CCR1/CCL5 (RANTES) receptor-ligand interactions modulate allogeneic T-cell responses and graft-versus-host disease following stem-cell transplantation

Abstract

Acute graft-versus-host disease (GVHD) and leukemic relapse are serious complications of allogeneic stem-cell transplantation (SCT). Recruitment of activated T cells to host target tissues or sites of leukemic infiltration (graft-versusleukemia [GVL]) is likely mediated by chemokine receptor-ligand interactions.We examined the contribution of donor cell CCR1 expression to the development of GVHD and GVL using a well-established murine SCT model (B6 3 B6D2F1) and CCR1-deficient mice (CCR1 ؊/؊ ). Allo-SCT with CCR1 ؊/؊ donor cells significantly reduced systemic and target organ GVHD severity, and CCR1 expression on both T cells and accessory cells contributed to GVHD mortality. Significant GVL activity was preserved following CCR1 ؊/؊ SCT, but the survival advantage diminished with increasing tumor burden. We then explored the effects of CCR1 expression on allo-specific T-cell responses. Although cytolytic effector function was maintained on a per-cell basis, T-cell proliferation and IFN␥ secretion were significantly reduced both in vivo and in vitro. T-cell function was partially dependent on interactions between CCR1 and CCL5.Collectively, these data demonstrate that CCR1 expression on donor cells contributes to the development of both GVHD and GVL, and suggest that CCR1/CCL5 receptorligand interactions modulate allo-specific T-cell responses occurring in this context. IntroductionAllogeneic stem-cell transplantation (allo-SCT) is an important therapeutic option for a variety of malignant and nonmalignant disorders. 1 Acute graft-versus-host disease (GVHD) is the most frequent and serious complication following allo-SCT and continues to limit the broader application of this therapy. 2 In the context of hematologic malignancies, a delicate balance exists between the harmful consequences of GVHD and the beneficial effects incurred when donor T cells attack recipient malignant cells, a process referred to as the graft-versus-leukemia (GVL) effect. 3,4 A better understanding of the mechanisms responsible for these graft-versushost reactions may ultimately allow for directed therapies that promote GVL while reducing GVHD. 5 The pathophysiology of acute GVHD is complex. Experimental and clinical data suggest that host antigen-presenting cells (APCs) present alloantigen to donor T cells and initiate a cascade of events resulting in the development of cytotoxic effectors and the release of inflammatory proteins including cytokines and chemokines. 6 Activated donor leukocytes subsequently traffic to specific host tissues, where they, along with soluble effectors, cause end organ damage and dysfunction.Leukocyte migration is characterized by an orchestrated process involving interactions between white blood cells (WBCs) and endothelial cells that are mediated by adhesion molecules, chemoattractants, and their receptors. Chemokines are a large family of chemotactic cytokines that interact with specific G-proteincoupled chemokine receptors. 7 Chemokines are involved in both the innate and adaptive immune responses, 8 and h...

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

“…11,[25][26][27]50,68 As suggested by Wysocki et al, 32 cellular sources of chemokines may differ between specific target organs. Our results showing peak CCL3 expression in the gut and tongue early after allo-BMT, followed by a continuous decline, strengthen the concept that increased CCL3 production in these organs derives from host cells, 50 whereas in contrast, the observed increase in CCL3 expression in the liver and lung over the first 3 Figure 7 Chemokine expression is increased both on mRNA and on protein levels in aGVHD target organs after allogeneic BMT.…”

“…Increased expression of a number of chemokines and chemokine receptors in GVHD target organs has been described earlier, [18][19][20][21] and previous studies have further shown that targeting one specific chemokine or chemokine receptor can result in the reduction of aGVHDrelated injury to various target organs. 11,[22][23][24][25][26][27][28][29][30][31][32] Interestingly, tropism and efficacy of such a strategy differed depending on the chemokine and/or the chemokine receptor involved, 33 suggesting that the enhanced expression of chemokines after allo-BMT may differ between organs with respect to quality, quantity and kinetics.…”

“…5,6 Chemokine expression can be enhanced by inflammatory cytokines, 7 and chemokines have an important role in recruiting cells of the innate and adaptive immune system to the sites of inflammation. [8][9][10] Furthermore, they can have additional functions in the context of leukocyte activation, 11 angiogenesis, 12,13 hematopoiesis 14 and organization or function of secondary lymphoid tissues. [15][16][17] The chemokine-chemokine receptor system shows high complexity and redundancy with more than one chemokine binding to one receptor and multiple receptors interacting with one chemokine.…”

Expansion of highly differentiated CD8+ T-cells or NK-cells in patients treated with dasatinib is associated with cytomegalovirus reactivation

“…Such chemotactic effects have been shown to be relevant for leukemia control. 45,46 Of note, some of these soluble factors are typically produced by antigen-specific CD8 þ T-cells during viral infections and are associated with anti-viral processes. Indeed, a causative role for infections with herpes viruses has already been postulated in the pathogenesis of LGL expansions.…”

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

“…5). Interestingly, both cytokines have previously been shown to be critically involved in allograft rejection, GVHD, and autoimmunity (67)(68)(69)(70)(71)(72)(73)(74).…”