Development of the acquired immune response is dependent on the signaling of CD40 by its ligand, CD154. These molecules govern both the magnitude and quality of humoral- and cell-mediated immunity. A litany of studies have conclusively documented that blockade of this ligand-receptor pair can prevent, and also intervene in, the progression of antibody- and cell-mediated autoimmune diseases, and can instill long-lived allogeneic and xenogeneic graft tolerance. Many effector mechanisms of inflammation are abolished as a result of CD154 blockade, but we are now beginning to understand that CD154 blockade may, in some instances, engender long-lived, antigen-specific tolerance. In the context of transplantation tolerance, we present a hypothesis that alpha CD154 blockade is most effective at inducing long-lived allospecific tolerance if anergy and regulation can be elicited prior to the onslaught of inflammation that is induced by grafting (preemptive tolerance). This facet of alpha CD154-induced tolerance appears to co-opt the normal processes of peripheral tolerance induced by immature DCs and can be exploited to induce long-lived antigen-specific tolerance. The underlying science and the prospects for inducing long-lived antigen-specific tolerance in a model of allograft tolerance through CD154 blockade are presented and discussed.

Development of allograft rejection continues to be the major determinant of morbidity and mortality post-lung transplantation. We have recently demonstrated that a population of donor-derived mesenchymal stem cells are present in human lung allografts and can be isolated and expanded ex vivo. In this study, we investigated the impact of lung resident mesenchymal stem cells (LR-MSCs), derived from allografts of human lung transplant recipients, on T cell activation in vitro. Similar to bone marrow derived MSCs, LR-MSCs did not express MHC II nor the co-stimulatory molecules CD80 or CD86. In vitro, LR-MSCs profoundly suppressed the proliferative capacity of T cells in response to a mitogenic or an allogeneic stimulus. The immunosuppressive function of LR-MSCs was also noted in absence of direct cell contact, indicating that LR-MSCs mediated their effect predominantly via a soluble mediator. LR-MSCs isolated from lung transplant recipients demonstrated PGE2 secretion at baseline (385 ± 375 pg/ml) which increased in response to IL-1β (1149 ± 1081 pg/ml). Addition of prostaglandin synthesis inhibitors (indomethacin and NS-398) substantially abrogated LR-MSC-mediated immunosuppression, indicating that PGE2 may be one of the major soluble mediators impacting T cell activity. This is the first report to demonstrate that human tissue-derived MSCs isolated from an allogeneic environment, have the potential to mediate immunological responses in vitro.

Induction of transplantation tolerance to alloantigens without general immunosuppression remains an enduring challenge. Injecting a donor-specific transfusion (DST) of spleen cells together with blocking ␣CD154 antibody prior to graft transplantation is an effective way to induce long-lived graft acceptance. Using a novel T-cell receptor (TCR) transgenic (Tg) model of CD4 ؉ T-cell-mediated rejection, this study sheds new insights into the cellular basis for enhanced graft survival induced by DST and ␣CD154. The study shows that DST and ␣CD154 induce an early, robust, abortive expansion of the Tg T cells that results in profound anergy. This is contrasted with the more delayed, regional, productive response elicited by an allogeneic graft. Studies show that the induction of tolerance to the allograft induced by DST is mediated by indirect presentation by host antigen-presenting cells. Based on these observations, we conclude that DST and ␣CD154 preemptively tolerize the alloreactive T-cell compartment to prohibit subsequent responses to the immunogenic allograft.