Chemokines and their Receptors in Human Renal Allotransplantation

• Authors: Denise Jennifer Lo, Emory University; Tim A. Weaver, Emory University; David E. Kleiner, NIH; Roslyn B. Mannon, NIH; Lynn M. Jacobson, University of Wisconsin; Bryan N. Becker, University of Wisconsin; S. John Swanson, NIH; Douglas A. Hale, NIH; Allan D Kirk, Emory University
• Journal Title: Transplantation
• Volume: Volume 91, Number 1
• Publisher: Lippincott, Williams & Wilkins | 2011-01-15, Pages 70-77
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1097/TP.0b013e3181fe12fc
• Subjects: Health Sciences, Pathology; Health Sciences, Medicine and Surgery
• Keywords: Chemokines; Renal Transplantation; RT-PCR

Abstract

Background Chemokines and their receptors play a critical role in leukocyte trafficking, and inhibition of select chemokines has been shown to attenuate kidney disease and allograft rejection in animal models. We therefore evaluated chemokine and chemokine receptor transcripts in human renal allograft biopsies, correlating transcript levels with clinical course and immunohistochemical analysis to relate chemokine expression to relevant clinical human disease phenotypes. Methods Renal biopsies were grouped as post-reperfusion (n=10), stable function (n=10), subclinical (n=10) or acute rejection (n=17), or calcineurin inhibitor nephrotoxicity (n=9) based on clinical presentation and histopathological assessment. Using quantitative real-time polymerase chain reaction analysis, chemokine transcripts were assessed relative to transcript levels in pre-procurement biopsies from live donor kidneys (n=15). Results Transcripts from several inflammatory chemokines (CCL3, CCL5, CXCL9, CXCL10 and CXCL11) and chemokine receptors (CCR5, CCR7 and CXCR3) were significantly elevated in allografts with subclinical and clinical acute rejection, indicating a strong polarization toward a TH1 effector phenotype during rejection. These transcripts also distinguished acutely rejecting allografts from allografts with non-rejection causes of renal dysfunction. Biopsies from patients with stable function without histological evidence of rejection had increased chemokine transcript levels that were qualitatively similar but quantitatively reduced compared to rejecting allografts. Conclusions This comprehensive evaluation of chemokines and their receptors in human renal transplantation defines associations between chemokine expression and clinical phenotypes, may have diagnostic utility, and highlights relevant pathways for therapeutic intervention.