Irradiated donor leukocytes promote engraftment of allogeneic bone marrow in major histocompatibility complex mismatched recipients without causing graft-versus-host disease

Graft rejection in allogeneic bone marrow transplantation (BMT) can occur w hen donor and recipient are mismatched at one or more major histocompatibil ity complex (MHC) loci. Donor T cells can prevent graft rejection, but may cause fatal graft-versus-host disease (GVHD). We tested whether irradiation of allogeneic donor lymphocytes would preserve their graft-facilitating ac tivity while inhibiting their potential for GVHD. Infusions of irradiated a llogeneic T cells did not cause GVHD in MHC-mismatched SJL --> (SJL x C57BL 6) F1, C57BL6 --> B10.RIII, and C57BL6 --> B10.BR mouse donor recipient BMT pairs. The 60-day survival among MHC-mismatched transplant recipients incr eased from 2% (BM alone) to up to 75% among recipients of BM plus irradiate d allogeneic splenocytes. Optimal results were obtained using 50 x 10(6) to 75 x 10(6) irradiated donor splenocytes administered in multiple injection s from day -1 to day +1. Recipients of an equal number of nonirradiated MHC -mismatched donor splenocytes uniformly died of acute GVHD. The graft facil itating activity of the irradiated allogeneic splenocytes was mediated by d onor T cells. Irradiation to 7.5 Gy increased nuclear NF kappa B in T cells and their allospecific cytotoxicity, Irradiated T cells survived up to 3 d ays In the BM of MHC-mismatched recipients without proliferation. Recipient s of irradiated allogeneic splenocytes and allogeneic BM had stable donor-d erived hematopoiesis without a significant representation of donor splenocy tes in the T-cell compartment. Irradiated allogeneic T cells thus represent a form of cellular immunotherapy with time limited biologic activity in vi vo that can facilitate allogeneic BMT without causing GVHD. (C) 1999 by The American Society of Hematology.