Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4+25+ T cells to allow an effective graft-versus-leukemia response

Abstract

After allogeneic hematopoietic cell transplantation (HCT), the high inverse correlation between graft-versus-host disease (GVHD) and leukemic relapse requires that calculated measures be taken to reduce GVHD pathology while retaining the graft-versus-leukemia (GVL) effect. We sought to determine whether donor CD4(+)CD25(+) regulatory T cells could control ongoing GVHD, thereby providing an initial window of time in which the alloreactive anti-host response is permitted to begin, with the intent of most effectively eliminating residual leukemia cells. Prevention of lethal GVHD by infusion of donor CD4(+)CD25(+) cells early after HCT (day 2) was achieved across a major histocompatibility complex barrier in the haploidentical C3H-->(B6xC3H)F(1) model. However, in vitro expansion of donor CD4(+)CD25(+) T cells, stimulated by recipient cells in the presence of high-dose interleukin-2, was required for successful regulation. In contrast, in the major histocompatibility complex-matched, minor histocompatibility antigen-disparate, CD8-mediated B10.BR-->CBA GVHD model, lethal disease could be completely prevented by a single infusion of freshly isolated donor CD4(+)CD25(+) cells administered as late as 10 days after HCT. Of importance, this late regulatory effect required only a 3:1 ratio of effector CD8:CD4(+)CD25(+) T cells, indicating a strong potential for the delayed infusion of CD4(+)CD25(+) cells to control GVHD across minor histocompatibility antigen barriers. Furthermore, this regulation did not interfere with complete and lasting donor engraftment of the hematopoietic compartment. Of most significance, the day 10 infusion of donor CD4(+)CD25(+) cells into CBA HCT recipients that had been challenged with the MMCBA6 myeloid leukemia cell line did not block an effective GVL response, despite reducing lethal GVHD. These results suggest that donor CD4(+)CD25(+) T cells infused soon after transplantation can ameliorate the development of GVHD without sacrificing a sufficient GVL effect.

Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease

“…1 Several groups have shown in different murine models that donor Tregs prevent the development of acute graft-versus-host disease (GVHD). [2][3][4][5] These findings have been extended to the clinic with encouraging results. [6][7][8][9] The timed addition of Tregs and CD4 1 and CD8 1 T cells preserve graft-vs-tumor (GVT) effects.…”

New perspectives on the biology of acute GVHD

“…80 In mouse BMT models, naturally occurring donor-derived Tregs suppress the proliferation of conventional T cells, prevent GVHD and preserve GVL effects depending on the ratio of effector T cells to Tregs. [81][82][83][84][85][86] Furthermore, viral immunity is preserved in the presence of Tregs after allogeneic HCT. 87 The mechanisms for suppression in the context of GVHD remain completely unknown.…”

Regulating regulatory T cells

“…Infusion of ex vivo activated and expanded Tregs significantly inhibited lethal GVHD in several murine models. 39,68,71,79 Furthermore, in some cases, the ex vivo expanded Tregs appeared to be better than freshly purified CD4 þ CD25 þ T cells in preventing GVHD. 71,79 Given these promising results, considerable efforts have been made to expand human Tregs for use in clinical setting.…”

“…39,68,71,79 Furthermore, in some cases, the ex vivo expanded Tregs appeared to be better than freshly purified CD4 þ CD25 þ T cells in preventing GVHD. 71,79 Given these promising results, considerable efforts have been made to expand human Tregs for use in clinical setting. Large-scale expansion of CD4 þ CD25 þ Tregs, up to 1000 times, using anti-CD3 and anti-CD28 microbeads and high doses of IL-2 has demonstrated the feasibility of bringing this new treatment modality to the bedside.…”

“…In addition, it has been demonstrated in another model of murine GVHD that the infusion of donor CD4 þ CD25 þ Tregs at a later time point, with the intention of providing the initial window of time in which the beneficial GVT response is permitted to begin, was effective in controlling ongoing GVHD. 71 Thus, the data accumulated from the animal studies clearly indicate that CD4 þ CD25 þ Tregs play a vital role in downregulating GVHD. The demonstration that Tregs could separate GVHD from GVT activity suggests that their immunosuppressive potential could be manipulated to reduce GVHD without detrimental consequence on GVT effect.…”