The chemokine receptor Cxcr3 is not essential for acute cardiac allograft rejection in mice and rats.
Chemokine receptors have gained attention as potential targets for novel therapeutic strategies. We investigated the mechanisms of allograft rejection in chemokine receptor Cxcr3-deficient mice using a model of acute heart allograft rejection in the strain combination BALB/c to C57BL/6. Allograft survival was minimally prolonged in Cxcr3-deficient mice compared to wild-type (wt) animals (8 vs. 7 days) and treatment with a subtherapeutic dose of cyclosporine A (CsA) led to similar survival in Cxcr3-deficient and wt recipients (13 vs. 12 days). At rejection grafts were histologically indistinguishable. Microarray analysis revealed that besides Cxcr3 only few genes were differentially expressed in grafts or in spleens from transplanted or untransplanted animals. Transcript analysis by quantitative RT-PCR of selected cytokines, chemokines, or chemokine receptors or serum levels of selected cytokines and chemokines showed similar levels between the two groups. Furthermore, in a rat heart allograft transplantation model treatment with a small molecule CXCR3 antagonist did not prolong survival despite full blockade of Cxcr3 in vivo. In summary, Cxcr3 deficiency or pharmacologic blockade does not diminish graft infiltration, tempo and severity of rejection. Thus, Cxcr3 does not appear to play a pivotal role in the allograft rejection models described here.
Autoimmunity, Transplantation and Inflammation, Novartis Institutes for Biomedical Research, Basel, Switzerland. Hans-Guenter.Zerwes@novartis.com
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Zerwes
J
J
Li
J
J
Kovarik
M
M
Streiff
M
M
Hofmann
L
L
Roth
M
M
Luyten
C
C
Pally
R P
RP
Loewe
G
G
Wieczorek
R
R
Bänteli
G
G
Thoma
B
B
Luckow
D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage*; D006084:Graft Rejection; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D054367:Receptors, CXCR3 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous
C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D016572:Cyclosporine