Anti-suppressor effect of cyclophosphamide on the development of spontaneous diabetes in NOD mice.
ABSTRACT In the NOD mouse, an autoimmune process beginning by 5 weeks of age with lymphocyte infiltration and destruction of insulin-secreting beta cells leads to overt diabetes which begins to appear by 11 weeks of age. Although there is a high incidence of insulitis by 10 weeks of age (greater than 80%) in both males and females, by 30 weeks of age diabetic symptoms have occurred in 53-80% of females and in 12-40% of males. Intraperitoneal injection of a high dose (200 mg/kg) of cyclophosphamide (CY) consistently induces the onset of diabetes in male and female NOD mice at an age when spontaneous diabetes rarely occurs. Spleen T cells from CY-induced diabetic mice are capable of transferring the disease into irradiated nondiabetic syngeneic recipients. This indicates that the diabetogenic effect of CY is not mediated by direct toxicity on pancreatic beta cells but is mediated by abrogation of a suppressor mechanism which may prevent activation of T cells responsible for the development of diabetes in the NOD mouse. Additionally, CY is only effective in NOD mice and not in F1 hybrids between NOD and other strains of mice. Thus, the potential beta cell aggressor mechanism is not present in these hybrids as it is in homozygous mice, which indicates that it is not under the control of dominant genes.
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ABSTRACT: Type I insulin dependent diabetes mellitus (IDDM) is an autoimmune disease . The non-obese diabetic (NOD) mouse, originally described by Makino et al. is an accurate experimental model of human IDDM; overt metabolic disturbances (glycosuria and hyperglycemia), spontaneously appear by 15 weeks of age and are preceded by a progressive infiltration of the islets of Langerhans with mononuclear cells termed “insulitis” . Insulitis appears by 5 weeks of age and is observed both in NOD males and females. Depending on the colony, the cumulative incidence of overt IDDM reaches 60–80% in females and 10–80% in males. There is compelling evidence confirming the essential role of T cell mediated immunity in the pathogenesis of IDDM: 1) neonatal thymectomy prevents the onset of disease  and athymic NOD nude mice are free of insulitis and IDDM , 2) IDDM can be adoptively transferred to NOD neonates, irradiated adult NOD mice and more recently to athymic NOD nude mice, by injection of splenic T cells from diabetic animals; both CD4+ and CD8+ lymphocytes are needed to achieve effective transfer of disease [4–6], 3) different immunointervention strategies specific for T cells are effective in preventing IDDM.01/1994;
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ABSTRACT: As more patient data is cross-referenced with animal models of disease, the primary focus on T(h)1 autoreactive effector cell function in autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, has shifted towards the role of T(h)17 autoreactive effector cells and the ability of regulatory T cells (T(reg)) to modulate the pro-inflammatory autoimmune response. Therefore, the currently favored hypothesis is that a delicate balance between T(h)1/17 effector cells and T(reg) cell function is critical in the regulation of inflammatory autoimmune disease. An intensive area of research with regard to the T(h)1/17:T(reg) cell balance is the utilization of blockade and/or ligation of various co-stimulatory or co-inhibitory molecules, respectively, during ongoing disease to skew the immune response toward a more tolerogenic/regulatory state. Currently, FDA-approved therapies for multiple sclerosis patients are all aimed at the suppression of immune cell function. The other favored method of treatment is a modulation or deletion of autoreactive immune cells via short-term blockade of activating co-stimulatory receptors via treatment with fusion proteins such as CTLA4-Ig and CTLA4-FasL. Based on the initial success of CTLA4-Ig, there are additional fusion proteins that are currently under development. Examples of the more recently identified B7/CD28 family members are PD-L1, PD-L2, inducible co-stimulatory molecule-ligand (ICOS-L), B7-H3, and B7-H4, all of which may emerge as potential fusion protein therapeutics, each with unique, yet often overlapping functions. The expression of both stimulatory and inhibitory B7 molecules seems to play an essential role in modulating immune cell function through a variety of mechanisms, which is supported by findings that suggest each B7 molecule has developed its own indispensable niche in the immune system. As more data are generated, the diagnostic and therapeutic potential of the above B7 family-member-derived fusion proteins becomes ever more apparent. Besides defining the biology of these B7/CD28 family members in vivo, additional difficulty in the development of these therapies lies in maintaining the normal immune functions of recognition and reaction to non-self-antigens following viral or bacterial infection in the patient. Further complicating the clinical translation of these therapies, the mechanism of action identified for a particular reagent may depend upon the method of immune-cell activation and the subset of immune cells targeted in the study.BioDrugs 11/2012; · 2.12 Impact Factor
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ABSTRACT: The corticosteroid-sparing immunosuppressive agents commonly used in dermatology include azathioprine, cyclophosphamide, methotrexate and cyclosporin. The pharmacology, use and adverse effects of these agents are reviewed. Azathioprine is an antimetabolite whose immunosuppressive effects involve mainly suppression of cellular cytotoxicity and to a lesser degree antibody responses. The role of genetic polymorphisms in its metabolism and efficacy and in the incidence of adverse effects is increasingly being recognised. Cyclophosphamide is an antimetabolite that has potent B cell inhibitory effects as well as a differential effect on subsets of macrophages. Its immunosuppressive effect is of more rapid onset than that of azathioprine. Intravenous pulse administration of cyclophosphamide is becoming more popular in an effort to decrease the overall dosage and toxicity. The immunomodulatory role of methotrexate is being more fully appreciated, as is the role of rescue therapy with folic and folinic acids in reducing haematological and gastrointestinal toxicity. Hepatotoxicity remains a major concern with methotrexate, and its use in renal insufficiency requires dosage modification. Cyclosporin has potent and well-defined T cell inhibitory effects, and its role is being expanded in inflammatory dermatoses. Cumulative renal toxicity currently limits its use. Recent clinical data on the use of these agents in blistering disorders, connective tissue diseases (systemic lupus erythematosus, cutaneous lupus erythematosus, dermatomyositis and scleroderma), eczematous disorders (chronic actinic dermatitis, severe chronic atopic dermatitis), vasculitides (Behçet’s disease and Wegener’s granulomatosis) and psoriasis are reviewed in a comparative manner. Azathioprine and cyclophosphamide have a major role in the treatment of autoantibody-mediated inflammatory skin disease. Cyclosporin and methotrexate have a greater role in primarily T cell—mediated inflammatory cutaneous disease.Clinical Immunotherapeutics. 04/1996; 5(4).