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(American Journal of Pathology. 2006;169:424-432.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051234

AMD3465, a Novel CXCR4 Receptor Antagonist, Abrogates Schistosomal Antigen-Elicited (Type-2) Pulmonary Granuloma Formation

Jerry S. Hu*, Christine M. Freeman*, Valerie R. Stolberg{dagger}, Bo Chin Chiu*, Gary J. Bridger{ddagger}, Simon P. Fricker{ddagger}, Nicholas W. Lukacs* and Stephen W. Chensue*{dagger}

From the Department of Pathology,* University of Michigan Medical School, Ann Arbor, Michigan; the Department of Pathology and Laboratory Medicine,{dagger} Veteran’s Administration Ann Arbor Healthcare System, Ann Arbor, Michigan; and AnorMED Incorporated,{ddagger} Langley, British Columbia, Canada

CXCR4 is a major receptor for CXCL12 and is known to participate in multiple physiological systems. The present study tested a second generation CXCR4 antagonist, AMD3465, for effects on highly defined models of Th1- and Th2-cell-mediated hypersensitivity-type pulmonary granuloma formation. Type-1 and type-2 granulomas were induced, respectively, by intravenous challenge of sensitized CBA/J mice with Mycobacteria bovis purified protein derivative- or Schistosoma mansoni egg antigen-coated beads. Before challenge, mice were implanted with osmotic pumps releasing AMD3465 at 5 µg/hour (6 mg/kg/day). Compared to vehicle, AMD3465 had minimal effect on type-1 inflammation or cytokine responses in draining lymph nodes, but the type-2 inflammation was significantly abrogated with reductions in lesion size and eosinophil content as well as abrogated interleukin (IL)-5, IL-10, and IL-13 cytokine production in draining lymph nodes. The biased effect of AMD3465 correlated with greater CXCR4 ligand expression in the type-2 model. Treatment during a primary response impaired lymph node IL-2 production after both Mycobacteria bovis purified protein derivative and Schistosoma mansoni egg antigen challenge indicating an unbiased effect during immune induction. In summary, CXCR4 blockade inhibited eosinophil recruitment during type-2 granuloma formation and interfered with primary and secondary T-cell activation events in lymphoid tissue, suggesting potential therapeutic application for chronic hypersensitivity diseases.




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C. M. Freeman, V. R. Stolberg, B.-C. Chiu, N. W. Lukacs, S. L. Kunkel, and S. W. Chensue
CCR4 Participation in Th Type 1 (Mycobacterial) and Th Type 2 (Schistosomal) Anamnestic Pulmonary Granulomatous Responses
J. Immunol., September 15, 2006; 177(6): 4149 - 4158.
[Abstract] [Full Text] [PDF]


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