No association was found with either HLA\DR4 or HLA\DR3 alleles, suggesting that T1D recurrence is usually more common in those with the highest HLA risk. survival according to recipient HLA genotype and donor\recipient HLA\sharing. Table S1A: Clinical, genetic, immunological, and biopsy data for 17 patients with HG\T1DR. Table S1B: Assessment of rejection in 17 patients with hyperglycemia with type 1 diabetes recurrence. Table S1C: Autoantibody status, duration of positivity, and time to events in 17 patients with hyperglycemia with type 1 diabetes recurrence. Table S2: Pre\ and posttransplant autoantibody prevalence. Table S3: Specificity and sensitivity for single and multiple autoantibodies for the development of type 1 diabetes recurrence. Table S4: SLC30A8 locus DNA\typing data for 19 simultaneous pancreasCkidney donorCrecipient pairs. AJT-16-235-s001.pdf (259K) GUID:?52BEE163-3B9A-4EBC-9FFD-215058520047 Abstract Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreasCkidney allografts for T1D recurrence and its risk factors. With long\term follow\up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal screening for T1D\associated autoantibodies recognized autoantibody positivity, quantity of autoantibodies, and autoantibody conversion after transplantation as crucial risk factors. JTE-952 Autoantibodies to the zinc transporter 8 experienced the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donorCrecipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D\predisposing HLA\DR3/DR4 genotype in the recipient and donorCrecipient sharing of HLA\DR alleles, especially HLA\DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant medical center to identify recurrent T1D and may lead to therapeutic improvements. AbbreviationsAZAazathioprineCyAcyclosporineESRDend\stage renal diseaseFKtacrolimusGAD6565\kDa glutamic acid decarboxylase isoformGADAGAD65 autoantibodyHGhyperglycemiaHG\T1DRhyperglycemia with T1D recurrenceHG\PCRhyperglycemia with pancreas chronic rejectionHG\UNDhyperglycemia of undetermined causeHRhazard ratioIA\2insulinoma\associated tyrosine phosphatase\like proteinIA\2AIA\2 autoantibodyMMFmycophenolate mofetilNGTnormal glucose toleranceOKT3anti\CD3, muromonabPPVpositive predictive valueSEMstandard error of the meanSPKsimultaneous pancreasCkidneyT1Dtype 1 diabetesZnT8zinc transporter 8ZnT8AZnT8 autoantibody Introduction Islet autoimmunity causes progressive loss of pancreatic beta cells, leading to impaired insulin secretion and the development of type 1 diabetes (T1D) 1. Several islet autoantigens are targeted by both cellular and humoral responses. Standardized assays measure autoantibodies to insulin, the 65\kDa glutamic acid decarboxylase isoform (GAD65), the insulinoma\associated tyrosine phosphatase\like protein (IA\2), and zinc transporter 8 (ZnT8). Autoantibodies are strong diagnostic and predictive T1D markers, with multiple JTE-952 autoantibodies conferring much higher risk than single autoantibody positivity 2, 3, 4, 5, 6, 7. Simultaneous pancreasCkidney (SPK) transplantation restores insulin secretion and renal function in T1D patients with end\stage renal disease (ESRD) 8. However, recipients may develop posttransplant diabetes, a broad clinical entity with multifactorial etiology including effects of immunosuppression, insulin resistance, weight gain, as well as others 9, 10. With improvements in immunosuppression, acute rejection has become less prevalent and immunological failures are typically ascribed to chronic rejection 8. However, another potential cause of immunological failure is usually T1D recurrence 11, 12. A growing literature suggests that islet autoimmunity may become reactivated and impact the endocrine function of pancreas transplants 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29. In this longitudinal study, we assessed T1D recurrence in a large cohort of 223 SPK recipients. We find that even with the current immunosuppression regimen, T1D recurrence is usually a common cause of posttransplant diabetes, no less frequent than diabetes resulting from pancreas chronic rejection. Further, we define immunological, genetic, and therapeutic risk factors for T1D recurrence. We show that monitoring islet autoimmunity and assessment of other risk factors help predict and correctly diagnose T1D recurrence. Subjects and Methods Subjects We analyzed T1D patients with ESRD who received SPK transplants. All JTE-952 experienced FANCE no detectable c\peptide response to a Sustacal/Boost test (Socit des.