Current methods of suppression of allograpft rejection in man employ a variety of agents that are immunologically nonspecific. Manipulation of an organ to reduce the immunogenicity offers no risk to the transplant recipient and is a potential adjunct to nonspecific immunosuppression. Recently ex vivo treatment of clinical bone marrow allografts with monoclonal antibodies has been successful in removing unwanted cells prior to transplantation. The research proposed in this application an attempt to develop a model in which intact organs can be treated with selectivity toxic monoclonal antibodies targeted specifically for passenger leukocytes, including dendritic cells, within the graft. Intact rat pancreases will be placed in an ex vivo normothermic, oxygenated hemoperfusion circuit and monoclonal reagents reactive with passenger leukocytes introduced into the blood perfusate. The primary goal will be to develop optimal conditions for depletion of dendritic cells with monoclonal antibody perfusion, i.e., toxin coupling, in order to determine if the effect of this form of donor organ treatment is marked enough to be considered efficacious for clinical organ transplantation trials. The maximum effect that dendritic cell depletion alone can have on allograft survival in non-immunosuppressed rats will be assessed as will the possible synergism this form of ex-vivo graft immodulation may have with standard low dose immunosuppression of the recipient. A second major aim will be to study the cellular and humoral recipient immune response to dendritic cell depleted rat pancreas allografts to determine the mechanism by which graft survival is prolonged, whether this is due primarily to reduced antigenicity of the graft or whether there is an active recipient regulatory response. Finally, the general applicability of ex vivo perfusion of organs with selectivity toxic monoclonal antibodies will be investigated by applying the techniques developed with rat pancreas transplantation to other rat organ transplants (heart and kidney) as well as solid organ transplants (kidney) in the swine, an animal in which both the vascular endothelium the immune system more closely approximates that of the human. The long-term goal of this laboratory is to develop treatment mechanisms for organ allografting which address the specific antigen disparity between donor and recipient rather than broad nonspecific suppression of the recipient's immune system.
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