Differential expression of chemokines and chemokine receptors in murine islet allografts: the role of CCR2 and CCR5 signaling pathways.
Chemokines and their receptors play a pivotal role in the initiation and amplification of the immune response. Investigated was their differential expression after syngeneic and allogeneic islet transplantation. During the 7 d after transplantation, the chemokines MCP-1, MCP-2, RANTES, MIG, IP-10, I-TAC, and two CC chemokine receptors CCR2 and CCR5 were highly expressed in allografts when compared with isografts. Disrupting the CCR2 and CCR5 pathways individually resulted in prolongation of the survival time 16.1 +/- 0.4 and 15.8 +/- 0.9 d, respectively, of fully major histocompatibility complex-mismatched islet grafts compared with wild-type controls (11.2 +/- 1.0 d). Blockade of both receptors had no synergistic effect. Rapamycin-treated wild-type recipients rejected their grafts at 17.4 +/- 2.2 d, in contrast to rapamycin-treated CCR2-/- recipients at 38 +/- 8.6 d (P = 0.025). The disruption of the CCR2 and CCR5 signaling, alone or in combination, moderately prolong islet allograft survival. However, the combination of low-dose immunosuppression and targeting of CCR2 greatly augmented islet graft survival.
Schröppel
Bernd
B
Division of Nephrology, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Zhang
Nan
N
Chen
Peng
P
Zang
Weiping
W
Chen
Dongmei
D
Hudkins
Kelly L
KL
Kuziel
William A
WA
Sung
Randall
R
Bromberg
Jonathan S
JS
Murphy
Barbara
B
D000818:Animals; D002470:Cell Survival; D018925:Chemokines / Q000096:biosynthesis*; D016207:Cytokines / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D017403:In Situ Hybridization; D007515:Islets of Langerhans / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation; D008214:Lymphocytes / Q000166:cytology; D008285:Major Histocompatibility Complex; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors
C515335:Ccr2 protein, mouse; D018925:Chemokines; D016207:Cytokines; D018076:DNA, Complementary; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D020123:Sirolimus