The Role of CC Chemokine Receptor 5 (CCR5) in Islet Allograft Rejection
- Reza Abdi1,
- R. Neal Smith2,
- Leila Makhlouf1,
- Nader Najafian1,
- Andrew D. Luster3,
- Hugh Auchincloss, Jr.4 and
- Mohamed H. Sayegh1
- 1Laboratory of Immunogenetics and Transplantation, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- 2Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- 3Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- 4Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
Abstract
Chemokines are important regulators in the development, differentiation, and anatomic location of leukocytes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4+ T helper 1 (Th1) cells. We sought to determine the role of CCR5 in islet allograft rejection in a streptozotocin-induced diabetic mouse model. BALB/c islet allografts transplanted into CCR5−/− (C57BL/6) recipients survived significantly longer (mean survival time, 38 ± 8 days) compared with those transplanted into wild-type control mice (10 ± 2 days; P < 0.0001). Twenty percent of islet allografts in CCR5−/− animals without other treatment survived >90 days. In CCR5−/− mice, intragraft mRNA expression of interleukin-4 and -5 was increased, whereas that of interferon-γ was decreased, corresponding to a Th2 pattern of T-cell activation in the target tissues compared with a Th1 pattern observed in controls. A similar Th2 response pattern was also observed in the periphery (splenocytes responding to donor cells) by enzyme-linked immunosorbent spot assay. We conclude that CCR5 plays an important role in orchestrating the Th1 immune response leading to islet allograft rejection. Targeting this chemokine receptor, therefore, may provide a clinically useful strategy to prevent islet allograft rejection.
Footnotes
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Address correspondence and reprint requests to Mohamed H. Sayegh, Laboratory of Immunogenetics and Transplantation, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. E-mail: msayegh{at}rics.bwh.harvard.edu.
Received for publication 19 December 2001 and accepted in revised form 24 April 2002.
CCL, CC chemokine ligand; CCR, CC chemokine receptor; CXCR, CXC chemokine receptor; ELISPOT, enzyme-linked immunosorbent spot; IFN, interferon; IL, interleukin; IP, inducible protein; MHC, major histocompatibility complex; Mig, monokine induced by interferon-γ; MIP, macrophage inflammatory protein; MLR, mixed lymphocyte response; RANTES, regulated on activation normal T-cell expressed and secreted; RPA, ribonuclease protection assay; Th, T helper.
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