T-helper cell deficiency resulting from human immunodeficiency virus (HIV) infection and alcohol abuse are common in the U.S. population and frequently coexist in the same individual. Currently, there is little information on how these two immunosuppressive states might interact with each other to alter host defense mechanisms against infection. It is our hypothesis that alcohol can function as a co-factor with T-helper cell deficiency to further compromise host immune functions and significantly increase host susceptibility to opportunistic infections. This proposal will test this hypothesis in a mouse model and has 3 Specific Aims:
Specific Aim 1 To characterize the interaction between alcohol and T-helper cell deficiency on specific cellular and cytokine defenses of the lungs. Mice will be placed on a standard alcohol diet and will be depleted of T- helper cells by weekly injection of an anti-CD4 antibody. Lung cells and systemic lymphoid cells will be recovered from alcohol and T-helper cell deficient mice and the immune functions of these cells will be compared to normal cells and to cells from animals treated with either alcohol alone or T-helper cell deficiency alone. Planned experiments will focus on alveolar macrophage oxidative metabolism and microbicidal activity, natural killer cell function, and release of interleukin-1 and tumor necrosis factor- alpha.
Specific Aim 2 To characterize the interaction between alcohol and T-helper cell deficiency during pulmonary infection with Pneumocystis carinii. Alcohol and T-helper cell deficient mice will be intratracheally inoculated with P. carinii to determine if alcohol alters host susceptibility to infection or the intensity of infection with this pathogen. Additional experiments will investigate whether alcohol delays the resolution or clearance of an established infection once T-helper cell deficiency has been reversed.
Specific Aim 3 To examine whether systemic or locally-delivered cytokines can reverse or attenuate the immune deficits associated with alcohol and T- helper cell deficiency and thereby restore host defense against infection with P. carinii. Based upon the results of experiments performed for Specific Aims 1 and 2 protocols will be developed to administer recombinant cytokines to alcohol and T-helper cell deficient mice in order to mitigate the immunologic defects associated with these two forms of immunosuppression and to treat or prevent infection with P. carinii. Studies will be performed with recombinant interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony stimulating factor administered either systemically (intravenous injection) or locally (aerosolization). The results of these experiments will provide important new information on how alcohol and T-helper cell deficiency interact to alter host immune functions and susceptibility to opportunistic infection. Information gained from this project may ultimately be extended to the study of HIV- infected patients and may lead to novel approaches to enhance immune function in these hosts or to treat opportunistic infections associated with the Acquired Immunodeficiency Syndrome.
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