DONOR BONE MARROW, CHIMERISM, HISTOCOMPATIBILITY AND RENAL ALLOGRAFT REJECTION

Abstract

18 Does donor bone marrow infusion have immunological effects on renal allograft recipients? From September 1994 through December 1997 63 cadaver renal transplant recipients of either 1 (n=21) or 2 (n=42) post-operative donor bone marrow cell (DBMC)-infusions have been followed, compared with 220 non-infused controls given equivalent immunosuppression (Tacrolimus, mycophenolate mofetil, methylprednisolone, and OKT3 induction). Additionally, 16 kidney recipients of DBMC-infusion from living-related donors (LRD) (1-infusion) were followed from November 1996 through December 1997, and given the same immunosuppression. With both CAD and LRD DBMC infusions, the DBMC was similarly processed, frozen under liquid nitrogen, and thawed for administration at the bedside, with similar cell viability in each group. Chimeric analyses were performed by the PCR-Flow technique. There were 8/63 biopsy-proven acute rejection episodes (AR) in the CAD DBMC-infused group, and 33/220 AR in the controls (p=N.S.). However, only 2/63 DBMC recipients had biopsy-proven chronic rejection (CR), while 35/220 showed CR in the controls (p=<.02). Actuarial patient and graft survival (1-40 months) were 93% and 92% in the CAD DBMC-infused group and 96% and 91% in the controls, respectively. If two infusions of CAD DBMC were used, the AR rate was 5% (2/42); while, if one infusion was given, it was 24% (6/21) (p=<0.02). In both groups mortality was not associated with rejection. AR was associated with at least a 5-fold decrease in peripheral blood PCR-Flow chimerism of Total, CD3+, and CD34+ DBMC mononuclear cells (monocyte-lymphocyte gate), i.e., a useful indicator of rejection-not seen with infections of any type. In the LRD DBMC-infused recipients, patient and graft survival were 100% and 100%, respectively (3-15 months), with PCR-Flow DBMC chimerism in peripheral blood being 2× higher than CAD DBMC-infused recipients at serial monthly intervals up to 15 months post-operatively (p=<0.01). However, only 25% of the total average DBMC were initially infused in the LRD group (i.e., 7 × 1010 cells CAD, vs. 1.5 × 1010 cells LRD). These results indicate 1) an effect of histocompatibility on DBMC chimerism, 2) a modulatory effect of DBMC on allograft rejection, 3) the utility of peripheral blood "real time" PCR-Flow as a serial monitoring tool for AR in DBMC-infused patients. We conclude that DBMC infusions have a positive clinical long-term immunoregulatory effect on renal allograft recipients using a heavy induction and early maintenance immunosuppressive regimen.