During the past 15 years, therapies based on administration of donor- or recipient-derived immunosuppressive (IS) / tolerogenic dendritic cells (DC), alone or in combination with immunosuppressants, have been used in murine models to prolong allograft survival. However, the mechanism of action of such therapeutic DC in vivo are practically unknown, since most studies have analyzed their effects in vitro, or in ex vivo assays after transplantation. Aim: Since IS-DC injected i.v are short-lived and transfer donor-Ag to recipients DC, we investigated the role of recipients DC in the beneficial effect of IS-DC therapies, by depleting the recipients conventional DC (cDC) by the time of the DC therapy. Methods: Bone marrow-derived maturation-resistant DC were used as prototypic IS-DC. CD11c-Diphtheria Toxin (DT) Receptor (DTR)-B6 (or BALB/c) chimeras were depleted of cDC by DT-injection 1 day before and 1, 3 and 5 days after IS-DC administration. In some experiments, CD11c-DTR-B6 chimeras were i.v. injected with CFSE-labeled 2C CD8 and 1H3.1 CD4 (TCRtg) allo-reactive T cells. Results: I.v. administration of donor (BALB/c) IS-DC to CD11c-DTR-B6 chimeras 7 days prior to transplantation, in combination with a short-course of rapamycin (RAPA), prolonged (p<0.001) survival of BALB/c cardiac grafts (MST=50±8 d). By contrast, when the chimeras were depleted by DT-injection of recipients cDC by the time of IS-DC therapy, the allograft survival was similar to that of recipients treated with RAPA alone (21±2 vs. 25±7 d, respectively). Similar findings were detected in the absence of RAPA, and in different strain combination (B6 ⇒ CD11c-DTR-BALB/c chimeras). In vivo experiments confirmed that the i.v. administered IS-DC live 1-3 days in the recipient, and that recipients quiescent cDC of the spleen present in a tolerogenic fashion donor allo-Ag acquired from the injected IS-DC to CD8 and CD4 TCRtg T cells. Conclusions: Our results indicate that i.v. injected donor or recipient IS-DC mediate their donor-specific immunosuppressive effects, not by themselves as classically accepted, but through recipients quiescent cDC located in graft-draining lymphoid organs.
To cite this abstract in AMA style:Wang Z, Divito S, Rojas-Canales D, Shufesky W, Sumpter T, Larregina A, Morelli A. Recipient’s Conventional Dendritic Cells (DC) Are the Mediators of the Beneficial Effects of Immunosuppressive DC-Based Therapies in Cardiac Transplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/recipients-conventional-dendritic-cells-dc-are-the-mediators-of-the-beneficial-effects-of-immunosuppressive-dc-based-therapies-in-cardiac-transplantation/. Accessed December 1, 2020.
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