Blockade of CCR5 and CXCR3 attenuates murine acute graft-versus-host disease through modulating donor-derived T cell distribution and function.

Abstract

Lymphocyte trafficking via chemokine receptors such as CCR5 and CXCR3 plays a critical role in the pathogenesis of aGVHD. Our previous studies showed that addition of CCR5 or CXCR3 antagonist could only slightly alleviate the development of aGVHD. Given the specificity of T lymphocytes bearing CXCR3 and CCR5, we investigated whether combined CCR5 and CXCR3 blockade could further attenuate murine aGVHD. A mouse model of aGVHD was established to assess the efficacy of CCR5 or/and CXCR3 blockade on the development of aGVHD. The distribution of lymphocytes was calculated by quantification of immunostaining cells. The immunomodulatory effect on T cells were assessed by evaluating T- cell proliferation, viability, and differentiation. Using murine allo-HSCT model, we demonstrated that blockade of both CCR5 and CXCR3 could efficiently alleviate the development of aGVHD. Further investigation on the immune mechanisms for this prophylactic effect showed that more T cells were detained into secondary lymphoid organs (SLOs), which may lead to reduced infiltration of T cells into GVHD target organs. Our study also showed that T cells detained into SLOs dampened the activation, suppressed the polarization toward Th1 and Tc1, and induced the production of Treg cells. These data suggest that concurrent blockade of CCR5 and CXCR3 attenuates murine aGVHD through modulating donor-derived T cell distribution and function, and this might be applicable for aGVHD prophylaxis in clinical settings.