CCR5 blockade modulates inflammation and alloimmunity in primates.
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 Delta32 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.
Division of Cardiac Surgery, Department of Surgery, University of Maryland and Baltimore Veterans Administration Medical Center, Baltimore, MD 21201, USA.
Carsten
C
Schröder
Richard N
RN
Pierson
Bao-Ngoc H
BN
Nguyen
Douglas W
DW
Kawka
Laurence B
LB
Peterson
Guosheng
G
Wu
Tianshu
T
Zhang
Martin S
MS
Springer
Sal J
SJ
Siciliano
Susan
S
Iliff
Julia M
JM
Ayala
Min
M
Lu
John S
JS
Mudgett
Kathy
K
Lyons
Sander G
SG
Mills
Geraldine G
GG
Miller
Irwin I
II
Singer
Agnes M
AM
Azimzadeh
Julie A
JA
DeMartino
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects / Q000276:immunology; D065100:CCR5 Receptor Antagonists; D016572:Cyclosporine / Q000008:administration & dosage; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D007518:Isoantibodies / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology; D008252:Macaca fascicularis; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage*; D013312:Stress, Physiological / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology; D014184:Transplantation, Homologous; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014652:Vascular Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
D065100:CCR5 Receptor Antagonists; C480490:CMPD 167; D007166:Immunosuppressive Agents; D007518:Isoantibodies; D011720:Pyrazoles; D016572:Cyclosporine; D014633:Valine