One of the most exciting frontiers in medicine today concerns the repair of traumatic injuries to the central nervous system (CNS). Improvements in treatment are helping many more patients survive CNS injury yet most injuries to the spinal cord and brain still cause lifelong disability. More research is critically needed. The majority of tissue damage after CNS injury results not from the primary injury but from secondary neurodegeneration that follows it, a process which, in principle, is amenable to therapeutic intervention. T cells have been shown to attenuate this secondary degeneration and to increase neuronal survival if their activity is well-controlled. There is a delicate balance between the beneficial effects of T cells and their ability to cause devastating autoimmune diseases. This balance is achieved by the naturally occurring CD4+CD25+Foxp3+ regulatory T cells (Treg), which limit beneficial immune neuroprotection, but at the same time prevent the development of catastrophic autoimmunity. Recent studies have shown that Treg cells control most components of the immune system, however, their powerful suppressive action must itself be regulated otherwise potentially beneficial immune responses would be hindered. We postulate that injured central nervous system (CNS) tissue releases damage-associated molecular patterns that temporary interrupt Treg- cell suppression, probably through toll-like receptor (TLR) 9, to permit protective immune response, elimination of causative agent(s), and tissue healing. The overall goal of the proposed research project is to investigate the role of Treg cells in modulating the CNS injury-associated inflammatory process in a way that allows a neuroprotective immune response to be induced while at the same time preventing destructive and possibly catastrophic autoimmunity. In the proposed research project we will examine the hypotheses that (1) the Treg- cell suppressive function changes during the course of the response to CNS injury (Aim1);(2) resurgence of Treg-cell function prevents destructive autoimmunity at a cost of ineffective neuroprotection (Aim 2);and (3) TLRs (particularly TLR9) are mediators between the tissue "damage signals" and Treg functionality (Aim 3). Understanding the role of Treg cells in CNS injury responses and its molecular basis will lead to new therapeutic strategies that will enhance the control of CNS injury and other neurodegenerative conditions, and minimize deleterious consequences such as induction of pathogenic autoimmune responses.

Public Health Relevance

One of the most exciting frontiers in medicine today concerns the repair of traumatic injuries to the central nervous system (CNS). Immune cells, namely T-lymphocytes, have been shown to increase neuronal survival, however, these protective cells have the ability to cause devastating autoimmune diseases if not well regulated. This balance is achieved and maintained by a sub-population of T lymphocytes, termed regulatory T-lymphocytes. In this research proposal we aim to understand the role of regulatory T-lymphocytes in CNS injury, which might help to develop new therapeutic strategies for CNS injuries based on modulation of these cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061973-05
Application #
8489353
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Utz, Ursula
Project Start
2009-09-30
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$315,783
Indirect Cost
$108,911
Name
University of Virginia
Department
Neurosciences
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Walsh, James T; Zheng, Jingjing; Smirnov, Igor et al. (2014) Regulatory T cells in central nervous system injury: a double-edged sword. J Immunol 193:5013-22
Walsh, James T; Watson, Nikki; Kipnis, Jonathan (2014) T cells in the central nervous system: messengers of destruction or purveyors of protection? Immunology 141:340-4
Smirnov, Igor; Walsh, James T; Kipnis, Jonathan (2013) Chronic mild stress eliminates the neuroprotective effect of Copaxone after CNS injury. Brain Behav Immun 31:177-82
Walsh, James T; Kipnis, Jonathan (2011) Regulatory T cells in CNS injury: the simple, the complex and the confused. Trends Mol Med 17:541-7
Derecki, Noel C; Cardani, Amber N; Yang, Chun Hui et al. (2010) Regulation of learning and memory by meningeal immunity: a key role for IL-4. J Exp Med 207:1067-80