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Priming of recipients by DST induces long-term survival of mismatched allografts in adult rats. Despite these recipients developing inducible T regulatory cells able to transfer long-term graft survival to a secondary host, a state of chronic rejection is also observed. We revisited the molecular donor MHC targets of the cellular response in acute rejection and analyzed the cellular and humoral responses in recipients with long-term graft survival following transplantation. We found three immunodominant peptides, all derived from LEW.1W RT1.D(u) molecules to be involved in acute rejection of grafts from unmodified LEW.1A recipients. Although the direct pathway of allorecognition was reduced in DST-treated recipients, the early CD4+ indirect pathway response to dominant peptides was almost unimpaired. We also detected early and sustained antidonor class I and II antibody subtypes with diffuse C4d deposits on graft vessels. Finally, long-term accepted grafts displayed leukocyte infiltration, endarteritis and fibrosis, which evolved toward vascular narrowing at day 100. Altogether, these data suggest that the chronic graft lesions developed in long-term graft recipients are the result of progressive humoral injury associated with a persisting indirect T helper response. These features may represent a useful model for understanding and manipulating chronic active antibody-mediated rejection in human.

Chronic rejection (CR) is a major cause of long-term graft loss that would be avoided by the induction of tolerance. We previously showed that renal transplant patients with CR have lower numbers of peripheral CD4(+)CD25(high) T cells than operationally tolerant patients, patients with stable graft function and healthy volunteers (HV). We explored here the profile of CD4(+)CD25(high) blood T cells in these patients focusing on their expression of the regulatory T cells (Treg) gene Forkhead Box P3 (FOXP3) and their suppressive function. We show that CR is associated with a decreased number of CD4(+)CD25(high)FOXP3(+)T cells with normal regulatory profile, whereas graft acceptance is associated with CD4(+)CD25(high)FOXP3(+)T cell numbers similar to HVs. These data suggest that Treg numbers, rather than their intrinsic suppressive capacity, may contribute to determining the long-term fate of renal transplants.

We analyzed the role of TNF-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T cells that shares functional properties with CD40L, and its receptor-activating NF-kappaB (RANK) which is mostly expressed on mature dendritic cells, during allogenic responses in vivo using a rodent heart allograft model. TRANCE mRNA was strongly up-regulated in acutely rejected allografts on days 4 and 5 posttransplantation whereas RANK was detected as early as day 1 but did not show further up-regulation during the first week. Immunofluoresence analyses of heart allografts showed that 80 and 100% of TRANCE and RANK-expressing cells were T cells and APCs, respectively. We show for the first time that short-term TRANCE blockade using a mouse RANKIg fusion molecule can significantly prolong heart allograft survival in both rat and mouse models. Similarly, rat heart allografts transduced with a RANKIg encoding recombinant adenovirus exhibited a significant prolongation of survival (14.3 vs 7.6 days, p < 0.0001). However, TRANCE blockade using RANKIg did not appear to inhibit allogeneic T and B cell priming humoral responses against RANKIg. Interestingly, TRANCE blockade induced strong up-regulation of CD40 ligand (CD40L) mRNA in allografts. Combined CD40L and TRANCE blockade resulted in significantly decreased chronic allograft rejection lesions as well as allogeneic humoral responses compared with CD40L blockade alone. We conclude that TRANCE-RANK interactions play an important role during acute allograft rejection and that CD40L-independent allogeneic immune responses can be, at least in part, dependent on the TRANCE pathway of costimulation.

Background: Dendritic cells secrete a population of "antigen-presenting vesicles," called exosomes, expressing functional class I and II major histocompatibility complex (MHC) and co-stimulatory molecules. The subcutaneous administration of syngeneic exosomes expressing tumor antigens has been shown to induce specific antitumor immune responses in vivo. The authors hypothesized that antigen presentation by exosomes, depending on the context of their administration, may induce tolerance rather than immunity., Methods: The authors therefore tested the capacity of exosomes derived from donor bone marrow dendritic cells, given before transplantation, to modulate heart allograft rejection., Results: The authors show here that donor type but not syngeneic exosomes induced a significant prolongation of allograft survival, with a few recipients having long-term graft survival. During the first week after transplantation, allografts from exosome-treated rats displayed a significant decrease in graft-infiltrating leukocytes and in the expression of interferon-gamma mRNA compared with allografts from untreated animals. Moreover, when tested in vitro, spleen CD4+ T cells from exosome-treated recipients displayed a significant decrease in anti-donor responses, suggesting a decrease in anti-donor T-cell responses. However, the authors also found that allogeneic donor-derived exosomes increased anti-donor MHC class II alloantibody production., Conclusions: The authors demonstrate an effect of allogeneic exosomes on the modulation of immune responses in vivo, suggesting that, like donor cells, exosomes can stimulate or regulate antigen-specific immune responses.