TY - JOUR
T1 - CCR5 blockade modulates inflammation and alloimmunity in primates
AU - Schröder, Carsten
AU - Pierson, Richard N.
AU - Nguyen, Bao Ngoc H.
AU - Kawka, Douglas W.
AU - Peterson, Laurence B.
AU - Wu, Guosheng
AU - Zhang, Tianshu
AU - Springer, Martin S.
AU - Siciliano, Sal J.
AU - Iliff, Susan
AU - Ayala, Julia M.
AU - Lu, Min
AU - Mudgett, John S.
AU - Lyons, Kathy
AU - Mills, Sander G.
AU - Miller, Geraldine G.
AU - Singer, Irwin I.
AU - Azimzadeh, Agnes M.
AU - DeMartino, Julie A.
PY - 2007/8/15
Y1 - 2007/8/15
N2 - Pharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Δ32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck's compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.
AB - Pharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Δ32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck's compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.
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U2 - 10.4049/jimmunol.179.4.2289
DO - 10.4049/jimmunol.179.4.2289
M3 - Article
C2 - 17675490
AN - SCOPUS:34848869334
SN - 0022-1767
VL - 179
SP - 2289
EP - 2299
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -