Uses of Interleukin

Proleukin is a recombinant human IL-2 that received approval for the treatment of renal cell carcinoma in 1992 and for the treatment of metastatic melanoma in 1998. It is also being evaluated for the treatment of non-Hodgkin s lymphoma (NHL). The therapy is restricted to patients with normal cardiac and pulmonary functions. 

The treatment generally consists of two treatment cycles, each lasting for 5 days and separated by a rest period. Every 8 h a dose of 600,000 IU/kg (0.037 mg/kg) is administered. The IV infusion period is 15 min and a maximum of 14 doses are administered. After a rest period of 9 days, another 14 doses are administered. Additional treatment can be given following an evaluation after 4 weeks. 

The most frequent adverse reactions associated with the administration of proleukin include fever, chills, fatigue, malaise, nausea and vomiting. It has also been associated with capillary leak syndrome (CLS). CLS is defined as a loss of vascular tone and effusion of plasma proteins and fluids into the extravascular space. This leads to hypotension and decreased organ perfusion, which may cause sudden death. Other side effects include anaphylaxis, injection site necrosis and possible autoimmune and inflammatory disorders. 

IL-2 has been tested for antitumor effects in cancer patients as part of LAK therapy. LAK cell therapy involves infusion into cancer patients of their own (autologous) 

HIV is a retrovirus that infects CD4+ cells. After HIV becomes integrated into the genome of the CD4+ cells, activation of these cells results in the replication of virus, which causes lysis of the host cells. Patients infected with HIV, and with AIDS, generally have reduced numbers of helper T cells and the CD4 CD8 ratio may be as low as 0.5 1 instead of the normal 2 1. As a consequence, very little IL-2 is available to support the growth and proliferation of CD4+ cells despite the presence of effector cells, B cells and cytolytic T cells. 

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Ehtesham M, Kabos P, Kabosova A, Neuman T, Black KL, Yu JS (2002b) The use of interleukin 12-secreting neural stem cells for the treatment of intracranial glioma. Cancer Res 62 5657-5663... 

Pau AK, Tavel JA. 2002. Therapeutic use of interleukin-2 in HIV-infected patients. Curr Opin Pharmacol. 2 433 139. 

Wright AKA, Briles DE, Metzger DW, Gordon SB. Prospects for use of interleukin-12 as a mucosal adjuvant for vaccination of humans to protect against respiratory pneumococcal infection. Vaccine 2008 26(38) 4893-903. 

The secondary stmcture elements are then identified, and finally, the three-dimensional protein stmcture is obtained from the measured interproton distances and torsion angle parameters. This procedure requites a minimum of two days of nmr instmment time per sample, because two pulse delays are requited in the 3-D experiment. In addition, approximately 20 hours of computing time, using a supercomputer, is necessary for the calculations. Nevertheless, protein stmcture can be assigned using 3-D nmr and a resolution of 0.2 nanometers is achievable. The largest protein characterized by nmr at this writing contained 43 amino acid units (51). However, attempts ate underway to characterize the stmcture of interleukin 2 [85898-30-2] which has over 150 amino acid units. 

Figure 9 Relative accuracy of comparative models. Upper left panel, comparison of homologous structures that share 40% sequence identity. Upper right panel, conformations of ileal lipid-binding protein that satisfy the NMR restraints set equally well. Lower left panel, comparison of two independently determined X-ray structures of interleukin 1(3. Lower right panel, comparison of the X-ray and NMR structures of erabutoxin. The figure was prepared using the program MOLSCRIPT [236].

The purported prophylactic use of Japanese herbal medicines to combat neuronal ageing has been related to their free-radical scavenging activity (Hiramatsu a al., 1992). Inhibition of the pro-inflammatory effects of cytokine interleukin-1 by recombinant endogenous interleukin-1 receptor antagonist in experimental rats is associated with alleviation of excitotoxic neuronal damage, an action which has also been related to the antiinflammatory effect of lipocortin 1 (Relton and Roth well, 1992). 

Denileukin diftitox is a combination of the active sections of interleukin 2 and diphtheria toxin. It binds to high-affinity interleukin 2 receptors on the cancer cell (and other cells), and the toxin portion of the molecule inhibits protein synthesis to result in cell death. The pharmacokinetics of denileukin diftitox are best described by a two-compartment model, with an a half-life of 2 to 5 minutes and a terminal half-life of 70 to 80 minutes. Denileukin diftitox is used for the treatment of persistent or recurrent cutaneous T-cell lymphoma whose cells express the CD25 receptor. Side effects include vascular leak syndrome, fevers/chills, hypersensitivity reactions, hypotension, anorexia, diarrhea, and nausea and vomiting. 

Clark-Lewis I, Schumacher C, Baggiofini M, Moser B. Structure-activity relationships of interleukin-8 determined using chemically synthesized analogs. Critical role of NH2-terminal residues and evidence for uncoupling of neutrophil chemo-taxis, exocytosis, and receptor binding activities. J Biol Chem 1991 266 23128-34. 

Watson and Kenney [62] describe the use of high-performance size-exclusion chromatography to examine the aggregation of interferon-y and interleukin-2 after storage at elevated temperature, after mechanical agitation, and following rapid freeze-thaw. An excellent review on SEC can be found in Ref. 63. 

The ability of natural products to inhibition of topoisomerase and precipitate apoptosis mentioned in this chapter are two abilities among several others, of which inhibition of microtubule formation, inhibition of DNA polymerase, protein kinases, protein phosphatase and aromatase, and the use of cytokines, interleukins, and tumor necrosis factor and yet uncovered cellular targets. 

Slater MD, Murphy CR. Co-expression of interleukin-6 and human growth hormone in apparently normal prostate biopsies that ultimately progress to prostate cancer using low pH, high temperature antigen retrieval. /. Mol. Histol. 2006 37 37-41. 

Fewell JG, Matar MM, Rice JS, Brunhoeber E, Slobodkin G, Pence C, Worker M, Lewis DH, Anwer K (2009) Treatment of disseminated ovarian cancer using nonviral interleukin-12 gene therapy delivered intraperitoneally. J Gene Med 11 718-728... 

After identification of those and many other immunological processes, several strategies were tested in the meantime to influence these processes. For example, administration of interleukin-2 was thought to activate cytotoxic cells and T-helper cells (6). However, clinical studies using this approach showed a disastrous outcome by displaying a bunch of serious side effects. 

The salicylates are also potent antipyretic agents, with the exception of diflunisal, which is only weakly active. Aspirin acts at two distinct but related sites. It decreases prostaglandin-induced fever in response to pyrogens and induces a decrease in interleukin-1 modulation of the hypothalamic control of body temperature. Thus, the hypothalamic control of body temperature returns, vasodilation occurs, heat dissipates, and fever decreases. Other uses of aspirin include inhibition of platelet aggregation via inhibition of thromboxanes, which has been shown to decrease the incidence of blood clots, myocardial infarction, and transient ischemic attacks. 

Meyer, J.D., J.E. Matsnnra, J.A. Rnth, E. Shelter, S.T. Patel, J. Bansch, E. McGonigle, and M.C. Manning, Selective precipitation of interleukin-4 using hydrophobic ion pairing a method for improved analysis of proteins formulated with large excesses of human serum albumin. Pharm Res, 1994. 11(10) 1492-5. 

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