Pneumocystis carinii (PC) pneumonia is a significant problem in immunocompromised patients, particularly those with HIV. It has been well documented that the presence of CD4+ T cells is required for resolution PC infections. In addition, it has recently been reported that mice that are deficient in B cells are susceptible to PC (4,9). This is important because AIDS patients have been shown to have B cell defects that may also render them susceptible to PC. Until recently, there have not been good animal models for studying the role of B cells in host defense to infectious diseases. Although B cell deficient mice have proven to be useful, it is not possible to determine whether susceptibility to PC in these mice is due to a lack of natural antibody, PC-specific antibody, or B cell effector functions such as antigen presentation, costimulation of T cells, or cytokine production. The goal of this proposal is to test the hypothesis that B cells play multiple roles in the resolution of PC including activating CD4+ cells through antigen presentation, producing protective antibody, and producing cytokines that lead to resolution of PC pneumonia (PCP). We will utilize existing mice that are transgenic for the B cell receptor as well as generate new murine models including 1) making mixed chimeric mice whose B cells are defective in expression of cytokines or costimulatory molecules and 2) generating new transgenic mice whose B cells express the Herpes Simplex Virus thymidine kinase gene. These new mice will have B cells that are susceptible to killing by ganciclovir. With these murine models we will address the following specific aims: 1) to determine whether B cell-T cell interactions are required for resolution of PCP; 2) to determine whether B cell-produced cytokines are required for the resolution of PC; 3) to determine whether protection against PCP is dependent on specific recognition of PC antigens by the B cells; 4) to determine whether natural antibody is required for resolution of PCP; and 5) To determine the kinetic requirements for B cell function in PC infection. Understanding host defense to PC is critical for developing vaccines or efficient therapies for preventing this potentially fatal infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL064524-01
Application #
6074995
Study Section
Special Emphasis Panel (ZHL1-CSR-Q (S2))
Project Start
1999-09-30
Project End
2004-08-31
Budget Start
1999-09-30
Budget End
2000-08-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
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