Interstitial pneumonitis (IP) contributes significantly to the noninfectious pulmonary complications in adult and pediatric AIDS. Animal models which display immunodeficiency-associated IP will be invaluable to investigations into the pathogenic mechanisms of this disease. We recently published that the murine retroviral model of AIDS (MAIDS), caused by the LP-BM5 murine leukemia virus, displays diffuse interstitial pneumonitis characterized by accumulation of T cells, B cells and macrophages, a decrease in diffusing capacity and subsequent development of pulmonary fibrosis and vascular pulmonary hypertensive disease. This murine retroviral model of AIDS will be used to test the following hypothesis. Interstitial pneumonitis in the setting of retroviral-induced immunodeficiency is caused by homing and activation of virus-specific or autoimmune T cells and macrophages to the lungs, leading to chronic cytokine secretion and effector cell function in situ. Temporal changes in T and B lymphocyte subsets during the development of IP will be analyzed by flow cytometric and immunohistological studies. The synthesis of T cell and macrophage cytokines and the replication of LP-BM5 retrovirus in lungs during development of interstitial inflammation will be analyzed by ELISA, bioassay and polymerase chain reaction. The contribution of lymphocyte subsets to the development of IP will be analyzed by adoptive transfer of lymphocytes into genetically susceptible C57B1/6 mice and in lymphocyte-deficient SCID mice. To ascertain whether pulmonary T and B lymphocyte specificity in MAIDS infected mice is anti- viral or autoimmune, antigen-induced cytokine secretion in vitro and binding of bronchoalveolar lavage antibody to lung tissue sections will be analyzed. The expression of lymphocyte homing receptors and vascular addressins in MAIDS-associated IP will be determined by flow cytometry, immunohistology and the function of these adhesion molecules in IP development will be analyzed by antibody blocking in vivo. Whether lung T cells induce secretion of macrophage-derived cytokines will be determined by in vitro tissue culture studies and in virus-infected SCID mice. Finally, the role of cytokines in the development of IP in MAIDS infected mice will be determined by blocking studies in vivo with anti- cytokine antibodies. The results of these studies will identify the role of antigen-specific lymphocytes in the development of IP and characterize the mechanism by which specific cellular adhesion molecules and cytokines contribute to immunodeficiency-associated interstitial pneumonitis in this murine retroviral model of AIDS.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053246-02
Application #
2231073
Study Section
Special Emphasis Panel (ZHL1-CSR-C (M1))
Project Start
1994-08-01
Project End
1998-07-30
Budget Start
1995-08-01
Budget End
1996-07-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506