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

Biology Reference

In-Depth Information

396

FIGURE 17.1

Chemokine cascades after HCT. Chemokines function in many aspects of GVHD pathophysiology. HCT preparative regimens induce proinflammatory cytokine secre-

tion that results in diffuse injury to a variety of tissues and upregulates chemokine expression. This proinflammatory environment enhances the ability of host antigen

presenting cells (APCs) to interact with mature donor T cells by [1] enhancing APC maturation, [2] facilitating the migration of APCs to secondary lymphoid tissue (via

upregulation of CCR7, CCR4, and CXCR4), and [3] upregulating MHC, adhesion, and costimulatory molecules. Once engaged, donor T cells are activated and differentiate

into T1 (acute), T17 (acute), or T2 (chronic) GVHD effector cells and preferentially express specific chemokine receptors. Thus, the expression of the cognate ligands for

these receptors may result in different outcomes during chronic or acute GVHD. In some cases, unique chemokine receptor:ligand interactions facilitate tissue-specific

homing of effector T cells to the skin (CCR4/CCR10) or gut (CCR9). Chemokines including CCL2, CCL3, and CCL5 can also enhance APC:T-cell interactions and, along

with CXCL10 and CXCL8, can positively influence the activation, recruitment, and function of other immune cells, including monocytes, NK cells, and neutrophils. By

contrast, chemokine receptor expression can orchestrate the immunomodulatory effects of Tregs, either to secondary lymphoid tissues (CCR7) or to inflamed target tissue

(CCR5, CXCR3). Finally a growing body of data supports the interplay between the adaptive and the innate immune responses during GVHD. Not only are monocytes

and macrophages “primed” by T-cell-generated IFN- γ to secrete cytopathic cytokines during the effector phase of GVHD, but infiltrating T cells may also modulate the

subsequent recruitment of accessory cells (macrophages and polymorphonuclear cells) by release of TNF- α , CCL3, and CCL5. In addition, neutrophils may contribute to

T-cell activation via the release of defensins, which, via Toll-like receptors, can enhance APC maturation and function.

be speculated/predicted. The first stage of GVHD involves the effects of HCT

conditioning regimens on host tissues. Stage 2 centers upon the activation

and expansion of donor T cells. Data suggest that blood-derived, host APCs

play a significant, but not exclusive, role in this response [10,11] . Alloantigen-

specific donor T-cell clones expand, migrate to GVHD target organs, and ulti-

mately secrete cytokines (and chemokines) that recruit other immune cells

to sites of inflammation. Inflammatory cytokine release, in combination

with direct cell-mediated killing, contributes to the third and final effector

phase of GVHD, which culminates in target tissue injury and dysfunction.

The possible roles of chemokines in each of these stages will be explored.

Chemokine biology