A successful transplantation requires the acceptance of the graft by the immune system. The activation of Dendritic cells (DCs) occurring during the transplantation procedure is an important cause of immunization against the graft and therefore of its rejection. A suppression of DC activation that could divert them from stimulating the immune response against the graft, it would allow induction of T cell tolerance and strongly improve the chances of success of any graft. We have recently discovered that the ligation of the Complement Receptor 3 (CR3), which is present on myeloid DCs and is normally bound by opsonized apoptotic cells, with a monoclonal Ab suppresses the ability of murine DCs to express pro-inflammatory cytokines such as IL-12 and TNFa and stimulate CD4 and CD8 T cells. Furthermore, CR3 ligation of DCs can bias their expression of cytokines toward a tolerogenic profile dominated by TGF-beta production and leading to T cell tolerance. In this exploratory project, we propose to determine the effects of the agonistic ligation of CR3 in preventing and suppressing graft rejection in experimental models of solid organ transplantation and begin to understand the underlying mechanisms. In particular, we propose in Aim 1 to determine the effects of CR3-ligation on the rejection of skin grafts. We will investigate the effects of the infusion of agonist anti-CR3 Abs in the acceptance of skin grafts through a single minor histocompatibility antigen (HY) barrier in a spontaneous model and in one induced by TLR stimulation.
In Aim 2, we will determine how CR3 ligation affects DC functions and the subsequent T cell responses against the skin grafts and through which cellular mechanisms. We will explore four possible T cells responses that have been implicated in the induction of tolerance in other systems graft tolerization: 1) inhibition of effector T cell response;2) class switch;3) deletion and anergy;and 4) T regulatory cell induction. This application aims to determine whether and how anti-CR3 therapy can be a new Ab therapy in the induction of tolerance in transplantation. Our fundamental goal is to generate a therapeutic protocol that can quickly and directly be applied first to larger animals and eventually to transplantation patients, in combination with the present immunosuppressive regime and, ultimately, in a novel tolerogenic regime.
We have recently discovered that the ligation of Complement Receptor 3 by a monoclonal antibody suppresses the immunogenic functions of dendritic cells. This exploratory project will test the role of this novel immunosuppressive agent in preventing and suppressing graft rejection in experimental models of solid organ transplantation. Our long-term goal is to discover biologic factors able to induce a stable tolerogenic function in dendritic cells that can be used in immunotherapy of conditions, such as transplantation and autoimmunity, in which excessive and inappropriate immune responses are causing morbidity and mortality.
