Endothelial chimerism and vascular sequestration protect pancreatic islet grafts from antibody-mediated rejection
Chien-Chia Chen, … , Thierry Defrance, Olivier Thaunat
Chien-Chia Chen, … , Thierry Defrance, Olivier Thaunat
Published November 20, 2017
Citation Information: J Clin Invest. 2018;128(1):219-232. https://doi.org/10.1172/JCI93542.
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Research Article Immunology

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

Abstract

Humoral rejection is the most common cause of solid organ transplant failure. Here, we evaluated a cohort of 49 patients who were successfully grafted with allogenic islets and determined that the appearance of donor-specific anti-HLA antibodies (DSAs) did not accelerate the rate of islet graft attrition, suggesting resistance to humoral rejection. Murine DSAs bound to allogeneic targets expressed by islet cells and induced their destruction in vitro; however, passive transfer of the same DSAs did not affect islet graft survival in murine models. Live imaging revealed that DSAs were sequestrated in the circulation of the recipients and failed to reach the endocrine cells of grafted islets. We used murine heart transplantation models to confirm that endothelial cells were the only accessible targets for DSAs, which induced the development of typical microvascular lesions in allogeneic transplants. In contrast, the vasculature of DSA-exposed allogeneic islet grafts was devoid of lesions because sprouting of recipient capillaries reestablished blood flow in grafted islets. Thus, we conclude that endothelial chimerism combined with vascular sequestration of DSAs protects islet grafts from humoral rejection. The reduced immunoglobulin concentrations in the interstitial tissue, confirmed in patients, may have important implications for biotherapies such as vaccines and monoclonal antibodies.

Authors

Chien-Chia Chen, Eric Pouliquen, Alexis Broisat, Francesco Andreata, Maud Racapé, Patrick Bruneval, Laurence Kessler, Mitra Ahmadi, Sandrine Bacot, Carole Saison-Delaplace, Marina Marcaud, Jean-Paul Duong Van Huyen, Alexandre Loupy, Jean Villard, Sandrine Demuylder-Mischler, Thierry Berney, Emmanuel Morelon, Meng-Kun Tsai, Marie-Nathalie Kolopp-Sarda, Alice Koenig, Virginie Mathias, Stéphanie Ducreux, Catherine Ghezzi, Valerie Dubois, Antonino Nicoletti, Thierry Defrance, Olivier Thaunat

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Figure 1

DSA did not affect pancreatic islet graft function.

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DSA did not affect pancreatic islet graft function. Pancreatic islet gra...
Pancreatic islet graft function of 49 patients was assessed every year using the β score (mean ± SD). Linear regression was used to estimate the relation between time and pancreatic islet graft function. (A) The regression line slope indicates the rate of islet graft attrition in the cohort. (B) Nine patients developed de novo donor-specific anti-HLA Abs (DSA), all in the first year after grafting. The rate of pancreatic islet graft attrition was estimated for the 9 patients with DSA (left, DSA+) and the remaining 40 patients without DSA (right, No DSA). (C) Islet graft survival curves for recipients on immunosuppression with (solid line) or without DSA (dashed line) are compared. NS, P = 0.3367, log-rank test.