Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI.
Allergen-induced asthma is characterized by chronic pulmonary inflammation, reversible bronchoconstriction, and airway hyperreactivity to provocative stimuli. Multiple CC-chemokines, which are produced by pulmonary tissue in response to local allergen challenge of asthmatic patients or experimentally sensitized rodents, chemoattract leukocytes from the circulation into the lung parenchyma and airway, and may also modify nonchemotactic function. To determine the therapeutic potential of local intrapulmonary CC-chemokine blockade to modify asthma, a recombinant poxvirus-derived viral CC-chemokine inhibitor protein (vCCI), which binds with high affinity to rodent and human CC-chemokines in vitro and neutralizes their biological activity, was administered by the intranasal route. Administration of vCCI to the respiratory tract resulted in dramatically improved pulmonary physiological function and decreased inflammation of the airway and the lung parenchyma. In contrast, vCCI had no significant effect on the circulating levels of total or allergen-specific IgE, allergen-specific cytokine production by peripheral lymph node T cells, or peritoneal inflammation after local allergen challenge, indicating that vCCI did not alter systemic Ag-specific immunity or chemoattraction at extrapulmonary sites. Together, these findings emphasize the importance of intrapulmonary CC-chemokines in the pathogenesis of asthma, and the therapeutic potential of generic and local CC-chemokine blockade for this and other chronic diseases in which CC-chemokines are locally produced.
Dabbagh
K
K
Department of Pediatrics and the Immunology Program, Stanford University School of Medicine, Stanford, CA 94305, USA. Comparative Medici.
Xiao
Y
Y
Smith
C
C
Stepick-Biek
P
P
Kim
S G
SG
Lamm
W J
WJ
Liggitt
D H
DH
Lewis
D B
DB
D000281:Administration, Intranasal; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D019742:Chemokines, CC / Q000037:antagonists & inhibitors*; D015608:Cowpox virus / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014764:Viral Proteins / Q000008:administration & dosage* / Q000235:genetics; D037521:Virulence Factors
D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; C414049:CCI protein, Cowpox virus; D019742:Chemokines, CC; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; D037521:Virulence Factors; D010047:Ovalbumin