Graft-versus-host disease (GVHD) remains a significant complication of allogeneic bone marrow transplantation (allo-BMT). Acute GVHD is mediated by immunocompetent donor T cells, which migrate to lymphoid tissues soon after infusion, recognize host alloantigens, and become activated upon interaction with host antigen-presenting cells (APCs). Recent work from our group and others suggests that activated effector T cells exit lymphoid tissues and traffic to mucosal sites and parenchymal target organs such as the gastrointestinal (GI) tract, liver, lung, and skin where they cause tissue damage. The molecular interactions necessary for effector cell migration during GVHD have become the focus of a growing body of research, as these interactions represent potential therapeutic targets. In this review we discuss chemokine and chemokine receptor interactions and adhesion molecules that have been shown to play roles in effector cell migration in experimental GVHD models, and we discuss a potential model for the role of chemokines during the activation phase of GVHD. (Blood. 2005;105: 4191-4199)

Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. Increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer

CD4 ؉ CD25 ؉ regulatory T cells (T regs ) have been shown to inhibit graft-versus-host disease (GVHD) in murine models, and this suppression was mediated by T regs expressing the lymphoid homing molecule L-selectin. Here, we demonstrate that T regs lacking expression of the chemokine receptor CCR5 were far less effective in preventing lethality from GVHD. Survival of irradiated recipient animals given transplants supplemented with CCR5 ؊/؊ T regs was significantly decreased, and GVHD scores were enhanced compared with animals receiving wild-type (WT) T regs . CCR5 ؊/؊ T regs were functional in suppressing T-cell proliferation in vitro and ex vivo. However, although the accumulation of T regs within lymphoid tissues during the first week after transplantation was not dependent on CCR5, the lack of function of CCR5 ؊/؊ T regs correlated with impaired accumulation of these cells in the liver, lung, spleen, and mesenteric lymph node, more than one week after transplantation. These data are the first to definitively demonstrate a requirement for CCR5 in T reg function, and indicate that in addition to their previously defined role in inhibiting effector T-cell expansion in lymphoid tissues during GVHD, later recruitment of T regs to both lymphoid tissues and GVHD target organs is important in their ability to prolong survival after allogeneic bone marrow transplantation. ( IntroductionAcute graft-versus-host disease (GVHD) is a severe and potentially fatal complication of allogeneic bone marrow transplantation (allo-BMT). Acute GVHD is caused by mature donor T cells that recognize alloantigens presented initially by host antigen presenting cells (APCs). 1,2 Our group has demonstrated that the accumulation of donor T cells during the peritransplantation period takes place primarily in lymphoid tissues, followed by recruitment to parenchymal tissues such as the gastrointestinal (GI) tract, liver, lung, and skin. 3 We and others have recently demonstrated that eliminating expression of the chemokine receptor CCR5 from donor T cells in an experimental GVHD model resulted in exacerbated GVHD and increased T-cell infiltration of the liver and lung in lethally irradiated recipient animals. 4,5 These data suggested that the primary role for CCR5 during GVHD in conditioned transplant recipients is not to direct effector-cell recruitment as originally hypothesized, but to down-modulate target organ inflammation.Chemokines are predominantly 8-kDa to 12-kDa chemotactic proteins, which bind a family of 7-transmembrane-spanning G protein-coupled receptors, and function primarily in leukocyte migration (reviewed in Moser et al 6 ). The chemokine receptor CCR5 is expressed on activated T helper-1/T cytotoxic-1 (T H 1/ T C 1) T cells, natural killer (NK) cells, macrophages, and dendritic cells. 7 The ligands for this receptor, CCL3, CCL4, and CCL5, are expressed at sites of inflammation during acute GVHD. 4,[8][9][10][11] CCR5 may play a role in directing effector cells to sites of inflammation. [12][13][14][15] Interestingly howeve...