Exposure of the lung to environmental agents in the workplace can cause hypersensitivity pneumonitis (HP) may either result in severe sustained severe inflammation and organ dysfunction or in virtually no changes of normal pulmonary anatomy and function. There is wide unexplained variability among individuals in the response to inhalational antigenic exposure. The investigators will use an established mouse model of experimental occupational hypersensitivity pneumonitis (EOHP) to determine if cytokines associated with Th2 subset of CD4+ cells are responsible for diminution of histologic changes in most exposed individuals and the role of memory cells. Repeated intratracheal administration (i.t.) of M.faeni, the fungal agent responsible for farmers lung, a hypersensitivity pneumonitis causes initially prominent (2 weeks), then attenuated (8 weeks), histopathologic changes in the lung. Lymphocytes derived from spleen, lymph node or peritoneal exudate from sensitized cultured in the presence of soluble M.faeni antigen in vitro can transfer susceptibility to M.faeni induced pulmonary inflammation to naive recipients. Specific cells which have the surface marker determinants CD3+, CD4+, CD8-, SlgM-, la- are responsible for the transfer, shown to be cell/dose related. Cells capable of transfer tend to localize in spleen and lungs. In this planned study of isolated CD4+ [competent cells (TH1) versus incompetent cells (TH2)] with and without cellular memory, the proposers will determine whether CD4+ cells which are VLA-4+, CD44+, E- selectin(lo), CD45RB(lo) can transfer adoptive EOHP. Second, they will determine if the cytokine profile of isolated competent CD4+ cells differs from isolated incompetent CD4+ cells. It is expected CD4+ """"""""T"""""""" cell lines to be developed from mice subjected to 2, 4 or 8 challenges with M.faeni will differ in their ability to adoptively transfer EOHP and differ in their cytokine production pattern. Changing the cytokine production pattern is expected to yield differences in adoptive transfer capability. Cells which adoptive transfer EOHP will be examined for difference in tracking and homing patterns to the lung, the target organ of this disease. Prior treatment with antibody to VCAM-1 will be studied in adoptive transfer recipient animals to determine whether this technology will ablate the ability to express adoptive EOHP. The results of this work are applicable to both HP and inhalation exposure to other airborne agents such as inorganic material and viable microorganisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044253-09
Application #
2714023
Study Section
Special Emphasis Panel (ZRG4-SOH (03))
Project Start
1990-07-01
Project End
2000-05-31
Budget Start
1998-06-01
Budget End
2000-05-31
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of New Mexico
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Schuyler, M; Gott, K; French, V (2004) The role of MIP-1alpha in experimental hypersensitivity pneumonitis. Lung 182:135-49
Masten, Barbara; McWilliams, Bennie; Lipscomb, Mary et al. (2003) Immune response to hepatitis B vaccine in asthmatic children. Pediatr Pulmonol 36:522-8
Schuyler, Mark; Gott, Katherine; Cherne, Amy (2003) Experimental hypersensitivity pneumonitis: role of MCP-1. J Lab Clin Med 142:187-95
Schuyler, Mark; Gott, Katherine; Cherne, Amy (2002) Is IL12 necessary in experimental hypersensitivity pneumonitis? Int J Exp Pathol 83:87-98
Schuyler, M; Gott, K; Cherne, A (2000) Mediators of hypersensitivity pneumonitis. J Lab Clin Med 136:29-38
Schuyler, M; Gott, K; Mapel, V et al. (1999) Experimental hypersensitivity pneumonitis: influence of Th2 bias. Int J Exp Pathol 80:335-48
Schuyler, M; Gott, K; Edwards, B (1999) Th1 cells that adoptively transfer experimental hypersensitivity pneumonitis are activated memory cells. Lung 177:377-89
Schuyler, M; Gott, K; Cherne, A (1998) Effect of glucan on murine lungs. J Toxicol Environ Health A 53:493-505
Schuyler, M; Gott, K; Fei, R et al. (1998) Experimental hypersensitivity pneumonitis: location of transferring cells. Lung 176:213-25
Schuyler, M; Gott, K; Cherne, A et al. (1997) Th1 CD4+ cells adoptively transfer experimental hypersensitivity pneumonitis. Cell Immunol 177:169-75

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