Abstract

The primary goal of this proposal is the elucidation of the mechanisms of the protective effects of ovine interferon tau (IFN tau) and ovine IFN tau/human IFNalphaD chimerics in treatment of experimental allergic encephalomyelitis, an animal model of multiple sclerosis (MS). These mechanism studies involve structure studies and use of the EAE mouse model to assess the chimerics as therapeutics for treatment of MS under conditions that minimize undesirable side effects.
The Specific Aims are: 1. Determination of the protective effects of ovine IFN tau/human IFNalphaD chimerics in treatment of EAE in the mouse model of MS with a focus on therapeutics efficacy versus toxic side effects. Toxic side effects are a problem in the use of type I IFNs in the treatment of MS. 2. Determination of the structural basis for the interaction of ovine IFN tau, human IFNalphaD, and chimerics of IFN tau/human IFNalphaD with the type I IFN receptor, with particular emphasis on the chimerics as it potentially relates to therapy of MS with minimal undesirable side effects. 3. Determination of the x-ray crystal structure of ovine IFN tau/human IFNalphaD chimeric and compare it to that of ovine IFN tau/human IFNalphaD, particularly with respect to the N-terminus, which may play a critical role as to whether a type I IFN is toxic or non toxic.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069959-11
Application #
6489244
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Mccarthy, Susan A
Project Start
1989-09-30
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
11
Fiscal Year
2002
Total Cost
$188,670
Indirect Cost

  Institution

Name
University of Florida
Department
Microbiology/Immun/Virology
Type
Schools of Earth Sciences/Natur
DUNS #
073130411
City
Gainesville
State
FL
Country
United States
Zip Code
32611

  Publications

Soos, Jeanne M; Stuve, Olaf; Youssef, Sawsan et al. (2002) Cutting edge: oral type I IFN-tau promotes a Th2 bias and enhances suppression of autoimmune encephalomyelitis by oral glatiramer acetate. J Immunol 169:2231-5
Torres, Barbara A; Perrin, George Q; Mujtaba, Mustafa G et al. (2002) Superantigen enhancement of specific immunity: antibody production and signaling pathways. J Immunol 169:2907-14
Soos, Jeanne M; Mujtaba, Mustafa G; Schiffenbauer, Joel et al. (2002) Intramolecular epitope spreading induced by staphylococcal enterotoxin superantigen reactivation of experimental allergic encephalomyelitis. J Neuroimmunol 123:30-4
Tanabe, T; Kominsky, S L; Subramaniam, P S et al. (2000) Inhibition of the glioblastoma cell cycle by type I IFNs occurs at both the G1 and S phases and correlates with the upregulation of p21(WAF1/CIP1). J Neurooncol 48:225-32
Subramaniam, P S; Larkin 3rd, J; Mujtaba, M G et al. (2000) The COOH-terminal nuclear localization sequence of interferon gamma regulates STAT1 alpha nuclear translocation at an intracellular site. J Cell Sci 113 ( Pt 15):2771-81
Mujtaba, M G; Villarete, L; Johnson, H M (1999) IFN-tau inhibits IgE production in a murine model of allergy and in an IgE-producing human myeloma cell line. J Allergy Clin Immunol 104:1037-44
Johnson, T M; Holaday, S K; Sun, Y et al. (1999) Expression, purification, and characterization of interferon-tau produced in Pichia pastoris grown in a minimal medium. J Interferon Cytokine Res 19:631-6
Radhakrishnan, R; Walter, L J; Subramaniam, P S et al. (1999) Crystal structure of ovine interferon-tau at 2.1 A resolution. J Mol Biol 286:151-62
Mujtaba, M G; Streit, W J; Johnson, H M (1998) IFN-tau suppresses both the autoreactive humoral and cellular immune responses and induces stable remission in mice with chronic experimental allergic encephalomyelitis. Cell Immunol 186:94-102
Subramaniam, P S; Cruz, P E; Hobeika, A C et al. (1998) Type I interferon induction of the Cdk-inhibitor p21WAF1 is accompanied by ordered G1 arrest, differentiation and apoptosis of the Daudi B-cell line. Oncogene 16:1885-90

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