Role of CXCL9/CXCR3 Chemokine Biology during Pathogenesis of Acute Lung Allograft Rejection

Belperio, John A.; Keane, Michael P.; Burdick, Marie D.; Lynch, Joseph P.; Zisman, David A.; Xue, Ying; Li, Kewang; Ardehali, A.; Ross, David J.; Strieter, Robert M.

doi:10.4049/jimmunol.171.9.4844

Cited by 113 publications

(111 citation statements)

References 52 publications

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“…It is intriguing, however, that the upregulation of IP-10 gene activity might not be that strictly dependent on IFN and has also been associated with alloantigen-independent organ damage (37,38). Moreover, recent evidence supports the notion of a dominant role of MIG over IP-10, especially in cellular alloantigen-driven acute rejection processes (14,26,31,39).…”

Section: Discussionmentioning

confidence: 81%

Prediction of Acute Renal Allograft Rejection by Urinary Monokine Induced by IFN-γ (MIG)

Hauser¹,

Spiegler²,

Kiss³

et al. 2005

Journal of the American Society of Nephrology

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Early diagnosis of acute allograft rejection (AR) is still decisive for long-term renal allograft survival. The aim of this study was to define the role of the chemokine monokine induced by IFN-␥ (MIG) (CXCL9) and IFN-␥-inducible protein 10 (IP-10) (CXCL10) as early markers of AR in renal transplantation (NTX). In a prospective study, 69 de novo renal transplant recipients were monitored and urine samples were collected after NTX for a median of 29 d. In pH-adjusted urine, MIG and IP-10 were determined by modified ELISA. AR was clinically diagnosed in 15 of 69 recipients and confirmed by biopsy in 14 of 15 AR patients (Banff classification). Corresponding to CXCR3-positive infiltrates in renal tissue, urinary MIG was elevated in 14 of 15 AR patients with a median of 2809 pg/ml (quartile 25% and 75% ‫؍‬ 870 and 13,000; n ‫؍‬ 15), being significantly (P < 0.0001) different from both nonrejecting allograft patients (NO-AR) (median, 25%, and 75%: 96, 1.0, and 161, n ‫؍‬ 54) and healthy controls (median, 25%, and 75%: 144, 19, and 208, n ‫؍‬ 13). Urinary MIG predicted AR with a sensitivity of 93% and a specificity of 89%. In AR and NO-AR groups, MIG values correlated well with IP-10 (P < 0.001). MIG values indicated both imminent rejection and response to successful antirejection therapy. MIG was not related to intercurrent infections or other causes for impairment of renal function. In a multivariate analysis, MIG correlated best (P < 0.001) with AR from all AR-associated parameters. In conclusion, urinary MIG serves as a very sensitive and specific predictor for AR, mirrors response to antirejection therapy, and thus may contribute to improved long-term renal allograft survival.

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Section: Discussionmentioning

confidence: 81%

Prediction of Acute Renal Allograft Rejection by Urinary Monokine Induced by IFN-γ (MIG)

Hauser¹,

Spiegler²,

Kiss³

et al. 2005

Journal of the American Society of Nephrology

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“…These chemokines direct recruitment of alloantigen-primed T cells and other effector leukocytes into the allograft (80)(81)(82). These chemokines include the CXCR3 ligands and the CCR5 ligands.…”

Section: Chemokines In the Rejection Responsementioning

confidence: 99%

Lung Transplantation: Opportunities for Research and Clinical Advancement

Wilkes¹

2006

Am J Respir Crit Care Med

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Lung transplantation is the only definitive therapy for many forms of end-stage lung diseases. However, the success of lung transplantation is limited by many factors: (1 ) Too few lungs available for transplantation due to limited donors or injury to the donor lung; (2 ) current methods of preservation of excised lungs do not allow extended periods of time between procurement and implantation; (3 ) acute graft failure is more common with lungs than other solid organs, thus contributing to poorer short-term survival after lung transplant compared with that for recipients of other organs; (4 ) lung transplant recipients are particularly vulnerable to pulmonary infections; and (5 ) chronic allograft dysfunction, manifest by bronchiolitis obliterans syndrome, is frequent and limits long-term survival. Scientific advances may provide significant improvements in the outcome of lung transplantation. The National Heart, Lung, and Blood Institute convened a working group of investigators on June 14-15, 2004, in Bethesda, Maryland, to identify opportunities for scientific advancement in lung transplantation, including basic and clinical research. This workshop provides a framework to identify critical issues related to clinical lung transplantation, and to delineate important areas for productive scientific investigation. Keywords: allograft dysfunction; infection; ischemia-reperfusion injury; lung transplantation; obliterative bronchiolitis; rejectionThe transplantation of organs offers the promise of life-saving and life-enhancing therapy for a variety of ailments. Lung transplantation (LTx) has become an acceptable therapy to palliate patients with a variety of end-stage lung diseases. However, lung transplantation has not turned out to be a panacea for chronic lung disease because of significant limitations in the entire transplant process (Figure 1). First, there are not nearly enough suitable donor lungs to meet the needs of all patients with end-stage lung disease. As a result, more patients die waiting for transplants than from mortality associated with a lung transplant. Second, early graft survival after LTx is worse than for other types of organs transplanted (1). Finally, late survival after successful LTx is hampered by the development of chronic allograft dysfunction and by the life-limiting complications associated with conventional immunosuppressive medications. Two factors impede progress to address these problems: (1 ) lung transplant centers lack the infrastructure to facilitate prospective, multicenter clinical studies of sufficient power to address clinical questions and (2 ) there are too few investigators studying the biology of lung transplantation.The NHLBI convened a workshop on June 14-15, 2004, to better understand these complex problems and to identify strategies to address these and prioritize them. The topics addressed by participants were wide-ranging. They included the following: lung use rates from conventional brain-dead organ donors; safe limits for donor lung function; consideration o...

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“…These three chemokines have been shown to stimulate the chemotaxis of CXCR3 ϩ -activated T cells and NK cells in vitro (10, 15, 18 -21). Moreover, CXCL9 and CXCL10 have been shown to be pivotal for T cell migration in various experimental disease models including transplant rejection (22)(23)(24)(25), infectious disease, autoimmunity and tumor immunity (26 -29). Taken together, these observations support the notion that CXCR3 signaling is fundamental to T and NK cell trafficking in cell-mediated immunity.…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

CXCR3 Signaling Reduces the Severity of Experimental Autoimmune Encephalomyelitis by Controlling the Parenchymal Distribution of Effector and Regulatory T Cells in the Central Nervous System

Müller¹,

Carter²,

Höfer³

et al. 2007

The Journal of Immunology

183

145

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The chemokine receptor CXCR3 promotes the trafficking of activated T and NK cells in response to three ligands, CXCL9, CXCL10, and CXCL11. Although these chemokines are produced in the CNS in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), their role in the pathogenesis of CNS autoimmunity is unresolved. We examined the function of CXCR3 signaling in EAE using mice that were deficient for CXCR3 (CXCR3−/−). The time to onset and peak disease severity were similar for CXCR3−/− and wild-type (WT) animals; however, CXCR3−/− mice had more severe chronic disease with increased demyelination and axonal damage. The inflammatory lesions in WT mice consisted of well-demarcated perivascular mononuclear cell infiltrates, mainly in the spinal cord and cerebellum. In CXCR3−/− mice, these lesions were more widespread throughout the CNS and were diffused and poorly organized, with T cells and highly activated microglia/macrophages scattered throughout the white matter. Although the number of CD4+ and CD8+ T cells infiltrating the CNS were similar in CXCR3−/− and WT mice, Foxp3+ regulatory T cells were significantly reduced in number and dispersed in CXCR3−/− mice. The expression of various chemokine and cytokine genes in the CNS was similar in CXCR3−/− and WT mice. The genes for the CXCR3 ligands were expressed predominantly in and/or immediately surrounding the mononuclear cell infiltrates. We conclude that in EAE, CXCR3 signaling constrains T cells to the perivascular space in the CNS and augments regulatory T cell recruitment and effector T cell interaction, thus limiting autoimmune-mediated tissue damage.

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Role of CXCL9/CXCR3 Chemokine Biology during Pathogenesis of Acute Lung Allograft Rejection

Cited by 113 publications

References 52 publications

Prediction of Acute Renal Allograft Rejection by Urinary Monokine Induced by IFN-γ (MIG)

Prediction of Acute Renal Allograft Rejection by Urinary Monokine Induced by IFN-γ (MIG)

Lung Transplantation: Opportunities for Research and Clinical Advancement

CXCR3 Signaling Reduces the Severity of Experimental Autoimmune Encephalomyelitis by Controlling the Parenchymal Distribution of Effector and Regulatory T Cells in the Central Nervous System

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