The role of CC chemokine receptor 5 (CCR5) in islet allograft rejection

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 enzymelinked 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.