Interleukin administration

One component of the age-ielated decline in immune function is decreased production of the lymphokine that promotes the growth of T-ceUs, interleukin 2 (IL-2). Administration of recombinant-derived IL-2, both in vitro and in vivo, appears to restore certain immune functions in aged mice. Recovery of T-regulatory effects on B-ceU differentiation has been reported in human cells from elderly patients treated with IL-1 and/or IL-2 (42). Similar effects have been observed in the presence of the pentapeptide thymopentin [69558-55-0] (Arg Lys Asp Val Tyr), a weU-known IL-2 inducer. Recombinant IL-2 adrninistered to aged mice for three weeks has been shown to correct the T-ceU functional deficiency associated with antigen-specific immunoglobulin production by certain lymphoid tissue (43). 

Interleukin 2 therapy is approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma, and it is a reasonable option for patients with this stage of the disease. 

Wada T, Tomosugi N, Naito T, et al. Prevention of proteinuria by the administration of anti-interleukin 8 antibody in experimental acute immune complex-induced glomerulonephritis. J Exp Med 1994 180 1135-1140. 

Interleukin-6 (IL-6) is a small polypeptide with a molecular mass of 26 kDa (see Table 2). IL-6 can be induced in various cell types, including fibroblasts, macrophages/monocytes, epithelial cells, T cells, B cells, and diverse tumor cells (L4). TNF, IL-1, and LPS can stimulate IL-6 gene expression in macrophages/monocytes and fibroblasts. In vivo studies showed that systemic administration of TNF, LPS, and IL-1 was followed by a rapid induction of circulating IL-6 (B49, J2). Also, endothelin (ET) at concentrations observed pathophysiolog-ically may trigger production of IL-6 (Ml7). 

H6. Hack, C. E., Ogilvie, A. C., Eisele, B., Jansen, P. M Wagstaff, J., and Thijs, L. G Initial studies on the administration of Cl-esterase inhibitor to patients with septic shock or with a vascular leak syndrome induced by interleukin-2 therapy. Prog. Clin. Biol. Res. 388, 335-357 (1994). 

Sanders et al. [133] found that although quercetin treatment of streptozotocin diabetic rats diminished oxidized glutathione in brain and hepatic glutathione peroxidase activity, this flavonoid enhanced hepatic lipid peroxidation, decreased hepatic glutathione level, and increased renal and cardiac glutathione peroxidase activity. In authors opinion the partial prooxidant effect of quercetin questions the efficacy of quercetin therapy in diabetic patients. (Antioxidant and prooxidant activities of flavonoids are discussed in Chapter 29.) Administration of endothelin antagonist J-104132 to streptozotocin-induced diabetic rats inhibited the enhanced endothelin-1-stimulated superoxide production [134]. Interleukin-10 preserved endothelium-dependent vasorelaxation in streptozotocin-induced diabetic mice probably by reducing superoxide production by xanthine oxidase [135]. 

Based upon recent controlled studies, there is considerable evidence that opioids such as morphine induce substantial effects on immune status. For example, it has been shown that morphine administration is associated with alterations in a number of immune parameters, such as natural-killer cell activity [12,13], proliferation of lymphocytes, [13, 14] antibody production [15,16], and the production of interferon [17]. Studies in our laboratory have shown that acute morphine treatment in rats suppresses splenic lymphocyte proliferative responses to both T- and B-cell mitogens, splenic natural-killer cell activity, blood lymphocyte mitogenic responsiveness to T-cell mitogens, and the in vitro production of the cytokines interleukin-2 and interferon-y [18-22], Furthermore, the immune alterations induced by morphine are dose-dependent and antagonized by the opioid-receptor antagonist, naltrexone (e.g., [22]). 

Holmin, S. and Mathiesen T. Intracerebral administration of interleukin-1 beta and induction of inflammation, apoptosis, and vasogenic edema. J. Neurosurg. 92, 108, 2000. 

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. 

Concurrent administration of etanercept (another TNF -blocking agent) and anakinra (an interleukin-1 antagonist) has been associated with an increased risk of serious infections, and increased risk of neutropenia and no additional benefit compared with these medicinal products alone. Other TNF -blocking agents (including infliximab) used in combination with anakinra also may result in similar toxicities. 

Also when the cytokine interleukin 2 (IL-2) was used for cancer treatment, serious adverse effects were noted resulting in the so-called vascular leak syndrome (VLS) [98, 99]. VLS is a life-threatening toxicity marked by vasopermeability with hypotension induced during high dose IL-2 treatment of cancer patients [100]. VLS is caused by endothelial activation and can be induced in lungs and liver of mice by IL2 administration [99]. The mechanism of IL-2-induced VLS is still poorly understood and at present there is no specific therapy for VLS. For the investigation of these... 

Anti-arthritic effect. Oral administration of AJA, a cannabinoid acid devoid of psychoactivity, reduced joint tissue damage in rats with adjuvant arthritis. Peripheral blood monocytes (PBM) and synovial fluid monocytes (SFM) were isolated from healthy subjects and patients with inflammatory arthritis, respectively, treated with AJA (0-30 mM) in vitro, and then stimulated with lipopolysaccharide. Cells were harvested for messenger RNA (mRNA), and supernatants were collected for cytokine assay. Addition of AJA to PBM and SFM in vitro reduced both steady-state levels of interleukin-ly (IL-ly) mRNA and secretion of IL-ly in a concentration-dependent manner. Suppression was maximal (50.4%) at 10 mM AJA (p < 0.05 vs untreated controls, n = 7). AJA did not influence tumor necrosis factor-a (TNF-a) gene expression in or secretion from PBM . 

Lotze, M.T., M.C. Custer, and S.A. Rosenberg, Intraperitoneal administration of interleukin-2 in patients with cancer. Arch Surg, 1986.121(12) 1373-9. 

Legha, S.S., S. Ring, O. Eton, A. Bedikian, A.C. Buzaid, C. Plager, and N. Papadopon-los. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Chn Oncol, 1998.16(5) 1752-9. 

The authors of the last report commented that generalized delayed type hypersensitivity to systemic administration of a glucocorticoid is rare. Despite the potent immunosuppressive effect of glucocorticoids on immunocompetent cells, the clinical features, the skin biopsy specimen, and the positive delayed skin test reactions strongly suggested an immunological mechanism T cells were clearly involved and the high concentrations of interleukins 5, 6, and 10 were consistent with a T helper type 2 reaction. The raised concentrations of interleukin-5 were probably responsible for the blood and tissue eosinophilia. 

Jacobs EL, Clare-Salzler MJ, Chopra D, Figlin RA. Thyroid function abnormahties associated with the chronic outpatient administration of recombinant interleukin-2 and recombinant interferon-alpha. J Immunother 1991 10(6) 448-55. 

Lee YL, Fu CL, Ye YL, Chiang BL Administration of interleukin-12 prevents mite Der p 1 allergen-IgE antibody production and airway eosinophil infiltration in an animal model of airway inflammation. Scand J Immunol 1999 49 229-236. 

Ben-Gary, H., McKinney, R. L., Rosengart, T., Lesser, M. L. and Crystal, R. G. (2002). Systemic interleukin-6 responses following administration of adenovirus gene transfer vectors to humans by different routes. Mol. Ther. 

Nishikubo, K., Murata, Y., Tamaki, S., Sugama, K., Imanaka-Yoshida, K., Yuda, N., Kai, M., Takamura, S., Sebald, W., Adachi, Y. and Yasutomi, Y. (2003). A single administration of interleukin-4 antagonistic mutant DNA inhibits allergic airway inflammation in a mouse model of asthma. GeneTher. 10, 2119-2125. 

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