Background The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. Methods We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 μg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. Results Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (−0.21 vs. −0.27 nmol per liter [−0.62 vs. −0.81 ng per milliliter], P = 0.045), as did stimulated secretion measured as the area under the curve (−0.72 vs. −1.02 nmol per liter per 2 hours [−2.20 vs. −3.08 ng per milliliter per 2 hours], P = 0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. Conclusions GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0804328

GAD treatment and insulin secretion in recent-onset type 1 diabetes

Type 1 diabetes mellitus (T1DM) results from the destruction of pancreatic β-cells that is mediated by the immune system. Multiple genetic and environmental factors found in variable combinations in individual patients are involved in the development of T1DM. Genetic risk is defined by the presence of particular allele combinations, which in the major susceptibility locus (the HLA region) affect T cell recognition and tolerance to foreign and autologous molecules. Multiple other loci also regulate and affect features of specific immune responses and modify the vulnerability of β-cells to inflammatory mediators. Compared with the genetic factors, environmental factors that affect the development of T1DM are less well characterized but contact with particular microorganisms is emerging as an important factor. Certain infections might affect immune regulation, and the role of commensal microorganisms, such as the gut microbiota, are important in the education of the developing immune system. Some evidence also suggests that nutritional factors are important. Multiple islet-specific autoantibodies are found in the circulation from a few weeks to up to 20 years before the onset of clinical disease and this prediabetic phase provides a potential opportunity to manipulate the islet-specific immune response to prevent or postpone β-cell loss. The latest developments in understanding the heterogeneity of T1DM and characterization of major disease subtypes might help in the development of preventive treatments. Although β-cell targeted autoimmune processes and β-cell dysfunction are known to occur in type 1 diabetes mellitus, the precise aetiology and pathological mechanisms are still largely unclear. This Review explores the current knowledge on the pathogenesis of type 1 diabetes mellitus and describes expected developments in the near future.

The heterogeneous pathogenesis of type 1 diabetes mellitus

Type 1 diabetes results from an immune-mediated destruction of pancreatic beta cells. The disease can be transmitted by bone marrow transplantation in humans1 and animals.2,3 Furthermore, T cells that are reactive to several islet autoantigens have been identified in both mice and humans.4,5 Although it is generally accepted that T cells have a role during the disease process, the possible role of B cells and autoantibodies in type 1 diabetes in humans has not been fully resolved. When they are activated, B cells can produce autoantibodies to pancreatic beta-cell antigens — such as glutamic acid decarboxylase 65 (GAD65), . . .

https://www.nejm.org/doi/pdf/10.1056/NEJMoa010465

Development of type 1 diabetes despite severe hereditary B-cell deficiency.

Background
After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease.

Materials and methods
In order to provide recognized expert practical guidelines for the use of this technology for all indications the European Dermatology Forum (EDF) proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task.

Results and conclusion
These guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/jdv.12311

Guidelines on the use of extracorporeal photopheresis.

A cloned T-lymphocyte line, BDC-2.5, was derived from a nonobese diabetic (NOD) mouse and has been found to exhibit specificity for islet cell antigen in vitro and in vivo. This clone is a CD4+ T-lymphocyte that proliferates and makes lymphokine in response to islet cell antigen- and NOD antigen-presenting cells. In an in vivo transplantation system in which islet grafts were made in the presence or absence of the BDC-2.5 T-lymphocytes, it was found that incorporation of the islet-specific T-lymphocytes into the graft site resulted in complete destruction of the transplanted tissue. Similar grafts made with pituitary tissue were not affected by the T-lymphocyte clone. These results suggest that the islet-specific T-lymphocytes mediate islet destruction in a tissue-specific manner.

T-lymphocyte clone specific for pancreatic islet antigen.

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.

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

Disappearance and reappearance of islet cell cytoplasmic antibodies in cyclosporin-treated insulin-dependent diabetics.

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Clinical trials of cyclosporin in IDDM.

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

Disappearance and reappearance of islet cell cytoplasmic antibodies in cyclosporin-treated insulin-dependent diabetics.