IMMUNE MODULATION IN ORGAN RECIPIENTS BY SINGLE OR MULTIPLE DONOR BONE MARROW INFUSIONS

Abstract

495 To augment donor cell chimerism, a single dose of 3-5×108 unmodified donor BM cells/kg body weight was infused into 221 nonconditioned primary allograft recipients. The mean recipient and donor age was 40 and 29 years respectively, with follow-up ranging from 3-1849d (816±464d). Additionally, since April 30, 1996, we have also accrued 32 organ recipients(liver n=6, kidney n=19) into a concurrent protocol involving multiple sequential infusions of unmodified BM (1×108 cells/kg/d) from d0-4 post-transplantation; the mean recipient age being 42 ± 14 years with a follow-up from 4-616 days. Organ recipients (n=129) for whom BM was not available were monitored as controls. Immunosuppression(IS) was with tacrolimus and steroids, CellCept being administered to 49 study and 17 control patients respectively. The infusion of BM (both single and multiple) was safe and except for 48 (19%), all study patients have optimal graft function; none being lost to causes uniquely ascribed to ancillary BM infusion. Of the control patients, 28 (20%) have been lost during the course of follow-up. Mild to moderate acute cellular rejection was evidenced in 158/251 (63%) study and 88/128 (69%) control patients. Mild, easily reversible GvHD was witnessed in only 2/221 (1%) patients receiving single BM infusion. Contrarily, fulminant GvHD was discerned in 1/32 (3%) recipients of multiple BM infusions exhorting an immediate discontinuation of this protocol. Due to concomitant existence of refractory donor-type EBV+ PTLD, this patient initially benefited from autologous LAK cell therapy, eventually succumbing at d147 post-transplantation. Among those at least one year post-transplantation, a steroid-free existence has been achieved in 94 (53%) study and 39 (40%) control patients. As reported previously, the presence of a higher incidence of multilineage chimerism was confirmed in the peripheral blood of evaluable study (∼95%) as compared to that to the control (∼53%) patients. Furthermore, serial in vitro immunological monitoring revealed the presence of a relatively higher incidence of donor-specific hypereactivity (DSH) in 57% of study(liver, lung, kidney) recipients as compared to that to controls (44%). On the contrary, a relatively lower incidence of DSH was evidence in both study and control heart and kidney + pancreas recipients. Whilst BM infusion is safe with incontrovertible evidence for augmentation of chimerism, its effect on allograft survival and on our ability to reduce or withdraw nonspecific IS is still indeterminate. It must be emphasized that unlike that in rodents, a longer follow-up will be required in outbred species such as humans for the discernment of the beneficial effects of BM infusion.