The role of alpha4 (CD49d) and beta2 (CD18) integrins in eosinophil and neutrophil migration to allergic lung inflammation in the Brown Norway rat.
We investigated the role of beta2 (CD18) and alpha4 (CD49d) integrins in eosinophil and neutrophil recruitment to lung parenchyma and bronchoalveolar lavage fluid (BALF) of allergen-challenged Brown Norway (BN) rats. Challenge of sensitized BN rats with ovalbumin induced an eosinophil- and neutrophil-rich infiltrate in BALF at 24 h, accompanied by an increase in BALF protein content. Treatment with either the TA-2 monoclonal antibody (mAb) against alpha4 (as an F[ab']2 fragment) or the WT.3 mAb against beta2 integrin significantly reduced eosinophil and neutrophil accumulation in BALF by 54 to 66% and eosinophil accumulation in the parenchyma by 48%. A significant difference in effect was observed between mAb TA-2 in intact immunoglobulin G or F(ab)2 form. Combined treatment with mAbs WT.3 plus TA-2 (F[ab]2) virtually abolished eosinophil accumulation in BALF and in the parenchyma, and reduced neutrophil accumulation in BALF by 91%. In contrast, neutrophil accumulation in the lung was not inhibited by these mAb treatments. The increase in BALF protein concentration was significantly inhibited by TA-2 (by 40%) and by WT.3 plus TA-2 in combination (71% inhibition). We conclude that eosinophil and neutrophil migration into the air space in allergic lung inflammation is partially CD18 (beta2)- and CD49d (alpha4)- dependent and that alpha4 integrins mediate essentially all of the CD18-independent migration. Similarly, eosinophil accumulation in the parenchyma is completely alpha4 and CD18 (beta2) integrin-dependent. In marked contrast, neutrophil accumulation in the lung in this allergen model can occur independently of both alpha4 and beta2 integrins.
Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada.
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Schneider
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Issekutz
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Issekutz
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D004804:Eosinophils / Q000276:immunology*; D007249:Inflammation / Q000276:immunology*; D039441:Integrin alpha4; D016023:Integrins / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000276:immunology*; D051381:Rats; D011914:Rats, Inbred BN; D012130:Respiratory Hypersensitivity / Q000276:immunology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D016023:Integrins; D039441:Integrin alpha4