Recent studies have identified a small but powerful subset of IL-10-producing CD1dhiCD5+ regulatory B lymphocytes (B10) that can limit CNS inflammation and clinical signs of neurological disease in rodent models. In this multi-PI application, we hypothesize that endogenous regulatory B-cells, including the B10 subset, limit infarct size in MCAO by controlling immune-mediated inflammation triggered both in the CNS and in peripheral immune organs by focal stroke. Further, we predict that either selective induction or passive transfer of B10 cells so as to augment B10 cell frequency will provide additional regulatory effects in wild type (WT) mice, and result in smaller infarct and improved functional stroke outcome.
The aims of this application are: 1) Determine the effects of B lymphocyte depletion and regulatory B10 cell restoration and treatment on infarct size, immune cellular composition and inflammatory signature in both spleen and brain hemispheres after MCAO. The hypothesis is that B cell KO mice sustain larger histological damage and poor functional outcome than do WT mice. We will determine the responsible B-cell subpopulations, including the IL-10-secreting B10 subset. 2) Evaluate the contribution of the PD-1/PD-L negative co-activation pathway to infarct size, immune cell composition and inflammatory signature in spleen and brain. The hypothesis is that activation of this receptor-ligand pathway in B lymphocytes, particularly CD1dhiCD5+ B-cells, alters outcomes from MCAO.
This aim will evaluate PD-1, PD-L1 and PD-L2 expression on B-cells, confirm our preliminary findings of increased infarct size in PD-1 KO mice, extend the analysis to PD-L1 and PD-L2 KO mice, and evaluate the contribution of B10- cells to the PD-1/PD-L negative co-activation after stroke by reconstituting PD-L KO mice with WT B10-cells. 3) Evaluate the mechanisms through which B-cells inhibit microglial (MG) activation and release of neurotoxic factors. The hypothesis is that B cells, particularly CD1dhiCD5+ B regulatory cells, improve post-ischemic outcomes by suppressing microglial activation, either via secreted factors or direct cell-cell contact that enables a PD-1 negative co-activation mechanism. Specifically, this aim will evaluate interaction between PD-L+ CD19+ B-cells or IL-10-producing CD1dhiCD5+ B-reg cells and activated PD-1+ MG. The proposed studies offer high impact for the stroke field by virtue of their: 1) complete novelty, 2) focus on the inflamma-suppressive regulatory capacity of select B-cell subsets and 3) ability to lay translational groundwork for regulatory B-cell therapy in acute stroke.

Public Health Relevance

Ischemic stroke is one of the leading causes of death and disability in the United States yet relatively little is known about the contribution to and effects on the immune system during stroke. We have focused on both early and late events in the peripheral immune system during stroke, have observed important changes in the spleen that occur simultaneously with the evolving brain injury, and are studying an important type of immune cells, B lymphocytes, which may have the ability to modulate both brain injury and spleen inflammation after a stroke event. If our initial findings are borne out, a class of B lymphocytes may offer protection to the injured brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS075887-03
Application #
8509042
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (03))
Program Officer
Bosetti, Francesca
Project Start
2011-08-15
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$353,475
Indirect Cost
$123,946
Name
Oregon Health and Science University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Yang, Liu; Kong, Ying; Ren, Honglei et al. (2016) Upregulation of CD74 and its potential association with disease severity in subjects with ischemic stroke. Neurochem Int :
Wang, Jianyi; Ye, Qing; Xu, Jing et al. (2016) DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury. Transl Stroke Res :
Bodhankar, Sheetal; Lapato, Andrew; Chen, Yingxin et al. (2015) Role for microglia in sex differences after ischemic stroke: importance of M2. Metab Brain Dis 30:1515-29
Liesz, Arthur; Hu, Xiaoming; Kleinschnitz, Christoph et al. (2015) Functional role of regulatory lymphocytes in stroke: facts and controversies. Stroke 46:1422-30
Bodhankar, Sheetal; Chen, Yingxin; Lapato, Andrew et al. (2015) Regulatory CD8(+)CD122 (+) T-cells predominate in CNS after treatment of experimental stroke in male mice with IL-10-secreting B-cells. Metab Brain Dis 30:911-24
Bodhankar, Sheetal; Chen, Yingxin; Lapato, Andrew et al. (2015) PD-L1 Monoclonal Antibody Treats Ischemic Stroke by Controlling Central Nervous System Inflammation. Stroke 46:2926-34
Bodhankar, Sheetal; Chen, Yingxin; Vandenbark, Arthur A et al. (2014) Treatment of experimental stroke with IL-10-producing B-cells reduces infarct size and peripheral and CNS inflammation in wild-type B-cell-sufficient mice. Metab Brain Dis 29:59-73
Offner, Halina (2014) Modeling immunity and inflammation in stroke: don't be afraid of mice? Stroke 45:e181-2
Bodhankar, Sheetal; Chen, Yingxin; Lapato, Andrew et al. (2014) Targeting immune co-stimulatory effects of PD-L1 and PD-L2 might represent an effective therapeutic strategy in stroke. Front Cell Neurosci 8:228
Bodhankar, Sheetal; Chen, Yingxin; Vandenbark, Arthur A et al. (2013) IL-10-producing B-cells limit CNS inflammation and infarct volume in experimental stroke. Metab Brain Dis 28:375-86

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