AMD3465, a novel CXCR4 receptor antagonist, abrogates schistosomal antigen-elicited (type-2) pulmonary granuloma formation
| Autor: | Simon P. Fricker, Gary Bridger, Nicholas W. Lukacs, Stephen W. Chensue, Valerie R. Stolberg, Christine M. Freeman, Jerry S. Hu, Bo Chin Chiu |
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| Rok vydání: | 2006 |
| Předmět: |
Interleukin 2
Receptors CXCR4 Granuloma Respiratory Tract Pyridines medicine.medical_treatment Pathology and Forensic Medicine Mice Th2 Cells medicine Animals RNA Messenger Lung Cells Cultured CXCR4 antagonist biology Dose-Response Relationship Drug Schistosoma mansoni Eosinophil biology.organism_classification medicine.disease Chemokine CXCL12 Eosinophils Lymphatic system medicine.anatomical_structure Cytokine Gene Expression Regulation Granuloma Antigens Helminth Immunology Cytokines Interleukin-2 Female Lymph Lymph Nodes Chemokines CXC medicine.drug Regular Articles |
| Zdroj: | The American journal of pathology. 169(2) |
| ISSN: | 0002-9440 |
| Popis: | 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 microg/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. |
| Databáze: | OpenAIRE |
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