Chemokines and graft-versus-host disease - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 413

complexity, redundancy, and pleiotropy inherent to the chemokine system
could significantly hamper successful translation of mechanistic insights
from bench to bedside. One way to overcome this problem could be the
use of agents that inhibit the binding capacity or the intracellular signal-
ing pathways of two or more receptors at the same time [117] . Such “pro-
miscuous antagonists” have been recently developed and act as functional
chemokine inhibitors [116] . One member of this group of broad-spectrum
chemokine inhibitors, NR58-3.14.3, has been successfully tested in murine
GVHD, reducing target organ injury to the lung and to the liver [118] .
Conclusions
GVHD remains the most significant barrier to successful outcomes follow-
ing allogeneic HCT. Diffuse injury to host tissues incurred by HCT condi-
tioning regimens results in a proinflammatory milieu that sets the stage for
chemokine upregulation, lymphocyte activation, and subsequent effector
leukocyte infiltration into target organs during the development of GVHD.
Chemokines are critical extracellular messengers that directly modulate
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FIGURE 17.2
Chemokines and leukocyte trafficking after allogeneic HCT. Leukocyte trafficking following allogeneic HCT is a complex process. After the infusion of the donor mar-
row or peripheral blood inoculum, HSCs home to the bone marrow microenvironment to recapitulate elements of the hematopoietic and peripheral immune systems in the
HCT recipient. Recent studies support a role for CXCR4 in both HSC homing and myeloid maturation. Upregulation of CCR7on the surface of host APCs occurs in parallel
and facilitates the migration of these cells to secondary lymphoid tissue, where they interact with mature donor T cells. Once engaged, donor T cells become activated
and differentiate into T1 effectors. Significant experimental data have shown that cells of the lymphoid and myeloid lineages synergize to cause systemic inflammation
and target organ damage that are characteristic of acute GVHD. The recruitment of cellular effectors to GVHD target tissue is dependent, in part, upon the upregulation
of chemokine receptors on donor leukocytes including CXCR3, CCR5, and CCR1 on T1 CTLs; CCR2 (and possibly CCR5) on cells of the monocyte/macrophage lineage;
and CXCR2 on neutrophils. Donor leukocytes that have been released from secondary lymphoid tissues or the bone marrow are recruited to GVHD target organs by the
respective chemokine ligands that have been upregulated by a proinflammatory environment that characterizes the evolving GVH reaction. In some cases unique chemo-
kine receptor:ligand interactions facilitate tissue-specific homing of effector T cells to the skin (CCR4:CCL17/CCL22 and CCR10:CCL27) or intestine (CCR9:CCL25).