The role of CC chemokine receptor 5 (CCR5) in islet allograft rejection.
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-gamma 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.
Abdi
Reza
R
Laboratory of Immunogenetics and Transplantation, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Smith
R Neal
RN
Makhlouf
Leila
L
Najafian
Nader
N
Luster
Andrew D
AD
Auchincloss
Hugh
H
Sayegh
Mohamed H
MH
D000818:Animals; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D006085:Graft Survival / Q000276:immunology*; D006650:Histocompatibility Testing; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000473:pathology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D018345:Mice, Knockout; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D019707:Receptors, Chemokine / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D018925:Chemokines; D016207:Cytokines; D019713:Receptors, CCR5; D019707:Receptors, Chemokine