EFFECT OF LIVING–RELATED DONOR BONE MARROW INFUSION ON CHIMERISM AND IN VITRO IMMUNOREGULATORY ACTIVITY IN KIDNEY TRANSPLANT RECIPIENTS

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TITLE: EFFECT OF LIVING–RELATED DONOR BONE MARROW INFUSION ON CHIMERISM AND IN VITRO IMMUNOREGULATORY ACTIVITY IN KIDNEY TRANSPLANT RECIPIENTS

R. O. Garcia–Morales,¹ J. M. Mathew,¹ G. Ciancio,¹ G. W. Burke III,¹ K. Suzart,¹ A. Rosen,¹ C. Ricordi,¹ N. S. Kenyon,¹ A. G. Tzakis,¹ V. Esquenazi,^1,2 J. Miller.^1,2

¹Surgery–Transplant, Univ Miami Med Sch, Miami, FL; ²Miami Vet Aff Med Ctr

Background. In a previously reported series of donor–specific bone marrow cell (DBMC) infusions in cadaver kidney transplant recipients(CAD), there appeared to be an improvement in long–term graft survival (6 years) and fewer chronic rejections correlating with increasing DBMC chimerism. Thus, we embarked on a study of DBMC infusion in living–related donor kidney transplant (LRD) recipients.

Methods. Between 11/96 and 05/00, 47 LRD received donor iliac crest marrow (1.8x10⁸±1.9x10⁸ cells/kg body weight ± S.D.) in a single infusion 4 days post–op. Either OKT3 (n = 26) or daclizumab (n = 21) were used for induction therapy, with maintenance tacrolimus, MMF, and methylprednisolone immunosuppression (ISP). They were prospectively compared with 39 non–infused LRD given equivalent ISP in the same time period. Clinical follow–up has ranged from 19.0 mos to 61.6 mos. PCR–Flow chimerism analysis and in vitro assays of immunoregulatory activity of chimeric cells were performed.

Results. The incidence of acute rejection over this period of time was 10.6% and 10.3%, respectively. ISP dosaging was somewhat lower over time in the DBMC group. Four year actuarial patient and graft survival for the DBMC–infused group was 98% and 98%, and for the control group was 98% and 95%, respectively (p = N.S.). DBMC chimerism in recipient iliac crest marrow has increased more rapidly than might be predicted from results previously seen in the CAD group, despite 4X fewer DBMC infused. DBMC and (donor) peripheral blood mononuclear cells inhibited MLR responses of the recipient to the donor more strongly than freshly obtained peripheral blood cells drawn from the donors or even compared with donor–aspirated BMC. Similarly, recipient–derived recipient cells from the same chimeric recipient more strongly inhibited the same MLR reactions autologously than a large group of non–chimeric (autologous) bone marrow modulating cells in similar reactions.

Conclusions. These observations confirm that an immunoregulatory process appears to have been generated by DBMC infusion, encouraging a further decrease in ISP dosaging using such assays in the future.