title: Irradiated donor leukocytes promote engraftment of allogeneic bone marrow in major histocompatibility complex mismatched recipients without causing graft-versus-host disease.
abstract: 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 x 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 x 10(6) to 75 x 10(6) 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 NFkappaB 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.
authors.affiliation: Bone Marrow and Stem Cell Transplantation Center, Emory University, Atlanta, GA 30322, USA. ewaller@emory.edu
authors.forename: E K
authors.initials: EK
authors.lastname: Waller
authors.forename: A M
authors.initials: AM
authors.lastname: Ship
authors.forename: S
authors.initials: S
authors.lastname: Mittelstaedt
authors.forename: T W
authors.initials: TW
authors.lastname: Murray
authors.forename: R
authors.initials: R
authors.lastname: Carter
authors.forename: I
authors.initials: I
authors.lastname: Kakhniashvili
authors.forename: S
authors.initials: S
authors.lastname: Lonial
authors.forename: J T
authors.initials: JT
authors.lastname: Holden
authors.forename: M W
authors.initials: MW
authors.lastname: Boyer
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D006085:Graft Survival / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000517:prevention & control; D006650:Histocompatibility Testing; D017708:Leukocyte Transfusion; D007962:Leukocytes / Q000276:immunology / Q000528:radiation effects; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D014184:Transplantation, Homologous