This is a revised competitive renewal application of a project based on our discovery of abeneficial role for the peripheral immune system in mouse facial motoneuron (FMN)reparative processes. In the initial funding period, the immune cellular and molecular components involved were identified:the CD4+ effector Th2 cell is necessary for FMN survival after facial nerve injury, via an antigen-dependent process requiring peripheral activation and central re-activation. &brain-derived neurotrophic factor (BDNF) is an essential molecule. Importantly, FACS analysis of lymph node cells taken from axotomized mice indicates that Thi/Th2 cytokine-secreting cells are generated in response to peripheral nerve injury. Functional recovery from facial paralysis induced by crush injury is impaired in immunodeficient mice, but can be restored to wildtype (WT) with immune reconstitution. It is hypothesizedthat CD4+effector T cells play distinct roles in motoneuron reparative processes, with the Tha cell mediating FMN survival through a central BDNF-dependent process and the Thi cell mediating functional recovery byparticipation in the lesion site pro-inflammatory response.
4 aims will test this hypothesis.
Aim #1 is to determine the mechanism underlying CD4+ effector T cell localization within the facial motor nucleus after facial nerve injury. Experiments will utilize immunodeficient mice reconstituted with GFP-expressing CD4+Tcells, in sifu hybridization with Thi/Th2 cytokine riboprobes, chemokine RT- PCR, and chemokine neutralization antibodies/knockout mice.
Aim #2. is to determine the mechanism underlying CD4+ T cell-mediated FMNsurvival after facial nerve injury, and will use WT and chimeric BDNF-negative mice to test the role of CD4+T cell-derived BDNF in FMNrescue.
Aim #3 is to determineif immune cell-mediated rescue of cranial motoneurons (FMN)from axotomy-induced cell death can be generalized to a spinal MN. WT,immunodeficient,and reconstituted immunodeficientmicewill be used to determine the impact ofthe immune system on sciatic MNviability after sciatic nerve injury.
Aim #4 is to determine if the Thi effector cell mediates functionalrecoveryfrom peripheral nerveinjury-induced paralysis. STAT4,T-bet, and STAT6deficient mice will be used with selective reconstitution experiments to determine the role of Thi/Th.2 effector cells in recovery of motor function, assessed with behavioral tests, after a facial or sciatic nerve crush injury. The immune system can have both protective and destructive effects in neural disease (such as amyotrophic lateral sclerosis, a fatal MNdisease) and/or trauma (such as spinal cord injury), but the regulatory nature ofsuch contradictory actions has yet to be determined. Understanding how the immune system benefits the injured nervous system holds great promise in the development of effective treatment strategies to offset disease or injury progression, and reduce disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040433-09
Application #
7729062
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Kleitman, Naomi
Project Start
2000-07-01
Project End
2010-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
9
Fiscal Year
2010
Total Cost
$311,402
Indirect Cost
Name
Loyola University Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Jones, Kathryn J; Lovett-Racke, Amy E; Walker, Chandler L et al. (2015) CD4?+?T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease. J Neuroimmune Pharmacol 10:587-94
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Mesnard-Hoaglin, Nichole A; Xin, Junping; Haulcomb, Melissa M et al. (2014) SOD1(G93A) transgenic mouse CD4(+) T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment. Brain Behav Immun 40:55-60
Haulcomb, Melissa M; Mesnard, Nichole A; Batka, Richard J et al. (2014) Axotomy-induced target disconnection promotes an additional death mechanism involved in motoneuron degeneration in amyotrophic lateral sclerosis transgenic mice. J Comp Neurol 522:2349-76
Mesnard, Nichole A; Haulcomb, Melissa M; Tanzer, Lisa et al. (2013) Delayed functional recovery in presymptomatic mSOD1(G93A) mice following facial nerve crush axotomy. J Neurodegener Regen 4:21-25
Xin, Junping; Fargo, Keith N; Tanzer, Lisa et al. (2012) Immune cell-mediated neuroprotection is independent of estrogen action through estrogen receptor-alpha. Metab Brain Dis 27:23-8

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