Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

Abstract

Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.immune reconstitution | graft composition | mice

Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease

“…43,44 Others have also suggested that the donor stem cell product may also contribute to a decreased capacity for robust B-cell reconstitution in allo-HSCT. 45 Finally, B-cell reconstitution after rituximab in the absence of autoantigen (such as is found in lymphoma patients or in autologous transplantation) occurs more rapidly, recapitulating B-cell ontogeny, suggesting that BCR specificity for autoantigens or alloantigens also contributes to B-cell pool composition during post-HSCT ontogeny. 9,16 Despite the small number of patients in this study, our findings provide data that will inform future translational studies.…”

Bone marrow T-cell infiltration during acute GVHD is associated with delayed B-cell recovery and function after HSCT

“…Several mouse models have shown that BM B lymphopoiesis is impaired by allo-reactive T cells. [45][46][47] Increased T-cell progenitors and an increased BM CD4/CD8 ratio were reported in cGVHD patients. 43,48 However, BM CD3 1 T-cell infiltration was not histologically investigated in these studies.…”

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.…”