PRECLINICAL STUDIES OF ALLOGRAFT TOLERANCE IN RHESUS-MONKEYS - A NOVEL ANTI-CD3-IMMUNOTOXIN GIVEN PERITRANSPLANT WITH DONOR BONE-MARROW INDUCES OPERATIONAL TOLERANCE TO KIDNEY ALLOGRAFTS

A major challenge in clinical transplantation today is to design a pra ctical and effective protocol for tolerance induction compatible with cadaver organ transplantation. A preclinical rhesus monkey kidney allo graft model using immediate peritransplant anti-CD3 immunotoxin (anti- CD3-IT) and donor bone marrow (DBM) is shown here to induce operationa l tolerance with prolonged graft survival in the absence of chronic im munosuppressive drugs. Bone marrow harvested from the kidney donor was depleted of mature alloantigen-presenting cells and T cells by removi ng DRbright cells and CD3(bright) cells, respectively. In outbred, maj or histocompatibility complex-incompatible donor-recipient pairs with high pretransplant mixed lymphocyte response and cytotoxic T lymphocyt e precursor activity, four of six allografts survived for periods of 1 20 days to >1.5 years. Graft acceptance after peritransplant treatment followed robust elimination of both peripheral blood T cells and lymp h node T cells. In most recipients given anti-CD3-IT and DBM infusion, anti-donor immunoglobulin G responses were completely inhibited. Micr ochimerism was observed in all recipients studied, including those not given DBM, but levels of microchimerism did not correlate with graft survival. Anti-CD3-IT induction in combination with modified DBM proto cols such as the depletion of mature T cells and DRbright antigen-pres enting cells may offer new opportunities to improve clinical tolerance protocols beyond those attempted in the clinic to date. Overall, thes e results with anti-CD3-IT show promise for development of cadaver tra nsplant tolerance induction.