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To the Editor:

I read with great interest the recent article by Zeremski et al.1 The authors have clearly demonstrated that intrahepatic levels of chemokine receptor 3 (CXCR3)–associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C. The findings of Zeremski et al. are highly important as they highlight the role of CXC3 in hepatic inflammation and the potential clinical applications of a state of CXCR3 deficiency or CXCR3 blockage.

For instance, blockage of CXCR3 function decreases the acute rejection of allografts.2 Similarly, CXCR3 deficiency seems to have a protective effect against cerebral malaria–induced mortality.3 Moreover, CXCR3 deficiency protects influenza-infected chemokine receptor 5–deficient mice from mortality.4 Clearly, induced CXCR3 deficiency has its advantages in certain clinical scenarios.

Interestingly, a number of new clinical antagonists of CXCR3 have emerged over the past few years that are proving to be of significant benefit in inducing a state of CXCR3 deficiency. For instance, NBI-74330 is a recently identified potent CXCR3 antagonist. In fact, NBI-74330 has been shown to decrease the migration of CXCR3+ effector cells, thereby decreasing the formation of vascular atherosclerotic plaques.5 Similarly, anti-CXCR3 neutralizing antibodies block graft-versus-host disease following allografts.6 Moreover, benzimidazole antagonists of CXCR3 have been identified recently.7 In fact, 3H-pyrido[2,3-d]pyrimidin-4-ones such as AMG 487 and 3H-quinazolin-4-ones are rapidly emerging as potent CXCR3 antagonists.8

However, CXCR3 blockade is also associated with significant side effects. For instance, accentuated renal fibrosis has been noticed following CXCR3 blockade.9 Clearly, CXCR3 blockade has major clinical advantages in certain clinical scenarios. However, further research is needed to fully elaborate its side effects to assess if it can be used for clinical applications in humans.

References

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  • 1
    Zeremski M, Petrovic LM, Chiriboga L, Brown QB, Yee HT, Kinkhabwala M, et al. Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C. HEPATOLOGY 2008; 48: 14401450.
  • 2
    Schnickel GT, Bastani S, Hsieh GR, Shefizadeh A, Bhatia R, Fishbein MC, et al. Combined CXCR3/CCR5 blockade attenuates acute and chronic rejection. J Immunol 2008; 180: 47144721.
  • 3
    Miu J, Mitchell AJ, Müller M, Carter SL, Manders PM, McQuillan JA, et al. Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency. J Immunol 2008; 180: 12171230.
  • 4
    Fadel SA, Bromley SK, Medoff BD, Luster AD. CXCR3-deficiency protects influenza-infected CCR5-deficient mice from mortality. Eur J Immunol 2008; 38: 33763387.
  • 5
    van Wanrooij EJ, de Jager SC, van Es T, de Vos P, Birch HL, Owen DA, et al. CXCR3 antagonist NBI-74330 attenuates atherosclerotic plaque formation in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 2008; 28: 251257.
  • 6
    He S, Cao Q, Qiu Y, Mi J, Zhang JZ, Jin M, et al. A new approach to the blocking of alloreactive T cell-mediated graft-versus-host disease by in vivo administration of anti-CXCR3 neutralizing antibody. J Immunol 2008; 181: 75817592.
  • 7
    Hayes ME, Wallace GA, Grongsaard P, Bischoff A, George DM, Miao W, et al. Discovery of small molecule benzimidazole antagonists of the chemokine receptor CXCR3. Bioorg Med Chem Lett 2008; 18: 15731576.
  • 8
    Storelli S, Verzijl D, Al-Badie J, Elders N, Bosch L, Timmerman H, et al. Synthesis and structure-activity relationships of 3H-quinazolin-4-ones and 3H-pyrido [2,3-d] pyrimidin-4-ones as CXCR3 receptor antagonists. Arch Pharm Chem 2007; 340: 281291.
  • 9
    Nakaya I, Wada T, Furuichi K, Sakai N, Kitagawa K, Yokoyama H, et al. Blockade of IP-10/CXCR3 promotes progressive renal fibrosis. Nephron Exp Nephrol 2007; 107: e12e21.

Shailendra Kapoor M.D.*, * Schaumburg, IL 60195.