AMD3465, a novel CXCR4 receptor antagonist, abrogates schistosomal antigen-elicited (type-2) pulmonary granuloma formation.
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.
Hu
Jerry S
JS
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.
Freeman
Christine M
CM
Stolberg
Valerie R
VR
Chiu
Bo Chin
BC
Bridger
Gary J
GJ
Fricker
Simon P
SP
Lukacs
Nicholas W
NW
Chensue
Stephen W
SW
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D015769:Granuloma, Respiratory Tract / Q000139:chemically induced* / Q000473:pathology; D007376:Interleukin-2 / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects* / Q000473:pathology*; D008198:Lymph Nodes / Q000187:drug effects; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics; D012550:Schistosoma mansoni / Q000276:immunology*; D018418:Th2 Cells / Q000187:drug effects
D000947:Antigens, Helminth; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; D007376:Interleukin-2; C503590:N-(1,4,8,11- tetraazacyclotetradecanyl-1,4-phenylenebis(methylene))-2-(aminomethyl)- pyridine; D011725:Pyridines; D012333:RNA, Messenger; D019718:Receptors, CXCR4