Alloantibody and Autoantibody Monitoring Predicts Islet Transplantation Outcome in Human Type 1 Diabetes

Abstract

Long-term clinical outcome of islet transplantation is hampered by the rejection and recurrence of autoimmunity. Accurate monitoring may allow for early detection and treatment of these potentially compromising immune events. Islet transplant outcome was analyzed in 59 consecutive pancreatic islet recipients in whom baseline and de novo posttransplant autoantibodies (GAD antibody, insulinoma-associated protein 2 antigen, zinc transporter type 8 antigen) and donor-specific alloantibodies (DSA) were quantified. Thirty-nine recipients (66%) showed DSA or autoantibody increases (de novo expression or titer increase) after islet transplantation. Recipients who had a posttransplant antibody increase showed similar initial performance but significantly lower graft survival than patients without an increase (islet autoantibodies P < 0.001, DSA P < 0.001). Posttransplant DSA or autoantibody increases were associated with HLA-DR mismatches (P = 0.008), induction with antithymocyte globulin (P = 0.0001), and pretransplant panel reactive alloantibody >15% in either class I or class II (P = 0.024) as independent risk factors and with rapamycin as protective (P = 0.006) against antibody increases. DSA or autoantibody increases after islet transplantation are important prognostic markers, and their identification could potentially lead to improved islet cell transplant outcomes.

Effect of Diabetes on Survival after Resection of Pancreatic Adenocarcinoma. A Prospective, Observational Study

“…C-peptide (AIA-PACK C-Peptide; Tosoh) was measured at baseline and prior to hospital discharge in 135 and 67 out of 364 patients, respectively. Autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), insulin (IAA) and zinc transporter 8 antigen (ZnT8A) were measured in 300 out of 364 patients by radio binding and immunoprecipitation assays as previously described [32]. Insulin resistance and β-cell function were estimated using the HOMA2 model (available from www.OCDEM.ox.ac.uk), following the recommendations for its appropriate use [33].…”

Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection

“…Whether DSA monitoring could guide the initiation of rejection treatment in islet recipients, however, remains to be tested because (i) the T cell subset providing help to B cells is not the one responsible for T cell-mediated rejection and the sensitivity to immunosuppressive drugs of these 2 subsets might be different and (ii) islet graft destruction in the clinic can also be mediated by the recurrence of type I diabetes, i.e., by autoreactive T cells, which are not involved in DSA generation. Interestingly, a recent clinical study has established that monitoring the fluctuations of DSA and autoantibody titers reliably identified islet graft recipients with a higher risk for rapid graft failure (14).…”

“…As with solid organ recipients, islet allograft recipients also develop DSA (11)(12)(13); however, the impact of DSA on islet graft function remains puzzling. Indeed, the few studies that have investigated whether DSA generation correlated with decreased islet graft survival have reached opposite conclusions (11)(12)(13)(14).…”

“…Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection Chien-Chia Chen, 1 Eric Pouliquen, 2 Alexis Broisat, 3 Francesco Andreata, 4 Maud Racapé, 5 Patrick Bruneval, 5 Laurence Kessler, 6,7 Mitra Ahmadi, 3 Sandrine Bacot, 3 Carole Saison-Delaplace, 1,2 Marina Marcaud, 2 Jean-Paul Duong Van Huyen, 5 Alexandre Loupy, 5,8 Jean Villard, 9 Sandrine Demuylder-Mischler, 10 Thierry Berney, 7,10 Emmanuel Morelon, 1,2,7,11 Meng-Kun Tsai, 12 Marie-Nathalie Kolopp-Sarda, 13 Alice Koenig, 1 Virginie Mathias, 14 Stéphanie Ducreux, 14 Catherine Ghezzi, 3 Valerie Dubois, 14 Antonino Nicoletti, 4 Thierry Defrance, 1 and Olivier Thaunat intensity [MFI]: 2,860; range: 700-8,900) in the first year after grafting, mainly against mismatched HLA II molecules (6/9, 66%). Interestingly, the rate of islet graft attrition of the 9 recipients with DSA was remarkably similar to the rate of islet graft attrition of patients without DSA (DSA vs. no DSA: -0.40 vs.…”

mTOR Inhibition Suppresses Posttransplant Alloantibody Production Through Direct Inhibition of Alloprimed B Cells and Sparing of CD8+ Antibody-Suppressing T cells

“…De novo DSA are particularly detrimental to cellular transplants, which have relatively smaller parenchymal cell mass and increased exposure to circulating antibodies 5 . Development of humoral alloimmunity after islet 6-8 and hepatocyte transplant 9 is associated with deterioration of graft function and is a barrier to long-term graft survival. Current therapies available for treatment of AMR include removal of deleterious alloantibodies, targeting IgG + cells, cellular depletion, or a combination of these strategies 10,11 .…”