Induction of Tolerance by Exosomes and Short‐Term Immunosuppression in a Fully MHC‐Mismatched Rat Cardiac Allograft Model

• Published in: American journal of transplantation Vol. 6; no. 7; pp. 1541 - 1550
• Main Authors: Pêche, H., Renaudin, K., Beriou, G., Merieau, E., Amigorena, S., Cuturi, M. C.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2006; Blackwell
• Subjects: Animals; Biological and medical sciences; Chronic Disease; Dendritic Cells - cytology; Dendritic Cells - immunology; Exocytosis; Exosomes; Graft Rejection - immunology; Graft Rejection - prevention & control; Graft Survival - drug effects; Graft Survival - immunology; Guanidines - pharmacology; heart allograft; Heart Transplantation - immunology; Histocompatibility Antigens - immunology; Immune Tolerance - drug effects; Immune Tolerance - immunology; immunosuppression; Immunosuppression Therapy; Intracellular Membranes - immunology; Isoantibodies - biosynthesis; Isoantibodies - immunology; Male; Medical sciences; Models, Animal; rat; Rats; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Time Factors; Tissue Donors; tolerance; Transplantation, Homologous; Heart; Short term; Incompatibility; Animal model; Rat; Major histocompatibility system; Rodentia; Transplantation; Homotransplantation; Exosomes; heart allograft; Vertebrata; Immunosuppression; Mammalia; Treatment; Exosome; Surgery; Animal; Immune tolerance; Graft; Circulatory system; tolerance
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2006.01344.x

Exosomes are MHC‐bearing vesicles secreted by a wide array of cells. We have previously shown that donor‐haplotype exosomes from bone marrow dendritic cells (DCs) injected before transplantation significantly prolong heart allograft survival in congenic and fully MHC‐mismatched Lewis rats. Here we show that donor exosomes administered after transplantation are similarly able to prolong allograft survival, however, without inducing tolerance. We therefore tested the effect of exosomes combined with short‐term LF 15‐0195 (LF) treatment, which blocks the maturation of DCs, so that donor‐MHC antigens from exosomes could be presented in a more tolerogenic environment. LF treatment does not preclude the development of a strong antidonor cellular response, and while LF, but not exosome, treatment inhibits the antidonor humoral response and decreases leukocyte graft infiltration, allografts from LF‐treated recipients were either acutely or strongly chronically rejected. Interestingly, when combined with LF treatment, exosomes induced a donor‐specific allograft tolerance characterized by a strong inhibition of the antidonor proliferative response. This donor‐specific tolerance was transferable to naïve allograft recipients. Moreover, exosomes/LF treatment prevented or considerably delayed the appearance of chronic rejection. These results suggest that under LF treatment, presentation of donor‐MHC antigens (from exosomes) can induce regulatory responses that are able to modulate allograft rejection and to induce donor‐specific allograft tolerance. A combination of treatment with LF 15‐0195 (a deoxyspergualine analog) with donor MHC antigens from exosomes induced responses that reduced allograft rejection.