Purified hematopoietic stem cell allografts reconstitute immunity superior to bone marrow

Abstract

Antigen-specific immune responses are impaired after allogeneic hematopoietic cell transplantation (HCT). The events contributing to this impairment include host hematolymphoid ablation and donor cell regeneration, which is altered by pharmacologic immune suppression to prevent graft-versus-host disease (GVHD). A generally accepted concept is that graft T cell depletion performed to avoid GVHD yields poorer immune recovery because mature donor T cells are thought to be the major mediators of protective immunity early post-HCT. Our findings contradict the idea that removal of mature donor cells worsens immune recovery post-HCT. By transplantation of purified hematopoietic stem cells (HSC) compared with bone marrow (BM) across donor and recipient pairs of increasing genetic disparity, we show that grafts composed of the purified progenitor population give uniformly superior lymphoid reconstitution, both qualitatively and quantitatively. Subclinical GVHD by T cells in donor BM likely caused this lymphodepleting GVHD. We further determined in the major histocompatibility complex (MHC)-mismatched pairs, that T cell restricted proliferative responses were dictated by donor rather than host elements. We interpret these latter findings to show the importance of peripheral antigen presentation in the selection and maintenance of the T cell repertoire.immune reconstitution ͉ mice ͉ T cell selection

Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

“…The data presented here and elsewhere (25) contradict the conventional view that grafts of rigorously purified stem/progenitor cells will produce inferior immunity, and suggest that such conclusions should be re-examined. The body of data demonstrating the deleterious effects of GVHR on BM and lymphoid function (13)(14)(15)(16)(17)(18)(19)(20)(26)(27)(28) is often overlooked or underestimated.…”

“…The body of data demonstrating the deleterious effects of GVHR on BM and lymphoid function (13)(14)(15)(16)(17)(18)(19)(20)(26)(27)(28) is often overlooked or underestimated. We previously reported that even low amounts of T cells cause subclinical, yet lympho-depleting, GVHR (25). Here, we focused on an mHA-antigen-mismatched strain combination and used grafts that allowed us to distinguish between "new" HSC-derived hematopoiesis versus expansion of donor lymphocytes.…”

Mixed chimerism through donor bone marrow transplantation

“…Recently, the main function of facilitating cells was reported to be the induction of recipient Tregs which in turn promote bone marrow engraftment [72]. Interestingly, another study suggested purified HSCs to be superior compared with unseparated bone marrow in terms of both GVHD avoidance and lymphoid recovery and therewith antigen-specific immune responses post-HSC transplantation [73].…”

Activated MHC-mismatched T helper-1 lymphocyte infusion enhances GvL with limited GvHD

“…[33][34][35] Moreover, murine studies provide evidence that allogeneic T-cells impair hematopoietic reconstitution after HCT. 36,37 On the other hand, CD62L − effector memory T-cells have been shown to promote donor BM stem/progenitor-derived T-cell reconstitution. 23 In our study, in contrast to SC, aTh-1 cell therapy induced mild, transient suppression of donor hematopoiesis.…”