The objective is to study experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), focusing on how the innate and adaptive immune systems interact to trigger and regulate the disease.
Two Specific Aims are proposed.
AIM 1 tests the hypothesis that the innate immune system contributes to the triggering of EAE. We will use Lewis (LEW) rats tolerized with MBP68-86 + incomplete adjuvant. These rats are protected against EAE, and ex vivo transfer of T cells from tolerant donors confers protection on LEW recipients. These rats also harbor encephalitogenic T cells that transfer EAE after in vitro culture with MBP68-86. Thus, pathogenic and suppressor (Treg) cells coexist in tolerized hosts, which provides a unique model to study triggering events in EAE. It has been reported that microbial CpG oligonucleotides, which interact with Toll-like receptors (TLRs) on APCs and trigger production of IL-12, promote inflammatory Thl responses.
In Aim 1 we will test the hypothesis that CpG will activate the encephalitogenic T cells, thus overcoming the regulatory function of Treg cells which normally prevent EAE in these animals. ? ? Aim 2 determines the mechanism by which natural killer (NK) cells, which are important components of the innate immune system, suppress T cell activation. It has been reported that NK cell depletion leads to exacerbation of EAE, and we have shown that NK cells inhibit the proliferation of activated encephalitogenic T cells. We will test the hypothesis that NK cells maintain immune homeostasis by preventing the inadvertent activation of autoreactive T cell clones that otherwise could elicit EAE.
In Aim 2 we will determine the mechanism by which NK cells suppress T cell activation. ? ? These studies will provide new insight into how microbes activate autoreactive T cells, and clarify the roles of innate and adaptive immunity in regulation of EAE by NK and Treg cells, respectively. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048070-02
Application #
6948771
Study Section
Special Emphasis Panel (ZRG1-BDCN-B (01))
Program Officer
Utz, Ursula
Project Start
2004-09-15
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$209,513
Indirect Cost
Name
Wayne State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Kheradmand, Taba; Wolf, Norbert A; Swanborg, Robert H (2009) Myelin basic protein-reactive T cells persist in an inactive state in the bone marrow of Lewis rats that have recovered from autoimmune encephalomyelitis. J Neuroimmunol 209:26-32
Kheradmand, Taba; Trivedi, Prachi P; Wolf, Norbert A et al. (2008) Characterization of a subset of bone marrow-derived natural killer cells that regulates T cell activation in rats. J Leukoc Biol 83:1128-35
Wolf, Norbert A; Amouzegar, Taba K; Swanborg, Robert H (2007) Synergistic interaction between Toll-like receptor agonists is required for induction of experimental autoimmune encephalomyelitis in Lewis rats. J Neuroimmunol 185:115-22
Trivedi, Prachi P; Amouzegar, Taba K; Roberts, Paul C et al. (2007) Regulation of adaptive immunity by cells of the innate immune system: bone marrow natural killer cells inhibit T cell proliferation. Adv Exp Med Biol 590:113-20
Trivedi, Prachi P; Roberts, Paul C; Wolf, Norbert A et al. (2005) NK cells inhibit T cell proliferation via p21-mediated cell cycle arrest. J Immunol 174:4590-7