Graft-facilitating doses of ex vivo activated gammadelta T cells do not cause lethal murine graft-vs.-host disease.
The purpose of this study was to examine the ability of gamma(delta) T cells to cause graft-vs.-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) and to determine whether these cells offered any therapeutic advantages relative to alphabeta T cells. Due to the paucity of naive gamma(delta) T cells in mice and humans, gamma(delta), T cells (obtained from alpha(beta) T cell-deficient murine donors) were ex vivo activated and expanded in interleukin (IL)-2 so as to achieve sufficient cell numbers and to serve as a more clinically feasible strategy. After transplantation into lethally irradiated hosts, donor gamma(delta) T cells were detected in target organs of GVHD such as the spleen and intestines 2 weeks after BMT and constituted the primary T cell subpopulation. Large doses (150 x 10(6)) of activated gamma(delta) T cells, which we have previously shown capable of facilitating engraftment in MHC-disparate recipients, failed to cause fatal GVHD in lethally irradiated recipients of MHC-incompatible donor marrow grafts (C57BL/6 [H-2b]-->B10.BR [H-2k] and C57BL/6 [H-2b]-B6D2F1[H-2b/d]). The absence of GVHD was confirmed by histologic analysis of target organs, splenic B cell reconstitution, and appropriate negative selection in the thymus, that were all comparable to those observed in mice transplanted with T cell-depleted BM only. While early splenic reconstitution was attributable to donor gamma(delta) T cells, analysis of durably engrafted chimeras 2 months posttransplant revealed that the vast majority of donor splenic T cells expressed the alpha(beta) T cell receptor. The results of secondary adoptive transfer assays showed that these cells were tolerant of recipient alloantigens in vivo, demonstrating that gamma(delta) T cells did not prevent the subsequent development of donor anti-host tolerance in BM-derived alpha(beta) T cells. When comparatively evaluated, the minimal number of naive alpha(beta) T cells necessary for donor engraftment caused significantly more fatal GVHD than the corresponding minimal dose of activated gamma(delta) T cells and thus had a superior therapeutic index. These studies indicate that doses of activated gamma(delta) T cells that are able to promote alloengraftment do not cause lethal GVHD in mice transplanted with MHC-incompatible marrow grafts.
Drobyski
W R
WR
Department of Medicine, Medical College of Wisconsin, Milwaukee, USA.
Majewski
D
D
Hanson
G
G
D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002678:Chimera / Q000276:immunology; D006082:Graft Enhancement, Immunologic / Q000379:methods*; D006086:Graft vs Host Disease / Q000209:etiology*; D007108:Immune Tolerance; D007422:Intestines / Q000166:cytology; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D017710:Lymphocyte Transfusion / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors; D014181:Transplantation Immunology; D014184:Transplantation, Homologous / Q000009:adverse effects
D007519:Isoantigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta