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 5

Endothelial chimerism in grafted islets.

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Endothelial chimerism in grafted islets. Each panel shows representative...
Each panel shows representative findings of 2 independent experiments. (A) C57BL/6 (gray) or CBA (red) heart was transplanted into C57BL/6 RAG2 KO recipients. Four weeks after transplantation, single-cell suspension was prepared by enzymatic digestion of the transplant and H-2k expression of CD45–CD31+ endothelial cells were assessed by flow cytometry. (B) The same approach was used to analyze H-2k expression of endothelial cells of freshly isolated C57BL/6 (gray) or CBA (red) islets. (C) Subcapsular implantation made the retrieval of grafted islets possible: operative views of islet graft before (left, white dashed circle) and during (right, white arrow) microdissection. (D and E) C57BL/6 islets were transplanted to C57BL/6 RAG2 KO recipients (gray), and CBA islets were grafted either to CBA (dark red) or C57BL/6 RAG2 KO recipients (light red). (D) Grafted islets were microdissected at indicated time points, and the proportion of endothelial cells of CBA origin (i.e., H-2k positive) was assessed by flow cytometry. (E) The proportion of endocrine cells (CD45–CD31–) of CBA origin (H-2k positive) was assessed in C57BL/6 (gray) and CBA (red) islets 6 weeks after grafting in C57BL/6 RAG2 KO recipient. (F) Blood glucose levels were measured twice weekly in C57BL/6 RAG2 KO mice grafted under the kidney capsule with CBA pancreatic islets. Evolution of glycemia (mean ± SD) is shown for recipients transferred with DSA alone (HB13 mAb, pink; n = 4) or in association with poly I:C (dark red; n = 3). Nephrectomy was performed at 120 days to confirm grafted islet function.