In pursuit of the ultimate: the initial Ahmedabad journey toward transplantation tolerance.
We designed a prospective clinical trial of 357 patients divided in two groups--treated (n = 201) and controls (n = 156)--to evaluate effects of donor hematopoietic stem cell transplantation (HSCT) with minimal nonmyeloablative conditioning for tolerance induction in living related donor renal allograft recipients. Conditioning included donor leukocyte infusions, target-specific irradiation, anti-T-cell antibody, cyclophosphamide, cyclosporine (CsA), followed by bone marrow (BM)-derived and peripheral blood stem cell (PBSC) infusion into thymus, liver, BM, and periphery, with mean total dose of 20 x 10(8) nucleated cells/kg body weight (BW) (mean CD34(+) count: 0.9%) pretransplantation. CsA (3 mg/kg BW/d) and prednisolone (10 mg/d) were used for immunosuppression. Azathioprine/mycophenolate mofetil were added in the event of an acute rejection episode. The controls underwent transplantation with three drug immunosuppression. With a mean follow-up of 21.5 months, the treated cohort showed better allograft function with mean serum creatinine (SCr), 1.42 +/- 0.31 mg% in contrast with the controls mean SCr, 1.61 +/- 0.52 mg% (P < .0001) at 23.9 months follow-up. One-year allograft/patient survival was 95%/96.7% versus 89%/93.4%, respectively. Peripheral blood chimerism by fluorescent in situ hybridization was 0.8% +/- 0.2% in the subset of treated patients with gender-mismatched donors. No graft-versus-host disease was noted. Nine patients with donor-specific cytotoxic alloantibodies pretransplantation showed a decrease in positivity to <15% post-HSCT and were transplanted safely. A transient rise in donor-specific cytotoxic alloantibodies was noted in 19 treated patients post-HSCT, 14 of whom returned to the transplantable range within 2 weeks and five required a desensitization protocol. "Prope" tolerance may be induced in living related donor renal transplantation across major histocompatability complex barriers using HSCT with minimal nonmyeloablative conditioning.
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Department of Nephrology and Transplantation Medicine, Institute of Transplantation Sciences, Gulabben Rasiklal Doshi and Kamlaben Mafatlal Mehta Institute of Kidney Diseases and Research Centre, Ahmedabad, Gujarat, India. ikdrcad1@sancharnet.in
Vanikar
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Modi
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Shah
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Shah
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Trivedi
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D000293:Adolescent; D000328:Adult; D000368:Aged; D001854:Bone Marrow Cells / Q000166:cytology; D002648:Child; D006085:Graft Survival / Q000276:immunology / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006650:Histocompatibility Testing; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods; D007194:India; D008875:Middle Aged; D014019:Tissue Donors; D018183:Transplantation Chimera; D023001:Transplantation Tolerance / Q000276:immunology*