, 1m47, 1m48, 1m49, 1m4a, 1m4b, 1m4c, 1nbp, 1pw6, 1py2, 1qvn, 1z92, 2b5i, 2erj, 3ink | ||||||||||||||
| Identifiers | ||||||||||||||
| Symbols | IL2; IL-2; TCGF; lymphokine | |||||||||||||
| External IDs | OMIM: 147680 MGI: 96548 HomoloGene: 488 | |||||||||||||
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| RNA expression pattern | ||||||||||||||
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| More reference expression data | ||||||||||||||
| Orthologs | ||||||||||||||
| Species | Human | Mouse | ||||||||||||
| Entrez | 3558 | 16183 | ||||||||||||
| Ensembl | ENSG00000109471 | n/a | ||||||||||||
| UniProt | P60568 | n/a | ||||||||||||
| RefSeq | NM_000586 (mRNA) | NM_008366 (mRNA) | ||||||||||||
| NP_000577 (protein) | NP_032392 (protein) | |||||||||||||
| Location | Chr 4: 123.59 - 123.6 Mb |
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| PubMed search | [1] | [2] | ||||||||||||
Interleukin-2 (IL-2) is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in 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 cells that are responsible for immunity.
Contents |
Discovery and characterization
IL-2 was the first interleukin molecule to be discovered. The discovery of the first soluble "hormone-like" mediator of the immune system galvanized the field of immunology as the important role of cytokines had not been previously realized. A soluble factor mitogenic for lymphocytes was first found in 1965 in the culture media of mixed leukocytes and named Blastogenic Factor (BF). [1] [2] Over the next decade many similar reports appeared that described mitogenic activities in lymphocyte conditioned media. A quantitative assay for T cell Growth Factor (TCGF) was developed based upon its activity to promote the long-term proliferation of T cells in culture. [3] Biochemical characterization of TCGF revealed it to be due to a variably glycosylated 15,500 dalton single protein molecule,[4] and the IL-2 molecule was first purified to homogeneity by immunoaffinity chromatography by Kendall Smith and his team at Dartmouth Medical School.[5] IL-2 was also the first cytokine shown to mediate its effects via a specific IL-2 receptor by Smith's team.[6], and it was also the first interleukin to be cloned and expressed from a complementary DNA (cDNA) library,[7]. Thus, despite being designated the number 2 interleukin, it was the first interleukin molecule, receptor and gene to be discovered. It was designated number 2 because Smith's data at the time indicated that IL-1, produced by macrophages, facilitates IL-2 production by T lymphocytes (T cells).[8][9]
IL-2 signaling pathway
Subsequently, IL-2 was discovered to be a member of a family of cytokines, which also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through a receptor complex consisting of IL-2 specific IL-2 receptor alpha (CD25), IL-2 receptor beta (CD122) and a common gamma chain (γc), which is shared by all members of this family of cytokines. Binding of IL-2 activates the Ras/MAPK, JAK/Stat and PI 3-kinase/Akt signaling modules. More comprehensive details are provided in NetPath.
Physiology and immunology
IL-2 is normally produced by the body during an immune response.[10][11] When environmental substances (molecules or microbes) gain access to the body, these substances (termed
IL-2 is also necessary during T cell development in the thymus for the maturation of a unique subset of T cells that are termed regulatory T cells (T-regs).[15][16][17] After exiting from the thymus, T-Regs function to prevent other T cells from recognizing and reacting against "self antigens", which could result in "autoimmunity". T-Regs do so by preventing the responding cells from producing IL-2[16] Thus, IL-2 is required to discriminate between self and non-self, another one of the unique characteristics of the immune system.
IL-2 has been found to be similar to IL-15 in terms of function.[18] Both cytokines are able to facilitate production of immunoglobulins made by B cells and induce the differentiation and proliferation of natural killer cells.[18][19] The primary differences between IL-2 and IL-15 are found in adaptive immune responses. For example, IL-2 participates in maintenance of T-Regs and reduces self-reactive T cells. On the other hand, IL-15 is necessary for maintaining highly specific T cell responses by supporting survival of CD8 memory T cells.
Uses in medicine
The World Reference Standard for IL-2 is produced by the National Institute of Biological Standards and Control in the UK. A recombinant form of IL-2 for clinical use is manufactured by Chiron Corporation with the brand name Proleukin. It has been approved by the Food and Drug Administration (FDA) for the treatment of cancers (malignant melanoma, renal cell cancer), and is in clinical trials for the treatment of chronic viral infections, and as a booster (adjuvant) for vaccines. The role of IL-2 in HIV therapy has been found to be ineffective.
Many of the immunosuppressive drugs used in the treatment of autoimmune diseases such as corticosteroids, and organ transplant rejection (cyclosporin, tacrolimus) work by inhibiting the production of IL-2 by antigen-activated T cells. Others (sirolimus) block IL-2R signaling, thereby preventing the clonal expansion and function of antigen-selected T cells.
References
- ^ Gordon J, Maclean LD (1965). "A Lymphocyte-stimulating Factor produced in vitro". Nature 208: 795–796. doi:.
- ^ Kasakura S, Lowenstein L (1965). Nature 208: 794–795. doi:.
- ^ Gillis S, Ferm M, Ou W, Smith KA (1978). "T cell growth factor: Parameters of production and a quantitative microassay for activity". J. Immunol. 120: 2027–2032.
- ^ Robb R, Smith KA (1981). "Heterogeneity of human T-cell growth factor(s) due to variable glycosylation". Mol. Immunol. 18: 1087–94. doi:. PMID 6977702.
- ^ Smith KA, Favata MF, Oroszlan S (1983). "Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics". J. Immunol. 131: 1808. PMID 6352804.
- ^ Robb RJ, Munck A, Smith KA (1981). "T cell growth factor receptors. Quantitation, specificity, and biological relevance". J. Exp. Med. 154 (5): 1455–74. doi:. PMID 6975347.
- ^ Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, Hamuro J (1983). "Structure and expression of a cloned cDNA for human interleukin-2". Nature. 302 (5906): 305. doi:. PMID 6403867.
- ^ Smith KA, Lachman LB, Oppenheim JJ, Favata MF (1980). "The functional relationship of the interleukins". J. Exp. Med. 151 (6): 1551–6. doi:. PMID 6770028.
- ^ Smith KA, Gilbride KJ, Favata MF (1980). "Lymphocyte activating factor promotes T-cell growth factor production by cloned murine lymphoma cells". Nature. 287 (5785): 853–5. doi:. PMID 6776414.
- ^ Cantrell DA, Smith KA (1984). "The interleukin-2 T-cell system: a new cell growth model". Science. 224: 1312–6. doi:. PMID 6427923.
- ^ Smith KA (1988). "Interleukin-2: inception, impact, and implications". Science. 240: 1169–76. doi:. PMID 3131876.
- ^ Stern J, Smith KA (1986). "Interleukin-2 induction of T-cell G1 progression and c-myb expression". Science. 233: 203–6. doi:. PMID 3523754.
- ^ Beadling C, Johnson KW, Smith KA (1993). "Isolation of interleukin 2-induced immediate-early genes". Proc. Nat. Acad. Sci. U.S.A. 90: 2719–23. doi:. PMID 7681987.
- ^ }Beadling CB, Smith KA (2002). "DNA array analysis of interleukin-2-regulated immediate/early genes". Med. Immunol. 1: 2. doi:. PMID 12459040.
- ^ Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995). "Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases". J. Immunol. 155: 1151–64. PMID 7636184.
- ^ a b Thornton AM, Shevach EM (1998). "CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production". J. Exp. Med. 188: 287–96. doi:. PMID 9670041.
- ^ Thornton AM, Donovan EE, Piccirillo CA, Shevach EM (2004). "Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function". J. Immunol. 172: 6519–23. PMID 15153463.
- ^ a b Waldmann TA (2006). "The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design". Nature Rev. Immun. 6 (8): 595–601. doi:. PMID 16868550.
- ^ Waldmann TA, Tagaya Y (1999). "The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens". Annu. Rev. Immunol. 17: 19–49. doi:. PMID 10358752.
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