Graft-facilitating doses of ex vivo activated gammadelta T cells do not cause lethal murine graft-vs.-host disease

Abstract

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.

Long term disease-free survival in acute leukemia patients recovering with increased γδ T cells after partially mismatched related donor bone marrow transplantation

“…Data from our laboratory and others indicate that gd T cells do not require MHC class II for their maturation 37 or proliferation in response to an allogeneic MHC disparity 38 and are not initiators of GvHD. 39 Moreover, Drobyski 40 showed that large doses of interleukin-2 (IL-2) expanded gd 41 showed that although activated gd and naive ab T cells exacerbated GvHD when infused together, delaying the infusion of ab T cells by 2 weeks resulted in improved survival. These findings are consistent with Ellison,42 who noted that gd T cells could be activated in the GvHD reaction but found no evidence that GvHD was initiated by gd T cells.…”

Analysis of donor NK and T cells infused in patients undergoing MHC-matched allogeneic hematopoietic transplantation

“…Along these lines, in a murine model of MHC-incompatible allogeneic bone marrow transplantation, injection of ex vivo activated and expanded ␥␦ T cells has been demonstrated to facilitate engraftment. 10 A role of NK cells in transplantation was initially described in 'hybrid resistance', in which F1 hybrid recipients reject parental bone marrow grafts, while accepting solid tissues. 11,12 More recently, in a murine model of MHC-incompatible allogeneic bone marrow transplantation, Murphy et al showed that infusion of in vitro IL-2 activated NK cells could prevent the development of graft-versus-host disease (GVHD), exert an anti-tumoral effect against a co-transplanted tumor cell line, and increase survival in recipient mice.…”

Clinical-scale single-step CD4+ and CD8+ cell depletion for donor innate lymphocyte infusion (DILI)

“…Several in vitro and in vivo studies have shown that gd T cells and NK cells induce potent antitumor effects without causing GVHD. [28][29][30][31] In addition, these innate lymphocytes may facilitate engraftment of human stem cells [32][33][34] and are even able to prevent or mitigate GVHD. 35 These findings are consistent with a recent analysis by Godder et al, 36 who demonstrated a long-term survival advantage without increased GVHD incidence in a group of high-risk acute leukemia patients recovering with increased gd T cells after partially mismatched related donor marrow transplantation.…”