Abstract T MP18: In Vivo Expansion of Regulatory T cells with Interleukin-2/Interleukin-2-antibody Complex Protects against Transient Ischemic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Haiyue Zhang ◽  
Peiying Li ◽  
Yanqin Gao ◽  
Jun Chen ◽  
Xiaoming Hu
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Brain Injury ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Treg Population ◽  
Antibody Complex

Background and Purpose: Our previous work documents the transfer of regulatory T cells (Tregs) in rodent models of ischemic stroke protects acute ischemic brain injury by regulating poststroke inflammatory response and thereby ameliorating BBB disruption. However, the low number of Tregs restricts the clinical feasibility of Treg transfer. Recently, in vivo expansion of Tregs with IL-2/IL-2-antibody complex (IL-2/IL-2Ab) was validated protective in autoimmune diseases model,renal ischemia reperfusion model and atherosclerosis. Here we investigate the beneficial effect of IL-2/IL-2Ab on ischemic stroke and decipher the underlying mechanisms. Methods: IL-2/IL-2Ab or isotype IgG was ip injected into C57/BL6 mice for 3 consecutive days. The mice are then subjected to 60-minute middle cerebral artery occlusion (MCAO) or sham operation. Brain infarction, inflammation and neurological performance was assessed up to 7 days after reperfusion. Results: Flow cytometry analysis reveals a marked increase of CD4+CD25+Foxp3+ Tregs in the blood, lymph nodes and spleens collected from IL-2/IL-2Ab-treated mice as compared to those from isotype-treated controls. Such Treg elevation could be observed since 3 days after IL-2/IL-2Ab injection and lasts until 7 days after MCAO. Immunochemistry staining confirms the increased number of Foxp3+ cells in the spleen at 3 days after MCAO in IL-2/IL-2Ab-treated mice. IL-2/IL-2Ab promotes function recovery up to 7 days after stroke, as revealed by significantly improved performance in corner test (n=6-9, ***p<0.001), rotarod test (n=8, **p<0.01), cylinder test (n=8, **p<0.01) and adhesive removal test (n=3, *p<0.05). Quantification of TTC staining and microtubule-associated protein (MAP2) staining shows reductions in brain infarct volume at 3 days (n=5-9,*p<0.05) and 7 days (n=7-9,*p<0.01), respectively, after MCAO. Meanwhile, we observed reduced infiltration of peripheral immune cells (CD3+ T cells, MPO+ neutrophils and F4/80+ macrophages) into the ischemic brain. Conclusions: Our finding suggests that IL-2/IL-2Ab treatment is a novel and clinical feasible immune therapy to expand Treg population in vivo, reduce post-stroke inflammatory responses and protect against ischemic brain injury.

scholarly journals In Vivo Expansion of Regulatory T Cells with IL-2/IL-2 Antibody Complex Protects against Transient Ischemic Stroke

2018 ◽  
Vol 38 (47) ◽  
pp. 10168-10179 ◽  
Author(s):  
Haiyue Zhang ◽  
Yuguo Xia ◽  
Qing Ye ◽  
Fang Yu ◽  
Wen Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Ischemic Stroke ◽  
Regulatory T Cells ◽  
Antibody Complex

scholarly journals Non-invasive tracking of CD4+ T cells with a paramagnetic and fluorescent nanoparticle in brain ischemia

2015 ◽  
Vol 36 (8) ◽  
pp. 1464-1476 ◽  
Author(s):  
Wei-Na Jin ◽  
Xiaoxia Yang ◽  
Zhiguo Li ◽  
Minshu Li ◽  
Samuel Xiang-Yu Shi ◽  
...  
Keyword(s):  
T Cells ◽  
Brain Injury ◽  
In Vivo Imaging ◽  
Inflammatory Diseases ◽  
Transfer Model ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Magnetic Resonance Imaging Mri ◽  
Infiltrating Lymphocytes

Recent studies have demonstrated that lymphocytes play a key role in ischemic brain injury. However, there is still a lack of viable approaches to non-invasively track infiltrating lymphocytes and reveal their key spatiotemporal events in the inflamed central nervous system (CNS). Here we describe an in vivo imaging approach for sequential monitoring of brain-infiltrating CD4+ T cells in experimental ischemic stroke. We show that magnetic resonance imaging (MRI) or Xenogen imaging combined with labeling of SPIO-Molday ION Rhodamine-B (MIRB) can be used to monitor the dynamics of CD4+ T cells in a passive transfer model. MIRB-labeled CD4+ T cells can be longitudinally visualized in the mouse brain and peripheral organs such as the spleen and liver after cerebral ischemia. Immunostaining of tissue sections showed similar kinetics of MIRB-labeled CD4+ T cells when compared with in vivo observations. Our results demonstrated the use of MIRB coupled with in vivo imaging as a valid method to track CD4+ T cells in ischemic brain injury. This approach will facilitate future investigations to identify the dynamics and key spatiotemporal events for brain-infiltrating lymphocytes in CNS inflammatory diseases.

scholarly journals Cancer Exacerbates Ischemic Brain Injury Via Nrp1 (Neuropilin 1)-Mediated Accumulation of Regulatory T Cells Within the Tumor

Stroke ◽  
2018 ◽  
Vol 49 (11) ◽  
pp. 2733-2742 ◽  
Author(s):  
Long Wang ◽  
Yuxi Zhou ◽  
Jiemin Yin ◽  
Yu Gan ◽  
Xin Wang ◽  
...  
Keyword(s):  
T Cells ◽  
Brain Injury ◽  
Regulatory T Cells ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Neuropilin 1

scholarly journals Ischemic Brain Injury and Regulatory T Cells

2019 ◽  
Vol 3 (1) ◽  
pp. 1-1
Author(s):  
Ito Minako ◽  
◽  
Srirat Tanakorn ◽  
Nakamura Toshihiro ◽  
Komai Kyoko ◽  
...  
Keyword(s):  
T Cells ◽  
Brain Injury ◽  
Regulatory T Cells ◽  
Ischemic Brain Injury ◽  
Ischemic Brain

Chronic colitis induces meninges traffic of gut-derived T cells, unbalances M1 and M2 microglia/macrophage and increases ischemic brain injury in mice

2019 ◽  
Vol 1707 ◽  
pp. 8-17 ◽  
Author(s):  
Yukun Feng ◽  
Xiaofei He ◽  
Shijian Luo ◽  
Xiaofeng Chen ◽  
Simei Long ◽  
...  
Keyword(s):  
T Cells ◽  
Brain Injury ◽  
Ischemic Brain Injury ◽  
Chronic Colitis ◽  
Ischemic Brain ◽  
M2 Microglia

Abstract TP269: Lncrna-u90926 Aggravates Ischemic Brain Injury via Promoting Neutrophils Infiltration After Experimental Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Jian Chen ◽  
Yun Xu
Keyword(s):  
Ischemic Stroke ◽  
Brain Injury ◽  
Expression Level ◽  
Neurological Deficits ◽  
Neurological Injury ◽  
Experimental Stroke ◽  
Ischemic Brain Injury ◽  
Triphenyltetrazolium Chloride ◽  
Ischemic Brain ◽  
Severity Scores

Background: Long non-coding RNAs (LncRNAs) are expressed at high levels in the brain in a variety of neuropathologic conditions, including stroke. However, the potential role of LncRNAs in ischemic stroke-associated microglial biological function and neurological injury remains largely unknown. Methods: Oxygen-glucose deprivation and transient middle cerebral artery occlusion (MCAO) in C57BL/6 mice were used as in vitro and in vivo ischemic stroke models. Microarray analysis was performed to explore the overall expression level changes of LncRNAs. Real-time polymerase chain reaction (RT-qPCR) was used to detect expression level of LncU90926 in brain, plasma and microglia. ShRNA-LncU90926 in lentivirus and microglia specific Adeno-associated virus (AAV) were used to knockdown LncU90926 in vitro and in vivo separately. Infarct volumes and neurological impairments were assessed by 2,3,5-triphenyltetrazolium chloride (TTC) staining, Neurological Severity Scores (NSS), rotarod test and grip strength respectively. Immunofluorescence staining and flow cytometry were performed to detect the number of neutrophils recruited to brain. RT-qPCR was used to detect the level of chemokines (CXCL, CCL2) and inflammatory mediators associated with neutrophils (MPO, MMP3 and TIMP1). Results: (1). LncU90926 was markedly up-regulated in the infarcted brain and plasma after MCAO. Both MCAO and OGD treatment induced remarkable up-regulation of LncU90926 in microglia. (2). LncU90926 knockdown definitely attenuated brain infarct size and neurological deficits after ischemic stroke. (3). LncU90926 knockdown in microglia reduced the number of neutrophils recruited to brain, and CXCL1 and CCL2 were down-regulated in both MCAO and OGD models. LncU90926 knockdown also induced reduction of MPO, MMP3 and TIMP1 in the infarcted brain. Conclusions: LncU90926 was up-regulated in microglia after experimental stroke, and aggravates ischemic brain injury through facilitating neutrophils infiltration via up-regulating microglial chemokine.

scholarly journals IL-2 administration increases CD4+CD25hi Foxp3+ regulatory T cells in cancer patients

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2409-2414 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Steven A. Rosenberg
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Interleukin 2 ◽  
Selective Inhibition ◽  
High Dose ◽  
Protein Levels ◽  
And Function ◽  
The Impact

Abstract Interleukin-2 (IL-2) is historically known as a T-cell growth factor. Accumulating evidence from knockout mice suggests that IL-2 is crucial for the homeostasis and function of CD4+CD25+ regulatory T cells in vivo. However, the impact of administered IL-2 in an immune intact host has not been studied in rodents or humans. Here, we studied the impact of IL-2 administration on the frequency and function of human CD4+CD25hi T cells in immune intact patients with melanoma or renal cancer. We found that the frequency of CD4+CD25hi T cells was significantly increased after IL-2 treatment, and these cells expressed phenotypic markers associated with regulatory T cells. In addition, both transcript and protein levels of Foxp3, a transcription factor exclusively expressed on regulatory T cells, were consistently increased in CD4 T cells following IL-2 treatment. Functional analysis of the increased number of CD4+CD25hi T cells revealed that this population exhibited potent suppressive activity in vitro. Collectively, our results demonstrate that administration of high-dose IL-2 increased the frequency of circulating CD4+CD25hi Foxp3+ regulatory T cells. Our findings suggest that selective inhibition of IL-2-mediated enhancement of regulatory T cells may improve the therapeutic effectiveness of IL-2 administration. (Blood. 2006;107:2409-2414)

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