Our general aim is to induce specific transplantation tolerance in human cadaver kidney transplant recipients. In our current protocol, patients are treated with total lymphoid irradiation (TLI) before transplantation, six doses of rabbit anti-human thymocyte globulin immediately after transplantation, and 10 mg of prednisone per day as the sole maintenance immunosuppressive regimen. In the absence of rejection episodes during the first eight months, the dose of prednisone is tapered such that no immunosuppressive drugs are given after one year. Thus far, seven out of seven transplant recipients in this treatment protocol have had no detectable rejection episodes and two have discontinued immunosuppressive drugs at the one year point. Therefore, our goals for the proposed grant period are as follows: 1) determine whether the lack of rejection episodes and ability to remove all immunosuppressive drugs is reproducible in a large series of patients (40); 2) determine whether the patients off drugs are specifically unresponsive (tolerant) to donor antigens as judged by the in vitro MLR and CML assays; 3) determine the cellular basis of tolerance by examining the reactivity of the purified helper T cell subset and cytotoxic T cell precursor subset obtained by the """"""""panning"""""""" procedure; 4) search for antigen-specific suppressor cells and determine their surface phenotype using immunofluorescent staining and analysis on the FACS; 5) determine the kinetics of impairment of immunity to Epstein-Barr virus infected cells; 6) determine the cellular basis of impairment using purified T cell subsets; 7) substitute a mixture of monoclonal anti-T cell antibodies for ATG in the TAP protoco1; 8) determine whether tolerance to rabbit ATG develops after TLI and 9) compare the efficacy, side effects and cost of the TAP protocol to that of conventional therapy (prednisone and azathioprine) and to cyclosporine.
| Strober, S; Dhillon, M; Schubert, M et al. (1989) Acquired immune tolerance to cadaveric renal allografts. A study of three patients treated with total lymphoid irradiation. N Engl J Med 321:28-33 |
| Saper, V; Chow, D; Engleman, E D et al. (1988) Clinical and immunological studies of cadaveric renal transplant recipients given total-lymphoid irradiation and maintained on low-dose prednisone. Transplantation 45:540-6 |
| Chow, D; Saper, V; Strober, S (1987) Renal transplant patients treated with total lymphoid irradiation show specific unresponsiveness to donor antigens the mixed leukocyte reaction (MLR). J Immunol 138:3746-50 |
