In this proposal, studies will be continued on the mouse MHC class II la antigens and a new program to study human class II genes will be initiated. In the mouse system, transgenic mice will be generated with exon shuffled la genes from the A(K,A), A(Q,A) and E(K,A) genes to determine the site on the la molecule which presents Mls antigen and super antigens to the T cells. The precise site on the la molecule will be further narrowed down by generating la mutant genes by site directed mutagenesis and producing transgenic mice with them. Regulation of A/alpha and E/beta genes will be determined by constructing la genes with different promotor regions and generating transgenic mice to examine the tissue expression. The importance of the N-linked oligosaccharides in the function of la molecules will be determined by mutating the oligosaccharide attachment sites on the la genes and producing transgenic mice with them. The recombination hot spot which has been identified in the E alpha gene will be determine by DNA sequencing. These studies in the mouse system will increase our understanding of the structure/function relationship of la genes. Using the transgenic technology, mice expressing human class II genes will be generated for further serological characterization and definition of determinants, specificities and epitopes on the human class II molecules and localization to specific chains and domains. These transgenic mice would also be utilized to study the regulation of human la genes. Studies will be initiated using anti- sense RNA to determine the feasibility of downregulating endogenous class II genes in vivo. Finally, structure/function of human class II genes will be studied using the transgenic mice. Since the class II genes play such a crucial role in immune response, self versus non-self regulation, susceptibility to disease and cancer, the information we gain from the mouse and human la genes and their products are critical to understanding the immune system and devising methods of disease prevention and immune therapy. Eventually transgenic mice will be produced expressing human cell II genes and human CD4 gene which will be used to generate a model for AIDS. The lab will continue to serve as a resource for mouse strains, embryo freezing and transgenic technology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI014764-21
Application #
2457681
Study Section
Special Emphasis Panel (NSS)
Project Start
1977-09-01
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
21
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Kong, Yi-Chi M; Flynn, Jeffrey C; Banga, J Paul et al. (2007) Application of HLA class II transgenic mice to study autoimmune regulation. Thyroid 17:995-1003
Flynn, J C; Meroueh, C; Snower, D P et al. (2007) Depletion of CD4+CD25+ regulatory T cells exacerbates sodium iodide-induced experimental autoimmune thyroiditis in human leucocyte antigen DR3 (DRB1*0301) transgenic class II-knock-out non-obese diabetic mice. Clin Exp Immunol 147:547-54
Rajagopalan, Govindarajan; Smart, Michele K; Murali, Narayana et al. (2007) Acute systemic immune activation following vaginal exposure to staphylococcal enterotoxin B--implications for menstrual shock. J Reprod Immunol 73:51-9
Taneja, Veena; Behrens, Marshall; Mangalam, Ashutosh et al. (2007) New humanized HLA-DR4-transgenic mice that mimic the sex bias of rheumatoid arthritis. Arthritis Rheum 56:69-78
Rajagopalan, Govindarajan; Patel, Robin; Kaveri, Srini V et al. (2007) Comment on: Human intravenous immunoglobulin for experimental streptococcal toxic shock: bacterial clearance and modulation of inflammation. J Antimicrob Chemother 59:157-9;author reply 159-60
Rajagopalan, Govindarajan; Sen, Moon M; Singh, Manisha et al. (2006) Intranasal exposure to staphylococcal enterotoxin B elicits an acute systemic inflammatory response. Shock 25:647-56
Rajagopalan, Govindarajan; Smart, Michele K; Patel, Robin et al. (2006) Acute systemic immune activation following conjunctival exposure to staphylococcal enterotoxin B. Infect Immun 74:6016-9
Rajagopalan, Govindarajan; Iijima, Koji; Singh, Manisha et al. (2006) Intranasal exposure to bacterial superantigens induces airway inflammation in HLA class II transgenic mice. Infect Immun 74:1284-96
Mangalam, Ashutosh K; Khare, Meenakshi; Krco, Christopher J et al. (2005) Delineation of the minimal encephalitogenic epitope of proteolipid protein peptide(91-110) and critical residues required for induction of EAE in HLA-DR3 transgenic mice. J Neuroimmunol 161:40-8
Taneja, Veena; Taneja, Neelam; Behrens, Marshall et al. (2005) Requirement for CD28 may not be absolute for collagen-induced arthritis: study with HLA-DQ8 transgenic mice. J Immunol 174:1118-25

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