CC Chemokine Receptor 5 Deficiency Does Not Prevent Local Immune Responses to Adenovirus Vector in Islet Transplant Recipients

Abstract

CC chemokine receptor 5 (CCR5) plays an important role in mediating inflammation. We examined the effect of CCR5 on the immune response to adenovirus vectors and graft function in islet transplant model. Syngeneic wild-type (WT) or CCR5-deficient (KO) mouse islets transduced with adenovirus encoding β-gal were transplanted under the renal capsule. After transplant, blood glucose, glucose tolerance, graft cellular infiltration, transgene and chemokine/receptor expression, and systemic anti-adenoviral/-β-gal immune response were evaluated. Diabetes was reversed in 1 d in both WT and KO untransduced recipients, while islets transduced with adenovirus failed to reverse diabetes until 10d post-transplant in WT recipients or even longer (>15d) in KO recipients (P < 0.05). A profound infiltration of CD4(+), CD8(+) cells and macrophages was observed in both WT and KO transduced grafts at 25 d. Though transgene expression was significantly reduced, insulin and β-gal expression persisted over 3mo. Glucose tolerance was impaired in all grafts in KO recipients compared with untransduced grafts in WT recipients at 25 d post-transplant, but was equivalent at 3 mo. Early expression of CCR2 mRNA was increased in transduced grafts in both WT and KO recipients. No systemic antivector immunity was demonstrated in any recipient group. Transduction of islets with adenovirus causes significant local inflammation in islet grafts and impairs early graft function in CCR5-deficient recipients, but long-term graft function is preserved. Thus, CCR5 absence does not prevent the local immune response to adenovirus transduction, and vector-associated graft dysfunction is not mediated by CCR5.