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CCR5 Blockade Modulates Inflammation and Alloimmunity in Primates¹

Carsten Schröder^2,*,, Richard N. Pierson, III^2,3,*,, Bao-Ngoc H. Nguyen^2,*,, Douglas W. Kawka, Laurence B. Peterson, Guosheng Wu^*,, Tianshu Zhang^*,, Martin S. Springer, Sal J. Siciliano, Susan Iliff, Julia M. Ayala, Min Lu, John S. Mudgett, Kathy Lyons, Sander G. Mills, Geraldine G. Miller, Irwin I. Singer^2,, Agnes M. Azimzadeh^*, and Julie A. DeMartino^2,

^* Division of Cardiac Surgery, Department of Surgery, University of Maryland and Baltimore Veterans Administration Medical Center, Baltimore, MD 21201; Department of Cardiothoracic Surgery, Vanderbilt University and Nashville Veterans Administration Medical Center, Nashville, TN 37232; Merck Research Laboratories, Rahway, NJ 07065; and Division of Infectious Disease, Department of Medicine, Vanderbilt University and Nashville Veterans Administration Medical Center, Nashville, TN 37232

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 32 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was presented in part orally and in abstract form at the American Transplant Congress and the International Society for Heart and Lung Transplantation annual meetings 2002–2006. This work was supported by a Merck Research Laboratory sponsored research agreement and gift, National Institutes of Health Grant U01 AI 066719, and an American Heart Association Award (0455722U) (to R.N.P.); National Institutes of Health Grant F32 HL079818 and Thoracic Surgery Foundation for Research and Education resident research awards (to B.-N.H.N.); Deutsche Forschungsgemeinschaft research award (to C.S.); and an Other Tobacco Related Diseases research grant from the Maryland Cigarette Restitution Fund Program.

² C.S. and R.N.P. contributed equally to the first authorship of this study. C.S. and B.-N.H.N. were primarily responsible for the conduct of the in vivo studies, and C.S. made the cardinal observation regarding the effect of CCR5 inhibition on the febrile response. In conjunction with J.A.D. and I.I.S., R.N.P. was primarily responsible for study design and manuscript authorship.

³ Address correspondence and reprint requests to Dr. Richard N. Pierson III, Division of Cardiac Surgery, University of Maryland, 22 South Greene Street, Room N4W94, Baltimore, MD 21201. E-mail address: rpierson{at}smail.umaryland.edu

⁴ Abbreviations used in this paper: CMPD 167, compound 167 (N-[(1R,3S,4S)-3-((4-(3-benzyl-1-ethylpyrazol-5-yl)piperidin-1-yl)methyl)-4-(3-fluorophenyl)cyclopentan-1-yl]-N-methyl-D-valine; bid, twice daily (bis in die); CAV, cardio allograft vasculopathy; CsA, cyclosporine; ISHLT, International Society of Heart and Lung Transplantation.

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