Leukocyte migration and graft-versus-host disease

Abstract

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.

Figure 1.

Inflammatory chemokines and receptors.^,- APC indicates antigen-presenting cell; B, B cell; D, dendritic cell; E, eosinophil; L, Langerhan cell; Ma, mast cell; Mϕ, macrophage; N, neutrophil; NK, natural killer cell; P, platelet; T1, T_H1/T_C1 cell; and T2, T_H2/T_C2 cell. DC indicates dendritic cell; GRO, growth-related oncogene; I-TAC, inducible T cell alpha chemoattractant; MCP, macrophage chemotactic protein; HCC, hemofiltrate CC chemokine; MIP, macrophage inflammatory protein; RANTES, regulated on activation normal T cell expressed and secreted; TARC, thymus and activation regulated chemokine; MDC, macrophage-derived chemokine; CTACK, cutaneous T-cell–attracting chemokine; MEC, mucosae-associated epithelial chemokine; and TECK, thymus-expressed chemokine.

Figure 2.

Chemokines and receptors in GVHD target organs. Boldface text denotes chemokines and receptors whose role in acute GVHD has not been demonstrated experimentally.

Figure 3.

Model for early donor T-cell migration during acute GVHD.^-,- (A) Recipients of allo-BM transplant receive conditioning therapy, followed by intravenous infusion of bone marrow or peripheral blood stem cells (containing mature donor T cells). Within the first hours after transplantation, donor T cells (green) accumulate in peripheral lymphoid tissues such as LNs, Peyer patches, and spleen. (B) Alloreactive donor T cells expand in peripheral lymphoid tissues, differentiating into T_H1/T_C1 effectors, and producing IFN-γ, TNFα, and other cytokines (light blue arrows). (C) Circulating IFN-γ synergizes with inflammatory mediators and bacterial products released into circulation by the conditioning regimen to induce production of interferon-inducible chemokines (blue gradient arrows) by APCs and endothelial and epithelial cells in target organs. (D) Activated effector T cells follow gradients of these chemokines during early target organ infiltration (green arrows). (E) Amplification of T-cell infiltrates: donor T cells having infiltrated target organs produce T-cell–tropic chemokines CCL3, CCL4, and CCL5 (and possibly others) (pink gradient arrows). (F) Effector cells continue to follow gradients of these chemokines to infiltrate target organs (green arrows), leading to tissue pathology and clinical manifestations of GVHD, represented by green infiltrates in GI tract, liver, lung, and skin.