115.5: Impact of GAD65 and IA2 autoantibodies on islet allograft survival
Bibliographic record
Abstract
Introduction: Islet autoantibodies have a role in the pathogenesis of T1D and they serve as markers of beta-cell autoimmunity. Islet transplantation (ITx) shows promise in treating T1D, but the role of islet autoantibodies on graft survival has not been clearly elucidated. We aimed to analyze the effect of GAD65 and IA2 autoantibody positivity on islet graft survival and on to the attainment of insulin independence in T1D ITx recipients. Method: A retrospective cohort of 47 ITx recipients was analyzed from 2000 to 2018 at our institution. Forty-four subjects received islets via intrahepatic portal infusion and 3 subjects into the omentum via laparoscopic approach. Induction immunosuppression consisted of anti-IL2 receptor antibody, anti-TNF and maintenance with dual combination of either sirolimus, tacrolimus or mycophenolate mofetil (Edmonton-like) in 38 subjects (80.9%). Nine (19%) subjects received induction with T-cell depletion and same maintenance. GAD65 and IA2 autoantibodies were analyzed pre-transplant and monthly post-transplant up to graft failure and categorized as follows: persistently negative, persistently positive, or seroconverters. Graft survival (c-peptide >= 0.5ng/mL) between groups was analyzed through U-Mann-Whitney test. Quade’s nonparametric ANCOVA was used for adjustment of confounders. Gain of insulin independence was analyzed by Kaplan-Meier and Log-Rank tests. P value <0.05 was considered statistically significant. Results: Subjects baseline characteristics are shown in table 1ITx recipients with persistent autoantibody negativity (n = 21) had longer graft function (98 [61 – 182] months;) compared to recipients with persistent autoantibody positivity (n = 18), even after adjustment for immunosuppressive induction protocol (P = 0.027).Graft survival time was shorter in the seroconverter group compared to the persistently negative group, but not statistically significant. Subjects persistently positive for GAD65 only (n = 8) had shorter graft survival compared to negative GAD65 only subjects (n = 21; P = 0.016). There was no difference in time of graft survival in subjects according to IA2 only positivity. The proportion of attainment of insulin independence was similar independent of autoantibody status. Conclusion: Persistent autoantibody positivity to GAD65 and/or IA2 reduced the time of islet graft survival in our cohort. The presence of islet autoantibodies, as markers of persistent autoimmunity, may represent an underappreciated contributing factor to the failure of transplanted beta cells. Whether induction with T-cell depletion may lead to improved survival independent of islet autoantibody status could not be evaluated in our cohort. Larger prospective studies are needed to further address the role of islet autoantibody status on islet graft survival. This study was supported by NIH grants R01 DK55347, R01 DK056953, R01 DK025802, DK070460, U42 RR016603, M01RR16587, UL1TR000460; the Miami Clinical and Translational Science Institute (CTSI) from the National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities; the Juvenile Diabetes Research Foundation International 4-200-946, 4-2004-361, 17-2012-361, 3-SRA-2017-347-M-B; the State of Florida; and the Diabetes Research Institute Foundation. The authors are grateful to the members of the cGMP Human Cell Processing Facility, the pre-clinical Human Immunology and Immunogenetics Program, the Clinical Cell Transplant Program (CCTP) at the Diabetes Research Institute (DRI), and the University of Miami CTSI for their support of this work. References: 1. Vendrame F, Pileggi A, Laughlin E, et al. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes. Apr 2010;59(4):947-57. doi:10.2337/db09-0498 2. Froud T, Ricordi C, Baidal DA, et al. Islet transplantation in type 1 diabetes mellitus using cultured islets and steroid-free immunosuppression: Miami experience. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. Aug 2005;5(8):2037-46. doi:10.1111/j.1600-6143.2005.00957.x 3. Burke GW, Vendrame F, Pileggi A, Ciancio G, Reijonen H, Pugliese A. Recurrence of autoimmunity following pancreas transplantation. Curr Diab Rep. Oct 2011;11(5):413-9. doi:10.1007/s11892-011-0206-y
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".