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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3222-3233
Irradiated Donor Leukocytes Promote Engraftment of Allogeneic Bone
Marrow in Major Histocompatibility Complex Mismatched Recipients
Without Causing Graft-Versus-Host Disease
Edmund K. Waller,
Alan M. Ship,
Stephen Mittelstaedt,
Timothy W. Murray,
Richard Carter,
Irina Kakhniashvili,
Sagar Lonial,
Jeannine
T. Holden, and
Michael W. Boyer
From the Bone Marrow and Stem Cell Transplantation Center, Emory
University, Atlanta, GA.
Graft rejection in allogeneic bone marrow transplantation (BMT) can
occur when donor and recipient are mismatched at one or more major
histocompatibility 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 activity while inhibiting their
potential for GVHD. Infusions of irradiated allogeneic T cells did not
cause GVHD in MHC-mismatched SJL  (SJL × C57BL6) F1, C57BL6 B10.RIII, and C57BL6 B10.BR mouse donor recipient BMT pairs.
The 60-day survival among MHC-mismatched transplant recipients
increased from 2% (BM alone) to up to 75% among recipients of BM plus
irradiated allogeneic splenocytes. Optimal results were obtained using
50 × 106 to 75 × 106 irradiated donor
splenocytes administered in multiple injections from day  1 to day
+1. Recipients of an equal number of nonirradiated MHC-mismatched
donor splenocytes uniformly died of acute GVHD. The graft facilitating
activity of the irradiated allogeneic splenocytes was mediated by donor
T cells. Irradiation to 7.5 Gy increased nuclear NF B in T cells and
their allospecific cytotoxicity. Irradiated T cells survived up to 3 days in the BM of MHC-mismatched recipients without proliferation.
Recipients of irradiated allogeneic splenocytes and allogeneic BM had
stable donor-derived hematopoiesis without a significant representation
of donor splenocytes in the T-cell compartment. Irradiated allogeneic T
cells thus represent a form of cellular immunotherapy with time-limited
biologic activity in vivo that can facilitate allogeneic BMT without
causing GVHD.
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