Donor specific unresponsiveness to organ allografts remains an elusive goal in clinical cadaveric transplantation, as most successful experimental protocols for the production of antigen specific immunosuppression require lengthy recipient pretreatment. The use of an induction course of anti-lymphocyte serum (ALS) beginning at the time of transplantation, followed by the transfusion to the recipient of donor specific bone marrow, has been shown to induce prolonged allograft survival and is applicable in clinical cadaveric transplantation. Our preliminary data in humans suggest that the transfusion of cryopreserved cadaver donor bone marrow following a short course of ALS is safe and does not induce graft versus host disease or allograft rejection. 36 patients have received a cadaveric renal allograft and donor bone marrow of which 33 were discharged from the hospital with functioning kidney transplants. 3 grafts have failed. 13 patients were withdrawn entirely from prednisone immunosuppression (follow-up 2-17 months). The primary purpose of this study is to further define the optimal use of donor bone marrow as a specific antigen in the induction of transplantation tolerance. The clinical trial involving cadaveric renal transplantation will be continued. Cellular immune responsiveness will be monitored by serial one-way mixed lymphocyte cultures (MLC) and CML against donor lymph node and spleen cells. The development of micro-chimerism may be an important component of the tolerogenic process and will be examined by restriction fragment length polymorphism analysis of pre and post transplant lymphocyte DNA. Non-specific immunosuppressive drugs are known to alter the development of tolerance. A canine model will be established to test the interaction with ALS/donor marrow and commonly used drugs in clinical transplantation such as cyclosporin A, azathioprine and prednisone. The optimal number of marrow cells, timing of infusion, multiple infusions and the precise cell type responsible for prolongation of allograft survival will be investigated in the canine. Information gained from the canine experiments will be used to modify and improve human immunosuppressive protocols. The results may give rise to improved allograft and patient survival in clinical transplantation while at the same time allow for reduced requirements for non-specific immunosuppressants with their undesirable side effects.
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| McDaniel, D O; Naftilan, J; Barber, W H (1993) Limiting detection of an amplification signal for HLA-D region and VNTR genes by 32P-PCR. Biotechniques 15:140-5 |
| Lagoo-Deenadayalan, S; Lagoo, A S; Barber, W H et al. (1993) A standardized approach to PCR-based semiquantitation of multiple cytokine gene transcripts from small cell samples. Lymphokine Cytokine Res 12:59-67 |
| Barber, W H; Mankin, J A; Laskow, D A et al. (1991) Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients. Transplantation 51:70-5 |
