Abstract

Lack of engraftment, graft-versus-host disease (GVHD) and tumor relapse are major issues that affect clinical outcome after allogeneic bone marrow transplantation (allo-BMT). Donor T cells in the graft present a dilemma in allo-BMT due to both the beneficial and deleterious clinical effects they can exert. Therefore, modulation of donor T cell function may represent a potential therapeutic approach in allo-BMT. In murine allo-BMT models, It has been demonstrated that donor T cell-derived IFN-gamma is required for optimal graft-versus-tumor (GVT) responses but it also plays complex roles by exhibiting both protective and pathogenic effects in GVHD development. We therefore investigated the role of IFN-gamma responsiveness by the donor T cells in allo-BMT through the use of IFN-gamma receptor deficient (IfnR−/−; RKO) mice. In these experiments, recipient BALB/c (H2d) mice received lethal total body irradiation. Irradiation was followed by the infusion of graded doses of T cell-depleted (TCD) allogeneic bone marrow cells (5 or 15 × 106) intravenously from major histocompatibility complex (MHC)-disparate wild type (WT) C57BL/6 (H2b, IfnR+/+) mice, with or without 0.5 × 106 T cells (or 3 × 106 splenocytes as a source of allogeneic T cells) from either WT (H2b, IfnR+/+) or RKO mice. Compared with transplantation of WT TCD-BMCs with T cells from a WT donor, we found that transplantation of WT TCD-BMCs with RKO T cells resulted in marked and significant increases in myeloid engraftment as determined by CFU-GM, peripheral neutrophil and platelet counts during the early phase of allo-BMT. Consistently, a significant increase serum G-CSF was also found on day 7 after allo-BMT with this group. This enhanced myeloid engraftment by RKO T cells occurred only in murine allo-BMT but not syngeneic BMT models, indicating it is a property of alloreactivity. Interestingly, no significant differences in donor T cell engraftment, nor in the percentage of Treg, Th17, CD4+ or CD8+ T cell subsets and IFN-gamma+ T cells, were observed in spleen. However, on day 7 after allo-BMT, significantly fewer donor T cells were observed in the gut in the recipient of RKO T cells compared to recipients of WT T cells. This reduction of donor T cells in gut was associated with a significant decrease in early acute GVHD lethality. This novel finding suggests transplantation of T cells lacking IFN-gamma receptors resulted in less donor T cell homing to the gut during the early phase of allo-BMT. We next addressed the ability of donor RKO T cells to provide GVT responses. A20 tumor-bearing BALB/c (H2d) mice were transplanted with WT C57BL/6 TCD-BMC. Compared with transplantation of 1 × 106 WT T cells with WT TCD-BMC, co-transplantation of 1 × 106 RKO T cells with WT TCD-BMC resulted in less GVHD-related mortality with greater anti-tumor effects. Taken together, these observations suggest that targeting IFN-gamma receptor signaling on donor T cells may help to improve the efficacy of allo-BMT by promoting donor myeloid engraftment and decreasing early acute GVHD lethality with greater GVT potential due to altered lymphocyte homing.

Disclosures: No relevant conflicts of interest to declare.

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