DURING the past decade a wealth of information concerning the pathogenesis of Type I diabetes has become available. Two spontaneous animal models of the disease have been discovered and characteriz...

Type I diabetes mellitus. A chronic autoimmune disease.

Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 X 10(-7) moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH2-terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56 degrees C and at pH 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism.

https://science.sciencemag.org/content/sci/226/4674/544.full.pdf

Cyclophilin: A Specific Cytosolic Binding Protein for Cyclosporin A

Background Type 1 diabetes mellitus is a chronic autoimmune disease caused by the pathogenic action of T lymphocytes on insulin-producing beta cells. Previous clinical studies have shown that continuous immune suppression temporarily slows the loss of insulin production. Preclinical studies suggested that a monoclonal antibody against CD3 could reverse hyperglycemia at presentation and induce tolerance to recurrent disease. Methods We studied the effects of a nonactivating humanized monoclonal antibody against CD3 — hOKT3γ1(Ala-Ala) — on the loss of insulin production in patients with type 1 diabetes mellitus. Within 6 weeks after diagnosis, 24 patients were randomly assigned to receive either a single 14-day course of treatment with the monoclonal antibody or no antibody and were studied during the first year of disease. Results Treatment with the monoclonal antibody maintained or improved insulin production after one year in 9 of the 12 patients in the treatment group, whereas only 2 of the 12 controls ...

Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes Mellitus

Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies.

Genetics, pathogenesis and clinical interventions in type 1 diabetes

We evaluated glomerular filtration in 17 recipients of heart transplants who were treated for 12 months or longer with cyclosporine (cyclosporin A). The control group consisted of 15 heart-transplant recipients who were treated with azathioprine and who had also survived for at least 12 months. Despite an equivalent cardiac output, the glomerular filtration rate was depressed (51 +/- 4 vs. 93 +/- 3 ml per minute, P less than 0.005) in transplant recipients treated with cyclosporine. Cyclosporine treatment was also associated with reduced renal plasma flow (320 +/- 21 vs. 480 +/- 30 ml per minute, P less than 0.001). A trend toward restricted transglomerular transport of neutral dextrans (radii, 2.4 to 5.8 nm) in cyclosporine-treated recipients suggested an intrinsic loss of ultrafiltration capacity by glomerular capillaries rather than a hemodynamic basis for the reduced glomerular filtration rate. Histopathologic examination of the kidneys of five cyclosporine-treated patients with glomerular hypofiltration revealed a variable degree of tubulointerstitial injury accompanied by focal glomerular sclerosis. Among the 32 heart-transplant recipients treated for more than 12 months with cyclosporine at our center, end-stage renal failure developed in 2. We conclude that long-term cyclosporine therapy may lead to irreversible and potentially progressive nephropathy. We recommend that cyclosporine be used with restraint and caution until ways are found to mitigate its nephrotoxicity.

Cyclosporine-associated chronic nephropathy

The results of uncontrolled trials in immunomodulation of insulin-dependent diabetes mellitus (IDDM) led to randomized controlled trials in Canada and Europe. In the Canadian open study, the rate of clinical remissions (target control of glycemia maintained with less than or equal to 0.15 U.kg-1.day-1 insulin) was unexpectedly high among 81 subjects who had been treated with cyclosporin for at least 3 mo (mean serum trough levels approximately 125 ng/ml by radioimmunoassay). Subjects entered the study within 14 wk of onset of symptoms and received 6 wk of insulin therapy. The clinical remission rate at 1 yr was 46%; of these patients, 84% were not receiving insulin. An effect on beta-cell function was suggested by recovery of plasma glucagon-stimulated C-peptide levels into the normal range in many patients, with maintenance of levels through 1 yr in patients in remission. On the basis of these findings, the French and Canadian-European study groups conducted randomized double-blind controlled trials of cyclosporin, which confirmed the results of the open studies in terms of clinical remission. The Canadian-European study also demonstrated enhancement of beta-cell function by cyclosporin by 3 mo, which was maintained for 1 yr. In the Canadian open study, most patients relapsed within a few weeks after discontinuation of cyclosporin, indicating the need for longer-term immunomodulatory therapy for maintenance of remission. The nature and degree of structural change in kidney biopsies from patients in these studies are under assessment. The results strongly support the hypothesis that autoimmune mechanisms mediate beta-cell damage in many patients with IDDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical trials of cyclosporin in IDDM.

Effects of immunosuppression with cyclosporine in insulin-dependent diabetes mellitus of recent onset: the Canadian open study at 44 months.

Effects of cyclosporine in recent-onset juvenile type 1 diabetes: Impact of age and duration of disease

In November 1982 a “pilot” (uncontrolled) clinical trial of the effects of the administration of ciclosporin to volunteer subjects with recent onset Type I diabetes mellitus was initiated. The rationale and preliminary findings in this study have been published earlier [1]. In this presentation we summarize further experience in this ongoing trial.

Effects of Ciclosporin on Insulin Secretion in Recent Onset Type I Diabetes Mellitus

Immunosuppression and type I diabetes.

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