fatigue) nausea/vomiting dry, itchy skin or rash weakness or shortness of breath diarrhea low blood pressure drowsiness or confusion loss of appetite 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 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 is generally well tolerated. this is also the case for intralesional il-2 in other forms of cancer, like nasopharyngeal carcinoma. pharmaceutical derivative 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 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). preclinical research 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/anti-il-2 mab immune complexes (il-2 ic) 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. history according to an immunology textbook: "il-2 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 the growth factors being studied by endocrinologists and biochemists".: 712 in the mid-1960s, studies reported "activities" in leukocyte-conditioned media that promoted lymphocyte proliferation.: 16 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.: 712 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.: 76 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.: 76–77 : 201 amgen later entered the field with its own proprietary, mutated, recombinant protein and cetus and amgen were soon competing scientifically and in the courts; cetus won the legal battles and forced amgen out of the field.: 151 by 1990 cetus had gotten aldesleukin approved in nine european countries but in that year, the u.s. food and drug administration (fda) refused to approve cetus' application to market il-2. 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.