alpha(4) integrin-dependent eosinophil recruitment in allergic but not non-allergic inflammation.
1. Although anti-alpha(4) integrin mAbs reduce eosinophil accumulation in several models of allergic inflammation, it is not clear whether this occurs via a direct action to block eosinophil alpha(4) integrins or indirectly on another cell type. The role of alpha(4) integrins on the accumulation of (111)In-labelled eosinophils in allergic and non-allergic inflammation in guinea-pig skin was therefore investigated. 2. Intradermal injection of antigen in sensitized skin sites induced accumulation of (111)In-eosinophils that was reduced up to 70% by two anti-alpha(4) integrin mAbs. In contrast, accumulation of (111)In-eosinophils to intradermal chemoattractants was unaffected by the same mAbs. 3. Accumulation of (111)In-eosinophils in allergic and non-allergic conditions was partly inhibited by a low dose of an anti-beta(2) integrin mAb. In combination with anti-alpha(4) integrin mAb, responses were not further reduced suggesting that these adhesion pathways are not additive or synergic. 4. Pretreating skin sites with antiserum or contaminating LPS did not reveal an alpha(4) integrin dependent pathway for chemoattractant-induced (111)In-eosinophil accumulation. These data suggest that alpha(4) integrins are involved in the response to antigen in sensitized skin sites. 5. Pretreating (111)In-eosinophil with alpha(4) integrin mAb blocked their adhesion to fibronectin in vitro but did not inhibit their accumulation in allergic inflammation suggesting that the blocking effect in vivo was eosinophil independent. 6. These data support the concept that targeting alpha(4) integrins on cells other than eosinophils could control eosinophil accumulation and have therapeutic potential in allergic diseases such as asthma and atopic dermatitis.
Teixeira
M M
MM
Applied Pharmacology, National Heart & Lung Institute, Imperial College School of Medicine, London, SW3 6LY.
Robinson
M K
MK
Shock
A
A
Hellewell
P G
PG
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D004804:Eosinophils / Q000502:physiology*; D005434:Flow Cytometry; D006168:Guinea Pigs; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism*; D007202:Indicators and Reagents; D007205:Indium Radioisotopes; D007249:Inflammation / Q000378:metabolism*; D039441:Integrin alpha4; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism*; D012867:Skin / Q000166:cytology; D015054:Zymosan / Q000494:pharmacology
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D007202:Indicators and Reagents; D007205:Indium Radioisotopes; D016201:Receptors, Lymphocyte Homing; D039441:Integrin alpha4; D015054:Zymosan