Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical symptoms in susceptible mice. In light of the potential viral etiology and similarities in the immune-mediated pathology and progression of chronic demyelination, this TMEV system is considered to be one of the best animal models for studying human multiple sclerosis (MS). The previous studies in the field are heavily based on CD4+ T cell responses to TMEV capsid epitopes in the periphery. We have recently focused our efforts on analysis of T cells infiltrating the CNS during the course of TMEV-infection in resistant and susceptible mice. Surprisingly, <5% of the CNS infiltrating CD4+ T cells are reactive to the capsid epitopes in susceptible SJL mice, compared to >45% in resistant C57BL/6 mice. The type, nature and reactivity of the remainder of CD4+ T cells in the CNS are unclear at this time. Our preliminary studies suggest that major CNS-infiltrating CD4+ T cells in virus infected susceptible SJL mice recognize non-capsid epitopes residing on viral RNA polymerase (3D). In addition, we have successfully generated I-AS-tetramers, transgenic mice carrying viral capsid protein genes and TCR transgenic mice expressing TMEV capsid-specific TCRs. Thus, further assessment of the reactivity of the Th cells in susceptible SJL mice will be very important in understanding the potential pathogenic mechanisms of demyelination and these studies are now feasible. We hypothesize that T cells in the CNS specific for non-capsid viral antigens following viral infection may play a critical role in protection or pathogenesis.
The specific aims for the proposed studies include: 1) Determination of the level, expansion and nature of capsid-specific CD4+ T cells in the CNS and periphery, including activation states and effector functions; 2) Identification of the specificity and nature of non-capsid viral epitope-reactive T cells infiltrating the CNS during TMEV-infection; 3) Assessment of the role of TMEV capsid- and noncapsid-specific T cells in the pathogenesis of demyelination. We believe that our proposed studies will yield important information on the potential control and pathogenic mechanism(s) against virus-induced immune-mediated demyelination, which is a relevant virus model for studying human MS. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033008-11
Application #
7114307
Study Section
Special Emphasis Panel (ZRG1-CNBT (01))
Program Officer
Utz, Ursula
Project Start
1994-05-01
Project End
2009-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
11
Fiscal Year
2006
Total Cost
$313,433
Indirect Cost
Name
Northwestern University at Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Kang, Min H; Jin, Young H; Kim, Byung S (2018) Effects of Keratinocyte-Derived Cytokine (CXCL-1) on the Development of Theiler's Virus-Induced Demyelinating Disease. Front Cell Infect Microbiol 8:9
Kang, Hyun Seok; Myoung, Jinjong; So, Eui Young et al. (2016) Transgenic expression of non-structural genes of Theiler's virus suppresses initial viral replication and pathogenesis of demyelination. J Neuroinflammation 13:133
Jin, Young-Hee; Kim, Byung S (2015) Isolation of CNS-infiltrating and Resident Microglial Cells. Bio Protoc 5:
Hou, Wanqiu; Jin, Young-Hee; Kang, Hyun Seok et al. (2014) Interleukin-6 (IL-6) and IL-17 synergistically promote viral persistence by inhibiting cellular apoptosis and cytotoxic T cell function. J Virol 88:8479-89
Jin, Young-Hee; Hou, Wanqiu; Kang, Hyun Seok et al. (2013) The role of interleukin-6 in the expression of PD-1 and PDL-1 on central nervous system cells following infection with Theiler's murine encephalomyelitis virus. J Virol 87:11538-51
Myoung, Jinjong; Kang, Hyun Seok; Hou, Wanqiu et al. (2012) Epitope-specific CD8+ T cells play a differential pathogenic role in the development of a viral disease model for multiple sclerosis. J Virol 86:13717-28
Jin, Young-Hee; Kang, Hyun Seok; Mohindru, Mani et al. (2011) Preferential induction of protective T cell responses to Theiler's virus in resistant (C57BL/6 x SJL)F1 mice. J Virol 85:3033-40
Kang, Hyun Seok; Kim, Byung S (2010) Predominant clonal accumulation of CD8+ T cells with moderate avidity in the central nervous systems of Theiler's virus-infected C57BL/6 mice. J Virol 84:2774-86
Jin, Young-Hee; Hou, Wanqiu; Kim, Seung Jae et al. (2010) Type I interferon signals control Theiler's virus infection site, cellular infiltration and T cell stimulation in the CNS. J Neuroimmunol 226:27-37
Hou, Wanqiu; Kang, Hyun Seok; Kim, Byung S (2009) Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. J Exp Med 206:313-28

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