Environmental factors, especially pathogenic microorganisms, have been implicated in the initiation or exacerbation of many destructive immunological processes. A successful cytotoxic T lymphocyte (CTL) response requires two consecutive signals. Signal 1 is the precise recognition by the T- cell receptor complex of antigen + MHC class I protein. Signal 2 is the delivery of """"""""help"""""""" occurring within a window of time subsequent to Signal 1. Because it depends on the delivery of antigen-nonspecific cytokines, Signal 2 is promiscuous in nature and thus a weak link in specific immunity. Conceptually, a wide range of microorganisms could provide help and thus promote the CTL response to completely unrelated antigens. The overall goal of the proposed work is to characterize the cellular mechanisms through which such organisms deliver help to CTL in vivo. The minor H antigen model system will be utilized because it is a uniquely sensitive experimental system for studying responses to weak transplantation antigens (referred to as Type I minor H antigens) in vivo that selectively stimulate the CD8+ T-cell subset, and thus, are strongly dependent upon help. This model serves as a realistic paradigm not only for allogeneic tissue transplantation, but also for tumor immunity and autoimmunity. The central hypothesis is that apparently unrelated immunological stimuli can deliver Signal 2 to the CTL response against a Type I minor H antigen. The application proposes to establish how help is delivered in vivo in a comparatively well-controlled experimental situation. The immunological consequences of Type I antigen presentation will be examined on different cell types. The studies will address whether help is provided to CTL by B-cells or during Th-B-cell collaboration. These studies should elucidate the cellular pathways by which Signal 2 can be delivered in vivo to CTL and provide a solid foundation for experiments that follow. P. acnes is a ubiquitous organism that colonizes the skin and displays features of a potent immunological adjuvant. Coincidentally, it has been found to promote help for the CTL response to minor H antigens. Next, the studies will characterize the effects of systemic delivery of help by P. acnes, examining whether it leads to tissue rejection or tolerance. The application will test the hypothesis that P. acnes induces a state of promiscuous help, which can pass the usual requirement for linked recognition between Th + CTL. These studies will provide a detailed examination into how a microbial adjuvant potentiates endogenous immunity. Finally, the application will establish three novel experimental paradigms that focus on the interaction of environment and the CTL and allograft response to a minor H antigen. The first examines differences in mouse colony environments. The second examines local administration P. acnes.The third examines the effects of bacterially- induced periodontal disease. These studies should provide a unique assessment of our hypothesis and create new experimental avenues to assess the role of environmental microbes on the host immune system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024544-09
Application #
2442439
Study Section
Immunobiology Study Section (IMB)
Project Start
1987-04-01
Project End
1998-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
9
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
Baker, Pamela J; Howe, Lisa; Garneau, Jessica et al. (2002) T cell knockout mice have diminished alveolar bone loss after oral infection with Porphyromonas gingivalis. FEMS Immunol Med Microbiol 34:45-50
Baker, Pamela J; Roopenian, Derry C (2002) Genetic susceptibility to chronic periodontal disease. Microbes Infect 4:1157-67
Baker, P J; Garneau, J; Howe, L et al. (2001) T-cell contributions to alveolar bone loss in response to oral infection with Porphyromonas gingivalis. Acta Odontol Scand 59:222-5
Baker, P J; DuFour, L; Dixon, M et al. (2000) Adhesion molecule deficiencies increase Porphyromonas gingivalis-induced alveolar bone loss in mice. Infect Immun 68:3103-7
Baker, P J; Dixon, M; Evans, R T et al. (2000) Heterogeneity of Porphyromonas gingivalis strains in the induction of alveolar bone loss in mice. Oral Microbiol Immunol 15:27-32
Baker, P J; Dixon, M; Roopenian, D C (2000) Genetic control of susceptibility to Porphyromonas gingivalis-induced alveolar bone loss in mice. Infect Immun 68:5864-8
Baker, P J (2000) The role of immune responses in bone loss during periodontal disease. Microbes Infect 2:1181-92
Klinge, H; Roopenian, D C (1999) The same genetic regions encode minor histocompatibility antigens detected in the context of different MHC haplotypes. Transplantation 67:1178-83
Baker, P J; Dixon, M; Evans, R T et al. (1999) CD4(+) T cells and the proinflammatory cytokines gamma interferon and interleukin-6 contribute to alveolar bone loss in mice. Infect Immun 67:2804-9
Baker, P J; Carter, S; Dixon, M et al. (1999) Serum antibody response to oral infection precedes but does not prevent Porphyromonas gingivalis-induced alveolar bone loss in mice. Oral Microbiol Immunol 14:194-6

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