Clinical immunosuppression for organ transplantation continues to be nonspecific in the sense that it does not differentiate among the responses to individual antigens. Because of this fact, beneficial and life-protecting immune responses are suppressed by the same regimens that suppress rejection. The main goal of the proposed research is to develop a method of suppressing the immune response to skin, renal and cardiac allografts with minimal concomitant suppression of other (protective) immune responses. We propose to combine donor alloantigen with a cytotoxic agent, the alpha emitting isotope lead-212, and use the combination to treat graft recipients prior to transplantation. The Alpha particles emitted by decay of lead-212 have ranges in soft tissue of 60-90 um. Thus, there would be a small sphere of intense radiation around each all antigen-212 complex that might injure or destroy specific antigen recognition cells of the recipient as they come into sustained contact with the radioactive alloantigen. We will absorb lead-212 onto cation exchange resin beads (1-6 um diameter) and then allow donor strain macrophages to ingest the lead coated beads. Radioactive donor strain macrophages will then be injected into the recipient. Initially, we will determine the optimal conditions for maximum reduction of specific precursors of helper and cytolytic T lymphocytes by lead-212 treatment. We will then begin to treat murine recipients of skin and cardiac allografts, and finally proceed to allografting in larger outbred animals (heart transplant in the rabbit and renal transplant in the dog). This general approach to specific immunosuppression may also be an effective way of deleting memory cells in presensitized recipients. If so, it could offer enourmous potential benefit to highly sensitized dialysis patients, many of whom must wait for years to receive a transplant, if they receive one at all.
