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 January 2, 2018; First 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 Transplantation

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 2

Experimental model recapitulates clinical findings.

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Experimental model recapitulates clinical findings. (A) Schematic of dif...
(A) Schematic of different experimental models of pancreas islet grafting. (B) View of operative site exposing recipient portal vein (white arrow), in which purified islets were injected. (C) Left: representative finding of immunofluorescence analyses performed 50 days after intraportal injection of syngeneic islets. Right: magnification of the white square shown on thumbnail. Scale bars: 500 μm (left); 100 μm (right). (D) Left: blood glucose level was measured twice weekly in WT C57BL/6 recipients. Evolution of glycemia (mean ± SD) is shown for C57BL/6 (syngeneic, gray; n = 2) and CBA (allogeneic, red; n = 5) grafts. Islet graft loss was defined by fasting glycemia of more than 350 mg/dl (dashed line). Right: survival curves for C57BL/6 (syngeneic, gray; n = 2) and CBA (allogeneic, red; n = 5) grafts. ***P = 0.0008, log-rank test. (E) Flow cytometry cross-match technique was used to quantify circulating DSA generated by WT C57BL/6 recipients in response to intraportal CBA islet graft. Individual values measured at peak of humoral alloimmune response of 2 independent experiments (white and blue symbols) are shown. The same technique was applied to monitor peak and trough levels of circulating DSA 30 days after starting passive i.v. transfer of immune serum. (F) Blood glucose levels were measured twice weekly in C57BL/6 RAG2 KO recipients of an intraportal CBA islet graft. Evolution of glycemia (mean ± SD) is shown for recipients transferred (green; n = 4) or not (black; n = 5) with immune serum. (G) H-2k expression was assessed on CBA (H-2k, upper row) and C57BL/6 (H-2b, lower row) freshly isolated pancreatic islets. Scale bar: 100 μm. (H and I) Cytotoxic potential of immune serum was evaluated in vitro using complement-dependent cytotoxic assay (mean ± SD) on CBA splenocytes (H) and CBA pancreatic islet cell suspension (I). ***P < 0.001, 1-way ANOVA.