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Shan He, Qi Cao, Yuhua Qiu, Jianqing Mi, Jingwu Z Zhang, Min Jin, Hailiang Ge, Stephen G Emerson, Yi Zhang, Yanyun Zhang, A New Approach to the Blocking of Alloreactive T Cell-Mediated Graft-versus-Host Disease by In Vivo Administration of Anti-CXCR3 Neutralizing Antibody, The Journal of Immunology, Volume 181, Issue 11, December 2008, Pages 7581–7592, https://doi.org/10.4049/jimmunol.181.11.7581
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Abstract
Chemokines and chemokine receptors play critical roles in directing the migration of alloreactive donor T cells into graft-vs-host disease (GVHD) target organs. However, blockade of GVHD by antagonist Ab against chemokine receptors remains an elusive goal. Using a mouse model of human GVHD, we demonstrate that in vivo administration of anti-CXCR3 Ab for 21 days (long-term), but not for 7 days (short-term), inhibits alloreactive CD8+ T cell-mediated GVHD. During a graft-vs-host reaction, infused donor CD8+ T cells generate two subsets of potent inducers of GVHD: CXCR3+CD8+ and CXCR3−CD8+ T cells. Compared with CXCR3+CD8+ T cells, CXCR3−CD8+ T cells produce less granzyme B, Fas ligand, IFN-γ, and TNF-α. Interestingly, stimulation with either dendritic cells or IL-2 induces a dynamic conversion between CXCR3+CD8+ and CXCR3−CD8+ T cells. Short-term anti-CXCR3 Ab treatment inhibits only CXCR3+CD8+ T cell-mediated GVHD, but not the disease induced by CXCR3−CD8+ T cells. Prolonged in vivo administration of anti-CXCR3 Ab significantly reduces the infiltration of alloreactive CD8+ T cells into GVHD target organs and inhibits GVHD mediated by either CXCR3+CD8+ or CXCR3−CD8+ T cells. Thus, we have established a novel and effective approach with the potential to give rise to new clinical methods for preventing and treating GVHD after allogeneic hematopoietic stem cell transplantation.
