Abstract

Acute graft-versus-host disease (GVHD) remains the major barrier of allogeneic bone marrow transplantation (allo-BMT). In the current view, GVHD fundamentally depends on donor T cells interaction with host derived dendritic cells (DC) leading to their activation, proliferation, and differentiation. We and others have demonstrated that transforming growth factor β1 (TGF-β1) treated DC (TGFβ-DC) have regulatory characteristic and could induce allogeneic specific immune tolerance in vitro. In the current study, we focused on the effects of recipient-derived TGFβ-DC in a murine GVHD model. After total body irradiation, 5.0×106 recipient-derived TGFβ-DC were injected into C57BL/6 (H-2b) with bone marrow-splenocyte grafts from major histocompatibility complex (MHC) disparate BALB/c mice (H-2d). Survival analysis showed TGFβ-DC co-transplantation resulted in significant prolongation of allograft survival and mean survival time (MST) was 44.3±4.5 days (p<0.01), whereas MST of untreated BMT recipient was 9.5±0.6 days (p<0.01). However, mature DC aggravated the GVHD and the MST was 6.6±0.6 days (p<0.01). In addition, donor-derived or the third party-C3H mice derived TGFβ-DC could not enhance the survival rate indicating that the protection effect of TGFβ-DC was recipient-specific. Consistent with clinical outcomes, the histopathologic studies showed no or mild GVHD evidences were found in recipient-derived TGFB-DC co-transplantation mice, while specific severe GVHD alternations occurred in the liver, skin and intestine in other groups. Flow cytometry analysis of TGFβ-DC labeled with 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) showed approximately 5% of TGFβ-DC in spleen mononuclear cells the next day after transplantation and half-life of the injected TGFβ-DC was around 20 days after transplantation. Furthermore, serum Th1 type cytokines of IFN-γ, IL-12 and IL-18 levels in TGFβ-DC co-transplantation mouse reduced compared with untreated BMT mouse, while serum IL-10 level was not changed. Taken together, these preliminary results indicate that TGFβ-DC co-transplantation may induce MHC-specific tolerance and attenuate the severity of GVHD by suppressing Th1 responses. Further research should be carried out to explore the optimal transplantation regimen and elucidate the mechanism.

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