Animal models

A spontaneous mutation in the gene encoding the (32-integrin has been described both in dogs and cattle. In the cattle model two point mutations were identified within the gene encoding bovine CD18. These animals suffered from recurrent infections and persistent mature neutrophilia associated with poor growth performance. The carrier frequency of the defective gene among Holstein cattle is approximately 15% in bulls and 6% in cows.

Using methods of homologous recombination in embryonic stem (ES) cells, it is possible to generate strains of mice deficient in specific adhesion molecules. A knockout mouse with CD 18 deficiency was found to be viable and fertile, with mild granulocytosis. The mutant mice showed an impaired inflammatory response to chemical peritonitis and delayed rejection of cardiac transplants (Table 1).

In another model, ICAM-l-deficient mice were generated. The animals developed normally and had mild granulocytosis. Deficient mice exhibited abnormalities of inflammatory response especially in impaired neutrophil emigration. In addition, leukocytes from these mice provide negligible stimulation for the mixed lymphocyte reaction. In a recent study using the ICAM-l-deficient mice, mutant mice were resistant to the lethal effects of high doses of endotoxin, which correlated with a significant decrease in neutrophil infiltration in the liver. As the production of various inflammatory cytokines is normal in these mice, the protective effects appear to be related to a diminution in critical leukocyte-endothelial interactions.

Mice lacking P-selectin develop normally. However, they exhibit striking leukocytosis, diminished rolling of leukocytes in mesenteric vessels and delayed recruitment of neutrophils to the peritoneal cavity after experimentally induced peritonitis. Mice deficient in L-selectin initially have normal levels of leukocyte rolling, but show a significant decline in rolling within the first hour. Furthermore, I.-sclectin knockout mice have a severe reduction in the number of lymphocytes localized in the peripheral lymph nodes. E-Selectin-deficient mice have a milder defect in neutrophil recruitment, and do not have leukocytosis. Administration of P-selectin-specific antibodies to the E-selectin knockout mice completely blocks neutrophil recruitment, suggesting that in this model some redundancy of function may exist between the two endothelial cell selectins.

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