Search

George S. Eisenbarth, MD, PhD, could be considered a natural conduit in the research of type 1 diabetes (T1D) and the fields of endocrinology and immunology. His recognition of T1D [...]

OBJECTIVE--The TrialNet Study Group evaluated rituximab, a B-cell-depleting monoclonal antibody, for its effect in new-onset patients with type 1A diabetes. Rituximab decreased the loss of C-peptide over the first year of follow-up and markedly depleted B lymphocytes for 6 months after administration. This article analyzes the specific effect of rituximab on multiple islet autoantibodies. RESEARCH DESIGN AND METHODS--A total of 87 patients between the ages of 8 and 40 years received either rituximab or a placebo infusion weekly for four doses close to the onset of diabetes. Autoantibodies to insulin (IAAs), GAD65 (GADAs), insulinoma-associated protein 2 (IA2As), and ZnT8 (ZnT8As) were measured with radioimmunoassays. The primary outcome for this autoantibody analysis was the mean level of autoantibodies during follow-up. RESULTS--Rituximab markedly suppressed IAAs compared with the placebo injection but had a much smaller effect on GADAs, IA2As, and ZnT8As. A total of 40% (19 of 48) of rituximab-treated patients who were IAA positive became LAA negative versus 0 of 29 placebo-treated patients (P < 0.0001). In the subgroup (n = 6) treated within 50 days of diabetes, LAAs were markedly suppressed by rituximab in all patients for 1 year and for four patients as long as 3 years despite continuing insulin therapy. Independent of rituximab treatment, the mean level of IAAs at study entry was markedly lower (P = 0.035) for patients who maintained C-peptide levels during the first year of follow-up in both rituximab-treated and placebo groups. CONCLUSIONS--A single course of rituximab differentially suppresses IAAs, clearly blocking IAAs for >1 year in insulin-treated patients. For the patients receiving insulin for >2 weeks prior to rituximab administration, we cannot assess whether rituximab not only blocks the acquisition of insulin antibodies induced by insulin administration and/or also suppresses preformed insulin autoantibodies. Studies in prediabetic non-insulin-treated patients will likely be needed to evaluate the specific effects of rituximab on levels of IAAs, Diabetes 60:2560-2565, 2011, Although the anti-CD20 monoclonal antibody rituximab (Rituxan; Genentech, Biogen-IDEC Pharmaceuticals) originally was introduced for therapy of B-cell lymphomas (1), and subsequently applied to a series of antibody-mediated autoimmune disorders, it [...]

OBJECTIVE--To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immuno-suppressed simultaneous pancreas-kidney (SPK) transplant recipients. RESEARCH DESIGN AND METHODS--We monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreaetive T-cells was studied with in vitro and in vivo assays. RESULTS--Autoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within ~1 year from hyperglycemia recurrence and revealed β-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell-directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell--directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for > 1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed β-cell loss in mice receiving autoreactive T-cells but not control T-cells. CONCLUSIONS--We demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating β-cell destruction. Markers of autoimmunity can help diagnose this under-appreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used., Type 1 diabetes is an autoimmune disease characterized by the lymphocytic infiltration of the pancreatic islets (insulitis), β-cell destruction, and loss of insulin secretion (1). Autoreactive CD4 and CD8 T-cells [...]

OBJECTIVE--Evidence supporting an association between complement (C) and type 1 diabetes (T1D) includes the identification of C-fixing islet cell autoantibodies in T1D sera and genetic associations with the major histocompatibility [...]

Type 1 diabetes results from the autoimmune destruction of pancreatic β-cells in genetically susceptible individuals. Growing evidence suggests that genetically determined variation in the expression of self-antigens in thymus may [...]

HLA-DQBL alleles confer susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). We investigated whether the susceptibility alleles DQB1*0302 and DQB1*0201 affect progression to diabetes among islet cell antibody-positive ([ICA.sup.+]) first-degree [...]

A role for heat shock proteins (HSPs) in autoimmunity has recently been suggested by several authors. Autoantibodies against HSPs have been associated with such autoimmune diseases as systemic Iupus erythematosus, [...]

A significant proportion of relatives of patients with insulin-dependent (type 1) diabetes with high titers of cytoplasmic islet cell autoantibodies (ICAs) do not progress to overt diabetes with up to 8 yr of follow-up. This may reflect that follow-up of such relatives has not been long enough to observe diabetes, that despite expression of identical ICAs, some relatives will not progress to diabetes; or that there is heterogeneity in what is identified as ICA. We identified a subset of ICA that was restricted in its species (not reacting with mouse islets) and cell-type reactivity within islets (Β -cell specific). Only one of eight relatives whose sera had the restricted pattern of reactivity progressed to overt diabetes, and on sequential evaluation, all but the one relative who progressed to diabetes have maintained normal first-phase insulin secretion to intravenous glucose. In contrast, by life-table analysis, 70% of relative expressing nonrestricted ICA became diabetic within 5 yr of follow-up (1 of 8 vs. 16 of 25 diabetic at last follow-up, P < 0.02). Moreover, preliminary data suggest a significant association of the human leukocyte antigen DQB1*0602 allele of DR2 haplotypes with the restricted ICA pattern (4 of 5 DQB1*0602 restricted vs. 0 nonrestricted ICA, P = 0.0006). We propose that expression of a genetically determined restricted ICA pattern confers a markedly lower risk for progression to diabetes. Our studies suggest that relatives with restricted ICA may comprise most [ICA.sup.+] relatives who do not develop diabetes or abnormal first-phase insulin secretion on follow-up of >5 yr and that expression of such autoantibodies may be associated with the 'protective' DQB1*0602 allele. Diabetes 41.347-53, 1992, Our understanding of the pathophysiology of insulin-dependent (type 1) diabetes has increased such that type diabetes is considered a chronic autoimmune disease with a long prodromal phase [1-3]. During this [...]

IA-2 is a 979 aa tyrosine phosphatase-like protein expressed in the secretory granules of pancreatic beta-cells, and an autoantigen in Type 1 diabetes. We have recently reported the pancreatic expression [...]

The IDDM2 susceptibility locus, the insulin gene (INS) minisatellite (VNTR), may influence susceptibility to type 1 diabetes through its effects on INS transcription levels in the thymus. Such effects may [...]

Growing evidence indicates that peripheral proteins, including the IDDM-associated autoantigens insulin, GAD, and IA-2, are expressed in the thymus through the autonomous, ectopic transcription/translation of the corresponding genes. The influence [...]

OBJECTIVE--Of deceased pancreas donors, 3-4% may have autoantibodies (AAb) to pancreatic islet cell antigens; these autoantibodies are well-established markers of type 1 diabetes. We investigated whether donor AAb positivity could [...]