The induction of specific tolerance to allografted tissues is the ultimate aim in transplantation. The pursuit of this goal has produced powerful non-specific immunosuppressants, e.g., azathioprine, prednisone, and cyclosporine A, with a number of important side effects, i.e., life-long immunosuppression with risks of opportunistic infections and the development of de novo malignant neoplasms. Recently, strategies to alter the immunogenicity of transplanted tissues have emerged. These treatments aim to eliminate the Ia-bearing antigen presenting cells (APCS) , or dendritic cells (DCs) thought to be responsible for the initiation of rejection. Little progress has been made in decreasing immunogenicity in solid vascularized allografts. Thus the current and long-term focus of our research activity is to develop methods to alter allograft immunogenicity and so prolong graft survival for vascularized organs. Initially, we would aim to demonstrate that anti-Ia antibodies and immunotoxins bind to isolated DCS, and impair their function in vitro. Isolated mouse hearts or organ allograft donors will then be treated with antibody or immunotoxin, and binding to DCs confirmed histologically. The perfused or pretreated allograft will be transplanted into syngeneic and allogenic recipients of varying histoincompatibility, initially without immunosuppression, to determine the deleterious effects of donor or isolated allograft pretreatment with the agents to be tested, as well as their ability to influence immunogenicity and prolong allograft survival. Rejection will be monitored using clinical and histological criteria. The need for adjuvant perioperative or long-term recipient immunosuppressive therapy will be assessed. Specific tolerance will be determined by the ability of the tolerant recipient to reject third party grafts, and for rejection to be provoked by an injection of donor DCs. Should anti-Ia antibody or immunotoxin compounds prove successful in the alteration of graft immunogenicity, with prolongation of allograft survival over that of control solutions, we would plan to pursue this work in larger outbred animal models, and ultimately in man. Thus, specific tolerance in the absence of maintenance immunosuppression might become a clinical reality.
| Pollak, R; Blanchard, J M (2000) Organ donor or graft pretreatment to prolong allograft survival: lessons learned in the murine model. Transplantation 69:2432-9 |
