The induction of alloantigen-specific unresponsiveness remains an elusive goal in organ transplantation. Here we identify plasmacytoid dendritic cells (pDCs) as phagocytic antigen-presenting cells essential for tolerance to vascularized cardiac allografts. Tolerizing pDCs acquired alloantigen in the allograft and then moved through the blood to home to peripheral lymph nodes. In the lymph node, alloantigen-presenting pDCs induced the generation of CCR4+ CD4+ CD25+ Foxp3+ regulatory T cells (Treg cells). Depletion of pDCs or prevention of pDC lymph node homing inhibited peripheral Treg cell development and tolerance induction, whereas adoptive transfer of tolerized pDCs induced Treg cell development and prolonged graft survival. Thus, alloantigen-presenting pDCs home to the lymph nodes in tolerogenic conditions, where they mediate alloantigen-specific Treg cell development and allograft tolerance.

One of the main unresolved questions in solid organ transplantation is how to establish indefinite graft survival that is free from long-term treatment with immunosuppressive drugs and chronic rejection (i.e., the establishment of tolerance). The failure to achieve this goal may be related to the difficulty in identifying the phenotype and function of the cell subsets that participate in the induction of tolerance. To address this issue, we investigated the suppressive roles of recipient myeloid cells that may be manipulated to induce tolerance to transplanted hearts in mice. Using depleting mAbs, clodronate-loaded liposomes, and transgenic mice specific for depletion of CD11c + , CD11b + , or CD115 + cells, we identified a tolerogenic role for CD11b + CD115 + Gr1 + monocytes during the induction of tolerance by costimulatory blockade with CD40L-specific mAb. Early after transplantation, Gr1 + monocytes migrated from the bone marrow into the transplanted organ, where they prevented the initiation of adaptive immune responses that lead to allograft rejection and participated in the development of Tregs. Our results suggest that mobilization of bone marrow CD11b + CD115 + Gr1 + monocytes under sterile inflammatory conditions mediates the induction of indefinite allograft survival. We propose that manipulating the common bone marrow monocyte progenitor could be a useful clinical therapeutic approach for inducing transplantation tolerance.

Ischemia/reperfusion injury (IRI) is a multi-factorial antigen-independent inflammatory condition that pro-Ischemia/reperfusion injury (IRI) is a multi-factorial antigenindependent inflammatory condition that has both immediate and long-term effects on the allograft. According to the classic understanding, acute ischemia leads to the activation of the endothelium with an increase in permeability and expression of many adhesion molecules. These molecules are crucial for the recruitment and infiltration of effector cells into the post-ischemic tissue. Transcription factors such as nuclear factor-jB (NF-jB) are induced and activated, leading to enhanced expression of inflammatory genes. The endothelial cells lose their anti-adhesive properties and develop a thrombogenic and adhesive surface. On reperfusion, the ischemia-primed endothelial cells are prone to leukocyte and platelet adhesion, further increasing endothelial cell permeability and cell activation. The adherent leukocytes release reactive oxygen species (ROS) and a variety of cytokines, enhancing the inflammatory reaction. Subsequently, the leukocytes transmigrate and enter the subendothelial space. IRI involves loss of energy, derangement of ionic homeostasis and cell death. This initial cascade of events has a profound effect on early graft function.Recently, the acute phase of IRI has been increasingly viewed as part of the innate immune response to the lack of vascular perfusion and oxygen. It has been long established that IRI will have lasting effects on the graft, as suggested by both clinical and experimental data. Recognition of novel molecular pathways as well as new insights in to the mechanisms of previously well-defined mediators of IRI, have established links among innate immunity, adaptive immune responses and organ regeneration, and thus long-term graft function (Figure 1). This review approaches these novel aspects of IRI in the context of solid organ transplantation, primarily concentrating on new observations with kidney, liver and heart allografts.

No abstract