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Neutralizing and Targeting Properties of a New Set of &agr;4&bgr;7-Specific Antibodies Are Influenced by Their Isotype

Abstract: The homing of lymphocytes to the mucosa is mainly controlled by &agr;4&bgr;7 integrin, and it is amplified during gut chronic inflammation, as occurs with HIV and/or inflammatory bowel diseases. We designed and applied an improved immunization strategy based on an innovative selection process to isolate new &agr;4&bgr;7+ lymphocyte–specific monoclonal antibodies that are able to prevent their migration into inflamed gut tissues and/or to counteract HIV infection in vitro. First, 5 monoclonal antibodies (1 IgA, 1 IgM, and 4 IgGs) were selected based on their capacity to recognize &agr;4 or &bgr;7 homodimers and &agr;4&bgr;7 heterodimers in transfected human cells. Their ability to block gp120/&agr;4&bgr;7 or MAdCAM-1/&agr;4&bgr;7 interactions was then measured in vitro with human T and B lymphocytes. In vitro, the anti-&agr;4&bgr;7 IgA isotype was found to have the highest affinity for the &agr;4&bgr;7 heterodimer, and it significantly reduced HIV replication in retinoic acid–treated &agr;4&bgr;7hi CD4+ human T cells. This &agr;4&bgr;7-specific IgA also displayed a high avidity for human and mouse &agr;4&bgr;7+ lymphocytes in both mouse and human inflammatory colitis tissues. These new antibodies, and in particular those with mucosa-targeting isotypes such as IgA, could therefore be potential novel therapeutic tools for treating HIV and inflammatory bowel disease.