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 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 4

Histological evaluation of DSA-mediated lesions.

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Histological evaluation of DSA-mediated lesions. C57BL/6 RAG2 KO mice we...
C57BL/6 RAG2 KO mice were used as recipients of either a CBA subcapsular islet graft or a CBA heart transplant. HB13 or PBS was infused i.v. twice weekly into recipient mice for 30 days, and grafts/transplants were harvested for histological analysis. (A) Representative findings of H&E stain are shown for the 4 experimental groups: (i) Heart + PBS, n = 13; (ii) Heart + DSA; (iii) Islet + PBS, n = 11; and (iv) Islet + DSA, n = 11. Scale bars: 50 μm. (B) Immunohistochemistry was performed to evaluate the morphology of microvasculature (CD31), classical complement pathway activation (C4d), and macrophage infiltration (CD68). Representative findings are shown for the 4 experimental groups. Scale bars: 50 μm. A trained pathologist graded intensity of each elementary lesion on a semiquantitative scale (score 1–5). Mean ± SD of the 4 experimental groups. *P < 0.05; **P < 0.01; ****P < 0.0001, 2-way ANOVA. (C) Transmission electron microscopy was used to assess the ultrastructural integrity of endothelial cells of CBA heart transplants (upper and middle rows) and CBA islet grafts (lower row) 30 days after the beginning of PBS (upper row) or HB13 transfer (middle and lower rows). Black arrowheads indicate swollen endothelial cells. P, adhesion of platelets. Scale bars: 3 μm.