During the past several years evidence has begun to accumulate that stress results in a suppression of immunological competence in man that may ultimately result in increased susceptibility to disease. The suppressive effects of stress may not necessarily result in an increased incidence of disease in apparently healthy individuals. Instead, stress induced immunosuppression together with suppression of immune responsiveness associated with cancer chemotherapy or infection by the Human Immunodeficiency Virus (HIV), may tip the balance to favor the establishment of infectious disease by potentially pathogenic microorganisms. Approximately 50% of individuals infected with HIV have Mycobacterial disease. Natural resistance to this group of microorganisms is mediated by mononuclear phagocytes. The ability to control the growth of these microorganisms maps to a gene (Bcg) on chromosome 1 in mice. The Bcg gene also regulates the expression of MHC class II Ia glycoproteins. The purpose of this investigation is to assess the effect of stress on Ia expression and on Mycobacterial resistance of congenic mice that differ only in their resistance to BCG. To accomplish this mice will be stressed by restraint. The level of Ia expression and of Mycobacterial growth will be evaluated as will the functional capacity of peritoneal macrophages from stressed mice. We will evaluate the mechanism of the differential response of macrophages from BCG resistant and BCG susceptible mice to ACTH, alpha-MSH, and corticosterone by determining the effect of these hormones on macrophage Ia expression and antimycobacterial activity in vitro. Their role in controlling the transcription and translation of MHC class II genes will be evaluated. The interaction of these hormones with other stress-related peptide hormones will also be explored. An understanding of how stress effects macrophage function controlled by the Bcg gene may provide fundamental knowledge to understand how macrophages control the growth of Mycobacteria and ultimately how infection of macrophages with HIV may alter the expression of Ia glycoprotein and the growth of Mycobacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH045679-03
Application #
3385492
Study Section
MH Acquired Immunodeficiency Syndrome Research Review Committee (MHAZ)
Project Start
1989-08-01
Project End
1992-07-31
Budget Start
1991-08-01
Budget End
1992-07-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
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Hilburger, M E; Zwilling, B S (1994) Antigen presentation by macrophages from bacille Calmette-Guerin (BCG)-resistant and -susceptible mice. Clin Exp Immunol 96:225-9
Brown, D H; Zwilling, B S (1994) Activation of the hypothalamic-pituitary-adrenal axis differentially affects the anti-mycobacterial activity of macrophages from BCG-resistant and susceptible mice. J Neuroimmunol 53:181-7
Brown, D; Faris, M; Hilburger, M et al. (1994) The induction of persistence of I-A expression by macrophages from Bcgr mice occurs via a protein kinase C-dependent pathway. J Immunol 152:1323-31
Zwilling, B S; Brown, D; Feng, N et al. (1993) The effect of adrenalectomy on the restraint stressed induced suppression of MHC class II expression by murine peritoneal macrophages. Brain Behav Immun 7:29-35
Brown, D H; Sheridan, J; Pearl, D et al. (1993) Regulation of mycobacterial growth by the hypothalamus-pituitary-adrenal axis: differential responses of Mycobacterium bovis BCG-resistant and -susceptible mice. Infect Immun 61:4793-800
McPeek, M; Salkowitz, J; Laufman, H et al. (1992) The expression of HLA-DR by monocytes from black and from white donors: different requirements for protein synthesis. Clin Exp Immunol 87:163-8
Zwilling, B S; Lafuse, W P; Brown, D et al. (1992) Characterization of ACTH mediated suppression of MHC class II expression by murine peritoneal macrophages. J Neuroimmunol 39:133-8
Faris, M; Zwilling, B S (1991) Characterization of the induction of persistence of major histocompatibility complex class II by hybrids of macrophages from bacillus Calmette Guerin-resistant mice. Eur J Immunol 21:1047-52
Faris, M; Zwilling, B S (1991) Characterization of the induction of persistent I-A expression by macrophages from Bcgr mice. J Leukoc Biol 49:289-93

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