Autoantibody Response to Islet Transplantation in Type 1 Diabetes

Islet allotransplantation into patients with autoimmune type 1 diabetes represents a reexposure to autoantigen. Here, measurement of antibodies to GAD and IA-2 autoantigens before and after islet transplantation in 36 patients (33 receiving islet plus kidney grafts with cyclosporin and steroid-based immunosuppression, and 3 receiving solitary islet transplants with mycophenolate but cyclosporin-free immunosuppression) demonstrated marked rises in GAD antibodies within 7 days posttransplantation in 5 patients (3 receiving islet after kidney transplants, and 2 receiving solitary islet transplants) and within 30 days in the third patient receiving solitary islet transplantation. GAD antibodies were of the IgG1 subclass, against major autoantigenic epitopes, and in cases of islet after kidney transplants, the responses were short-lived and not accompanied by HLA antibodies. Two of these patients had subsequent marked rises of IA-2 antibodies, and an additional patient had a marked rise in IgM-GAD antibodies 3 years after transplantation. Insulin independence was not achieved in patients with autoantibody elevations and was significantly less frequent in these patients. These data are consistent with a reactivation of autoimmunity that may be dependent on immunosuppression therapy and is associated with impaired graft function

Recurrence of Type 1 Diabetes After Simultaneous Pancreas-Kidney Transplantation, Despite Immunosuppression, Is Associated With Autoantibodies and Pathogenic Autoreactive CD4 T-Cells

ObjectiveTo investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients.Research design and methodsWe monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays.ResultsAutoantibodies 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 approximately 1 year from hyperglycemia recurrence and revealed beta-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 beta-cell loss in mice receiving autoreactive T-cells but not control T-cells.ConclusionsWe demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used

Cellular Islet Autoimmunity Associates with Clinical Outcome of Islet Cell Transplantation

Islet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin-independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Twenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters--including time until insulin independence, insulin independence at one year, and C-peptide levels over one year--remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.In this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Clinicaltrials.gov NCT00623610

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

Background: Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. Approach: An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence-Based Laboratory Medicine Committee of the American Association for Clinical Chemistry jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. Content: In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A$_{1c}$ (HbA$_{1c}$) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of HbA$_{1c}$. The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. Summary: The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended

Olimpia Fulvia Morata (1526-1555): Eloquent Magistra

A short biographical chapter on Olimpia Fulvia Morata and a translation of an excerpt of a work of hers

The Civil Magistrates of Geneva and the Placement of Pastors in France on the Eve of the First War of Religion (1562)

This article analyses excerpts from letters sent by French Reformed congregations and politically-engaged Calvinist laymen in 1562. In these dispatches, the churches, lay notables, and local magistrates of Montpellier, Grenoble, Gap, Nîmes, Issoire and Rouen requested pastors to Geneva or thanked the town’s authorities for ministers previously sent there. However, these six letters were not addressed to the Venerable Company of Pastors, but specifically to the syndics and Small Council of Geneva. While the role of the Company in the sending of Geneva-trained pastors to France on the eve of the Wars of Religion is known, the participation of the Republic of Geneva’s political authorities in these activities needs more scholarly attention. This article seeks to offer a discussion of this topic through analysis of correspondence and other sources held in the Archives d’État de Genève

The Monsters of Gaul: The Implications of the Concordat of Bologna (1516) for French Episcopal Elections

Questo articolo riguarda le implicazioni dell'attuazione del Concordato di Bologna (1516) per la collazione e l'elezione ai benefici concistoriali, e in particolare l'elezione dei vescovi, nel regno di Francia. Il Concordato, emanato dal Concilio Lateranense V, prevedeva le presentazioni reali di candidati all'approvazione della Santa Sede. Sostituendo la cosiddetta Pragmatica Sanzione di Bourges (1438), rappresent\uf2 uno spartiacque nell'evoluzione dell'ideologia gallicana. Infatti, poich\ue9 la Sanzione era entrata nei decreti del Concilio di Basilea, la sua abolizione richiedeva che il peso dell'autorit\ue0 conciliare fosse saldamente radicato in termini canonici. Alla fine, l'eredit\ue0 conciliare dell'ideologia gallicana fu profondamente modificata dal nuovo regime avviato dal Concordato e gli effetti duraturi di quest'ultimo e le implicazioni per l'ancien regime Chiesa di Francia furono importanti.This article is about the implications of the implementation of the Concordat of Bologna (1516) for the collation of, and election to, consistorial benefices, and in particular the election of bishops, in the kingdom of France. The Concordat, issued by the Fifth Lateran Council, instated royal presentments of candidates for the Holy See to approve. As it replaced the so-called Pragmatic Sanction of Bourges (1438), it represented a watershed in the evolution of the Gallican ideology. Indeed, since the Sanction had made its way into the decrees of the Council of Basel, its abolition required the weight of conciliar authority to be firmly grounded in canonical terms. Eventually, the conciliar heritage of the Gallican ideology was profoundly modified by the new regime initiated by the Concordat and the latter's long-lasting effects on, and implications for, the ancien regime Church of France were momentous

Afterword

Afterword to the volume "War and Peace in the Religious Conflicts of the Long Sixteenth Century