Role of CXCR3-induced donor T-cell migration in acute GVHD

Duffner, Ulrich; Liu, Bao; Hildebrandt, Gerhard C.; Teshima, Takanori; Williams, Debra; Reddy, Pavan; Ordemann, Rainer; Clouthier, Shawn G.; Lowler, Kathy; Liu, Chen; Gérard, Craig; Cooke, Kenneth R.; Ferrara, James L.M.

doi:10.1016/s0301-472x(03)00198-x

Cited by 148 publications

(138 citation statements)

References 28 publications

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“…11 However, chemokine expression in target organs is influenced by transplant conditioning and recipient strain. 16,17 In this study, we focused on the liver, intestine and lung as target organs of acute GVHD and examined the expression of the ligands for CXCR3, CXCL9, CXCL10 and CXCL11 in these organs during acute GVHD.…”

Section: Resultsmentioning

confidence: 99%

“…5,7,16,17 In addition, expression of CXCR3 and CCR5, the receptors for Th1-associated chemokines (CXCL9, CXCL10 and CXCL11) and CCL3, CCL4 and CCL5, respectively, also increases significantly in the liver, lung and intestine during acute GVHD. 11,13,16 These findings suggest that in addition to CCR5 and its ligands, Th1-associated chemokines and their receptor CXCR3 are also associated with infiltration of donor T cells into target organs such as the liver, lung and intestine in conditioned GVHD.…”

Section: Introductionmentioning

confidence: 92%

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17] Several chemokines such as CCL2, CCL3, CCL4, CCL5, CCL11, CXCL9, CXCL10 and CXCL11, are expressed in the liver, intestine and lung during experimental GVHD. Studies using conditioned murine GVHD models have demonstrated a consistent pattern in the kinetics of expression of these chemokines.…”

Section: Therapy For Acute Gvhd By Cxcr3 Regulatory T Cells H Hasegawmentioning

confidence: 99%

“…3 Expression of several chemokines in target organs during GVHD has been demonstrated in a number of experimental models. [4][5][6][7][8][9][10][11][12][13][14][15] Published data on the role of chemokines in GVHD are somewhat conflicting, since upregulation of chemokines in target organs during GVHD is influenced by transplant conditioning and recipient strain. 16,17 In conditioned murine GVHD models, the expression of chemokines such as CCL2, CXCL9, CXCL10 and CXCL11 is upregulated in the liver early after GVHD induction.…”

Section: Introductionmentioning

confidence: 99%

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Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model

et al. 2007

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Adoptive transfer of CD4 + CD25 + regulatory T cells has been shown to have therapeutic effects in experimental graft-vshost disease (GVHD) models. Chemokines play an important role in the recruitment of alloreactive donor T cells into target organs during GVHD. In this study, we investigated the effectiveness of targeted delivery of CD4 + CD25 + regulatory T cells via a transfected chemokine receptor on reduction of organ damage during acute GVHD. High levels of expression of Th1-associated chemokines (CXCL9, CXCL10 and CXCL11) and their receptor CXCR3 were observed in the liver, lung and intestine of GVHD-induced recipient mice. Recipient mice that had undergone transfer of CD4 + CD25 + Foxp3 + CXCR3-transfected T cells (CXCR3-Treg cells) showed significant amelioration of GVHD changes in the liver, lung and intestine in comparison with recipient mice that had received CD4 + CD25 + Foxp3 + T cells (Treg cells) or naturally occurring CD4 + CD25 + regulatory T cells. This was due to more pronounced migration of CXCR3-Treg cells and their localization for a longer time in Th1-associated chemokine-expressing organs, resulting in stronger suppressive activity. We succeeded in preparing chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression upon accumulation in target organs. This method may provide a new therapeutic approach for organ damage in acute GVHD.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 92%

Section: Therapy For Acute Gvhd By Cxcr3 Regulatory T Cells H Hasegawmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Therapeutic effect of CXCR3-expressing regulatory T cells on liver, lung and intestinal damages in a murine acute GVHD model

et al. 2007

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“…125 T cells expressing the CXCR3 and CCR5 receptors cause acute GVHD in the GI tract and liver. [126][127][128] Interestingly, CCR5 expression on Tregs has also been found to be a critical mediator of GVHD. 129 Integrins and their ligands are also implicated in donor T-cell trafficking into target organs.…”

Section: Exogenous Administration Of Ifn-g or T Cells From Ifn-g-defimentioning

confidence: 99%

New perspectives on the biology of acute GVHD

Paczesny

Hanauer

Sun

et al. 2009

Bone Marrow Transplant

158

126

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The use of allogeneic hematopoietic cell transplantation (HCT) has increased as new techniques have been developed for transplantation in patients who previously would not have been considered HCT candidates. However, its efficacy continued to be limited by the development of frequent and severe acute GVHD. The complex and intricate pathophysiology of acute GVHD is a consequence of interactions between the donor and host innate and adaptive immune responses. Multiple inflammatory molecules and cell types are implicated in the development of GVHD that can be categorized as:(1) triggers that initiate GVHD by therapy-induced tissue damage and the antigen disparities between host and graft tissue; (2) sensors that detect the triggers, that is, process and present alloantigens; (3) mediators such as T-cell subsets (naive, memory, regulatory, Th17 and natural killer T cells) and (4) the effectors and amplifiers that cause damage of the target organs. These multiple inflammatory molecules and cell types that are implicated in the development of GVHD have been described with models that use stepwise cascades. Herein, we provide a novel perspective on the immunobiology of acute GVHD and briefly discuss some of the outstanding questions and limitations of the model systems.

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