The long term aims of this project are designed to elucidate how microbial mitogens can influence host susceptibility to disease or to participate in disease, and to apply this knowledge to the development of immunoregulatory substances which might be of benefit in the treatment of human disease based upon immunological dysfunction. The immediate specific aims for the current grant period are: 1. to determine the structural features of the M. arthritidis T cell mitogen (MAM) that are important for interaction with I-E protein accessory cell surface receptor and for biological activity in respect to: a)further develop procedures for production of homogeneous MAM; b) determination of the primary amino acid sequence of MAM; c) identification of active moieties of MAM by means of; i) specific residue derivatization, and ii) biologic and I-E binding activities of proteolytic or chemically derived oligopeptides from MAM. 2. Mechanism (s) of MAM-induced inhibition of T cell responses to mitogens in respect to: a) changes in cell populations in vivo following injection of MAM; b) cytokine production in vivo in response to MAM; c) MHC restriction of suppression; d) identification of the effector cell responsible for inhibition (i.e. is, cytolytic or natural killer cells or macrophages; e) role of soluble factors in suppression; f) effectiveness and potential toxicity of multiple doses of MAM on T cell function. 3. Effects of MAM on various parameters of immune function in respect to: a) inhibition of T cell responses to foreign antigens in vivo: b) inhibition of the in vitro response of node T cells and T cell hybridomas to antigens; c) inhibition of humoral antibody responses to T cell dependent and independent antigens; d) inhibition of the mixed lymphocyte reaction to mixtures of disparate MHC or Mls determinants: e) prolongation of allograft survival with a view to practical use of MAM as a new immunomodulator.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR002255-31
Application #
3154645
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1978-03-01
Project End
1994-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
31
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Mu, Hong-Hua; Hasebe, Akira; Van Schelt, Adam et al. (2011) Novel interactions of a microbial superantigen with TLR2 and TLR4 differentially regulate IL-17 and Th17-associated cytokines. Cell Microbiol 13:374-87
Hasebe, Akira; Mu, Hong-Hua; Washburn, Leigh R et al. (2007) Inflammatory lipoproteins purified from a toxigenic and arthritogenic strain of Mycoplasma arthritidis are dependent on Toll-like receptor 2 and CD14. Infect Immun 75:1820-6
Mu, Hong-Hua; Humphreys, Jennifer; Chan, Fok Vun et al. (2006) TLR2 and TLR4 differentially regulate B7-1 resulting in distinct cytokine responses to the mycoplasma superantigen MAM as well as to disease induced by Mycoplasma arthritidis. Cell Microbiol 8:414-26
Hasebe, Akira; Pennock, Nathan D; Mu, Hong-Hua et al. (2006) A microbial TLR2 agonist imparts macrophage-activating ability to apolipoprotein A-1. J Immunol 177:4826-32
Cole, Barry C; Mu, Hong-Hua; Pennock, Nathan D et al. (2005) Isolation and partial purification of macrophage- and dendritic cell-activating components from Mycoplasma arthritidis: association with organism virulence and involvement with Toll-like receptor 2. Infect Immun 73:6039-47
Mu, H-H; Pennock, N D; Humphreys, J et al. (2005) Engagement of Toll-like receptors by mycoplasmal superantigen: downregulation of TLR2 by MAM/TLR4 interaction. Cell Microbiol 7:789-97
Mu, H H; Sawitzke, A D; Cole, B C (2001) Presence of Lps(d) mutation influences cytokine regulation in vivo by the Mycoplasma arthritidis mitogen superantigen and lethal toxicity in mice infected with M. arthritidis. Infect Immun 69:3837-44
Sawitzke, A; Joyner, D; Knudtson, K et al. (2000) Anti-MAM antibodies in rheumatic disease: evidence for a MAM-like superantigen in rheumatoid arthritis? J Rheumatol 27:358-64
Mu, H H; Sawitzke, A D; Cole, B C (2000) Modulation of cytokine profiles by the Mycoplasma superantigen Mycoplasma arthritidis mitogen parallels susceptibility to arthritis induced by M. arthritidis. Infect Immun 68:1142-9
Cole, B C (1999) Mycoplasma-induced arthritis in animals: relevance to understanding the etiologies of the human rheumatic diseases. Rev Rhum Engl Ed 66:45S-49S

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