Immunocompetence in Recipients of Hematopoietic Stem Cell/Renal Transplants.

Abstract

We are conducting a phase 2 trial to induce donor-specific tolerance to living donor renal Tx (IND 13947). Subjects receive fludarabine (days -5,-4,-3), cyclophosphamide (50 mg/ky days -3 and +3), and 200 cGy TBI. The kidney Tx is performed day 0. G-CSF mobilized peripheral blood stem cells processed to remove GVHD-producing cells and retain graft facilitating cells (FC) are administered on day +1. The conditioning is well tolerated and the subjects are managed as outpatients. This approach has resulted in high levels of durable chimerism and immunosuppression (IS)-free graft survival without GVHD or engraftment syndrome in mismatched related/unrelated recipients. Twelve subjects are completely off IS from 2 months to 3 years. Others are in the process of tapering. We have prospectively analyzed recovery of immune function, persistence of vaccination memory, and response to vaccination in subjects with high levels of chimerism. Chimerism testing was performed using molecular short tandem repeat (sensitivity +5%). Three of four subjects who had been vaccinated to hepatitis B prior to Tx and whose donors had not been vaccinated retained their immunity following Tx. All subjects tested exhibited memory for varicella and the majority did as well for measles(9/11), mumps(8/11), and rubella(5/10). A blood group disparity was present in 9 chimeric D/R pairs. One chimeric subject converted to donor blood type, 3 exhibited mixed donor/host RBC chimerism, and 5 retained their own blood type. Six chimeric subjects have been immunized with pneumococcal vaccine after Tx. All generated an antibody response to vaccination. Recovery of CD8+ and CD4+ central memory, naïve, and effector memory T cells occurred within one year post-Tx to levels that were not significantly different from pre-Tx. In addition, CD31+/CD45RA+CD8+ and CD4+ T cells representative of recent thymic emigrants were present by 3 months, demonstrating de novo thymic production of T cells after Tx. Taken together, these data suggest that immunologic recovery is robust in these nonmyeloablatively conditioned tolerant chimeric subjects. DISCLOSURES:Bozulic, L.: Employee, Regenerex LLC. Badder, M.: Employee, Regenerex LLC. Eliott, M.: Employee, Regenerex LLC. Ildstad, S.: Other, Regenerex LLC, CEO.