CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease

Abstract

The complete repertoire of cellular and molecular determinants that influence graft-vs-host disease (GVHD) is not known. Using a well-established murine model of GVHD (B6→bm12 mice), we sought to elucidate the role of the donor non-T cell compartment and molecular determinants therein in the pathogenesis of GVHD. In this model the acute GVHD-inducing effects of purified B6 wild-type (wt) CD4+ T cells was inhibited by wt non-T cells in a dose-dependent manner. Paradoxically, unlike the chronic GVHD phenotype observed in bm12 mice transplanted with B6wt unfractionated splenocytes, bm12 recipients of B6ccr2-null unfractionated splenocytes developed acute GVHD and died of IFN-γ-mediated bone marrow aplasia. This switch from chronic to acute GVHD was associated with increased target organ infiltration of activated CD4+ T cells as well as enhanced expression of Th1/Th2 cytokines, chemokines, and the antiapoptotic factor bfl1. In vitro, ccr2−/− CD4+ T cells in unfractionated splenocytes underwent significantly less activation-induced cell death than B6wt CD4+ T cells, providing another potential mechanistic basis along with enhanced expression of bfl1 for the increased numbers of activated T cells in target organs of B6ccr2−/− splenocyte→bm12 mice. Collectively, these findings have important clinical implications, as they implicate the donor non-T cell compartment as a critical regulator of GVHD and suggest that ccr2 expression in this cellular compartment may be an important molecular determinant of activation-induced cell death and GVHD pathogenesis.

Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease

“…In CD4 þ T-cell-mediated hepatic aGVHD, CCR2 deficiency of donor T cells rather led to increased T-cell infiltrates. 82 Therefore, the exact role of CCR2 may differ in relation to the degree of MHC mismatch and a leukocyte subpopulation, and seems to vary between specific GVHD target organs.…”

Leukocyte migration and graft-versus-host disease

“…However, when CCR2-deficient whole splenocytes were transferred, a significant increase in activated CD4 ϩ T cells was observed in the spleen, suggesting that CCR2 affects the recruitment or function of a regulatory population that does not express CD4. 119 Liver. Several studies have demonstrated expression of the chemokine ligands CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10, and CXCL11 in the liver during experimental GVHD.…”

Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17] Several chemokines such as CCL2, CCL3, CCL4, CCL5, CCL11, CXCL9, CXCL10 and CXCL11, are expressed in the liver, intestine and lung during experimental GVHD. Studies using conditioned murine GVHD models have demonstrated a consistent pattern in the kinetics of expression of these chemokines.…”

“…3 Expression of several chemokines in target organs during GVHD has been demonstrated in a number of experimental models. [4][5][6][7][8][9][10][11][12][13][14][15] Published data on the role of chemokines in GVHD are somewhat conflicting, since upregulation of chemokines in target organs during GVHD is influenced by transplant conditioning and recipient strain. 16,17 In conditioned murine GVHD models, the expression of chemokines such as CCL2, CXCL9, CXCL10 and CXCL11 is upregulated in the liver early after GVHD induction.…”