Abstract
Delayed administration of donor lymphocyte infusion (DLI) to established mixed chimeras has been shown to achieve anti-tumor responses without graft-vs.-host disease (GVHD). Herein we show that de novo donor BM-derived T cells that are tolerant of the recipients are important in preventing GVHD in mixed chimeras receiving delayed DLI. Mixed chimeras lacking donor BM-derived T cells developed significantly more severe GVHD than those with donor BM-derived T cells after DLI, even though both groups had comparable levels of total T cells at the time of DLI. Post-DLI depletion of donor BM-derived T cells in mixed chimeras, as late as 20 days after DLI, also provoked severe GVHD. Although both CD4 and CD8 T cells contributed to the protection, the latter were significantly more effective, suggesting that inhibition of GVHD was not mainly mediated by CD4 regulatory T cells. The lack of donor BM-derived T cells was associated with markedly increased accumulation of DLI-derived alloreactive T cells in parenchymal GVHD target tissues. Thus, donor BM-derived T cells are an important factor in determining the risk of GVHD and therefore, offer a potential therapeutic target for preventing and ameliorating GVHD in the setting of delayed DLI in established mixed chimeras.
Highlights
Allogeneic hematopoietic cell transplantation remains a potentially curative treatment for leukemias and lymphomas, but its clinical utility has been limited by morbidity and mortality from graft-vs.-host disease (GVHD)
Histological examination confirmed severe inflammatory infiltrates and the associated tissue lesions in GVHD target organs from the long-term surviving RagKO, but not WT, mixed hematopoietic chimeras (MCs) (Figure 1D). These results indicate that the lack of pre-existing donor bone marrow (BM)-derived lymphocytes is an important risk factor for persistent GVH responses and GVHD in established MCs after delayed Donor lymphocyte infusion (DLI)
The present study provides evidence that donor BM-derived T cells, CD8 T cells that develop post-BM transplantation (BMT) in the presence of recipient antigens, are highly protective against GVHD in established MCs receiving delayed DLI
Summary
Allogeneic hematopoietic cell transplantation (allo-HCT) remains a potentially curative treatment for leukemias and lymphomas, but its clinical utility has been limited by morbidity and mortality from graft-vs.-host disease (GVHD). Donor lymphocyte infusion (DLI), at doses that would induce lethal GVHD in freshly-irradiated mice, mediates effective anti-tumor responses without severe GVHD in established mixed hematopoietic chimeras (MCs) [1,2,3]. Delayed DLI following the establishment of mixed chimerism has been shown to have the potential to cure hematopoietic malignancies in clinical trials [5,6,7]. In comparison to mouse studies in which anti-tumor effects can be reliably achieved by delayed DLI without severe GVHD [1,2,3], a higher incidence of GVHD was noted in mixed chimeric patients after DLI [5,6,7]
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