Cyclosporine is an 11 aminoacid cyclic peptide of fungal origin endowed with potent immunosuppressive activity. Unlike the conventional immunosuppressants, cyclosporine does not interfere with DNA metabolism, but it selectively and reversibly inhibits lymphocyte T-helper activation by inhibiting the production of interleukin-2 which plays a role in immune response development. Cyclosporine has little effect on lymphocytes B and does not modify the production of antibodies when it is in progress. The drug is effective in preventing spontaneous or autoantigen-induced auto-immune diseases in animals. The best studied models are experimental allergic encephalomyelitis, uveitis in the rat and spontaneous diabetes of BB rats. However, cyclosporine has no effect on diseases exclusively due to the pathogenic action of antibodies, such as spontaneous thyroiditis of the obese chicken. It is also possible to obtain a curative effect, this type of model being nearer to therapeutic conditions in humans than the previous models.

Animals↗

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[Cyclosporin and autoimmune diseases. 2: Human autoimmune diseases].

The effectiveness of cyclosporin against human auto-immune diseases has been well established in uveitis, rheumatoid arthritis and insulin-dependent diabetes. No firm conclusion can be drawn from trials conducted in other diseases, since the results are discordant or based on an insufficient number of subjects. In view of the side-effects, and notably the risk of nephrotoxicity, of the drug, the blood levels of cyclosporine must be measured and the patient's renal function evaluated at regular intervals. For the time being, these risks reduce the prescription of cyclosporin to the severe forms of autoimmune diseases, i.e. those which resist conventional corticosteroid therapy. Things are different with diabetes, since cyclosporin is the only immunosuppressant which has proved effective in inducing remissions. But whether such remissions can be maintained in the long term remains uncertain, and this type of treatment is still limited to therapeutic trials.

Autoimmune Diseases↗

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Non-Th2 regulatory T-cell control of Th1 autoimmunity.

The Th1/Th2 concept brought an attractive explanation of the active self tolerance which appears to control the onset of pathogenic autoimmunity. New data coming from various independent horizons indicate that self immunoregulation could also depend to a large extent on non-Th2 cells. Original data derived from the day-3-thymectomy model, selective T-cell lymphocytopenia and nonobese diabetic mice are discussed in an effort to analyze similarities and differences in phenotype (CD25, CD62L and CD45RB) and cytokine pattern (notably interleukin (IL)-4, IL-10 and transforming growth factor (TGF)beta) of regulatory cells involved in these models. The relationship of these cells with Th3, Tr1 and natural killer (NK) T cells are also discussed. The hypothesis is proposed that CD25 CD62L T cells mediate the physiologic regulation of self regulation whereas Th2 and Th3 cells are essentially induced following sensitization against autoantigens.

Antigens↗

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Aberrant function and long-term survival of mouse beta cells exposed in vitro to high glucose concentrations.

In vitro culture of murine Langerhans islets usually ends in islet death after 1-3 wk. Given contradictory published data, we studied the influence of glucose on the function and survival of islets from DBA/2 mice. Islets were cultured on plastic microwells, using 1, 2, or 11 g/l glucose concentrations. Using our routine technique, insulin secretion was evaluated after islet incubation for 15 min in basal medium [(sIS), 1 g/l glucose], followed by 15 min in stimulating medium [(sIS), 3 g/l glucose, 20 mM/l arginine, 5 mM/l theoophylline]. Insulin secretion of islets cultured in 1 g/l glucose remained stable and normal over a period of 2 mo [Day 7: bIS, 6.3 +/- 3.1 microU/50 microliters; sIS, 16.6 +/- 6.8 microU/50 microliters. Day 60: bIS, 6.0 +/- 4.0 microU/50 microliters; sIS, 21.3 +/- 10.5 microU/50 microliters]. Islet morphology also remained normal. Islets cultured in 2 g/l glucose showed elevated insulin response under basal and stimulating conditions during 2-3 wk, followed by a dramatic drop in insulin secretion [Day 7: bIS, 19.5 +/- 5.7 microU/50 microliters; sIS, 80.9 +/- 10.7 microU/50 microliters. Day 60: bIS, 5.4 +/- 5.0 microU/50 microliters; sIS, 2.7 +/- 1.4 microU/50 microliters]. Severe morphologic alterations appeared rapidly and islet destruction was nearly complete by 60 days. At 11 g/l glucose, functional and morphological islet alterations were accelerated [Day 7: bIS, 10.3 +/- 2.7 microU/50 microliters; sIS, 18.8 +/- 4.9 microU/50 microliters. Day 21: bIS and sIS almost undetectable].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Ontogeny of thymus factor secretion.

The circulating thymic factor (TF) detected by 0-conversion assay has been followed up in ontogeny. Serum TF evaluation in pregnant thymectomized mice and in new born mice indicates that TF secretion starts on day 12-13 of foetal life and has reached the adult's level at birth.

Animals↗

PubMedDate not supplied

[Non-specific cytotoxic activity in lepromatous leprosy: preliminary results].

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Cytotoxicity Tests, Immunologic↗

PubMedDate not supplied

The effects of interleukin-1 on pancreatic beta cell function in vitro depend on the glucose concentration.

Insulin-dependent diabetes mellitus is characterized by progressive autoimmune destruction of pancreatic Beta cells mediated by ill-defined effector mechanisms. Experimental data suggest that cytokines, e.g. interleukin 1 and tumor necrosis factor, could play a fundamental role. The aim of this study was to analyze the effect of recombinant IL-1 beta (rIL-1 beta) on both islet functional capacity and morphology, using long-term cultures and various glucose concentrations. Islet cultured with 1 g/l (5.5 mmol/l) glucose maintained normal insulin- secretion and morphology for more than two months. In contrast, islets cultured with 2 g/l (11 mmol/l) glucose showed an altered insulin secretion and a shorter survival (40 days). At 11 g/l (60 mmol/l) glucose, islets died by 2 weeks of culture. rIL-1 beta exerted a cytotoxic effect on islet cells only when added to cultures containing supraphysiological glucose concentrations. But, in the presence of 1 g/l glucose, the addition of rIL-1 beta (40 ng/ml) for prolonged periods (14 days), did not alter islet function. Our results suggest that in auto-immune type I diabetes, IL-1 beta represents an aggravating factor in lesion formation more than a primary pathogenic mechanism.

Animals↗