The long-term objective of this project is to understand the mechanisms of alcohol-induced immunosuppression and how such immunosuppression predisposes to infection. The experimental hypothesis is that alcohol ingestion prevents optimal recruitment of T Iymphocytes into lung tissue in response to an infectious challenge, leading to impaired generation of lymphocyte-derived cytokines and to increased susceptibility to opportunistic infection.
Specific Aims will test predictions of this hypothesis in mice that are administered alcohol, to model either binge drinking or chronic consumption. Infection with P. carinii will serve as an experimental model of opportunistic infection.
Specific Aim 1. To test the concept that alcohol impairs recruitment of T-lymphocytes in to lung tissue in response to challenge with P. carinii. Experiments will investigate how alcohol affects numbers of CD4+ and CD8+ lymphocytes in blood and spleen, lymphocyte expression of LFA-l, VLA 4, and ICAM-1, lymphocyte chemotaxis in vitro, and lymphocyte recruitment into lung tissue following challenge with P. carinii.
Specific Aim 2. To test the concept that alcohol suppresses local release of T Iymphocyte derived cytokines in response to challenge with P. carinii. Experiments will investigate how alcohol affects lymphocyte release of interferon-gamma, IL-2, IL-4, and IL-5 and expansion of the Th1 lymphocyte subset in lung tissue following challenge with P. carinii.
Specific Aim 3. To test the concept that upregulation of interferon-gamma in lung tissue attenuates the immune deficits associated with alcohol and thereby restores host defense against P. carinii infection. Experiments will utilize in vivo transfer of the interferon-gamma gene into alcohol treated mice to restore defects in lymphocyte recruitment and cytokine release and augment host defense against infection with P. carinii in spite of continued alcohol treatment. The results of these experiments will provide new information on how alcohol interferes with lymphocyte mediated host defense against infection and may lead to novel approaches to restore immune function in the alcoholic host or to treat opportunistic infections associated with HIV infection.
Showing the most recent 10 out of 15 publications
