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Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice

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Abstract

Stroke induces a biphasic effect on the peripheral immune response that involves early activation of peripheral leukocytes followed by severe immunosuppression and atrophy of the spleen. Peripheral immune cells, including T lymphocytes, migrate to the brain and exacerbate the developing infarct. Recombinant T-cell receptor (TCR) Ligand (RTL)551 is designed as a partial TCR agonist for myelin oligodendrocyte glycoprotein (MOG)-reactive T cells and has demonstrated the capacity to limit infarct volume and inflammation in brain when administered to mice undergoing middle cerebral artery occlusion (MCAO). The goal of this study was to determine if RTL551 could retain protection when given within the therapeutically relevant 4 h time window currently in clinical practice for stroke patients. RTL551 was administered subcutaneously 4 h after MCAO, with repeated doses every 24 h until the time of euthanasia. Cell numbers were assessed in the brain, blood, spleen and lymph nodes and infarct size was measured after 24 and 96 h reperfusion. RTL551 reduced infarct size in both cortex and striatum at 24 h and in cortex at 96 h after MCAO and inhibited the accumulation of inflammatory cells in brain at both time points. At 24 h post-MCAO, RTL551 reduced the frequency of the activation marker, CD44, on T-cells in blood and in the ischemic hemisphere. Moreover, RTL551 reduced expression of the chemokine receptors, CCR5 in lymph nodes and spleen, and CCR7 in the blood and lymph nodes. These data demonstrate effective treatment of experimental stroke with RTL551 within a therapeutically relevant 4 h time window through immune regulation of myelin-reactive inflammatory T-cells.

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Acknowledgements

The authors wish to thank Dr. Sushmita Sinha and Ms. Sandhya Subramanian for helpful discussions and Ms. Eva Niehaus for assistance in preparing the manuscript. This work was supported by NIH Grant NR003521 (PDH), NIH Grant NS047661 (AAV), the Collins Medical Trust (SD), AHA grant 09POST2190040 (SD), and the Biomedical Laboratory R&D Service, Department of Veterans’ Affairs.

Conflict of interest

Drs. Offner, Burrows, Vandenbark, and OHSU have a significant financial interest in Artielle ImmunoTherapeutics, Inc., a company that may have a commercial interest in the results of this research and technology. This potential conflict of interest has been reviewed and managed by the OHSU and VAMC Conflict of Interest in Research Committees.

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Authors and Affiliations

  1. Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR, 97239, USA

    Arthur A. Vandenbark & Halina A. Offner

  2. Department of Anesthesiology & Peri-Operative Medicine, Oregon Health & Science University, Portland, OR, 97239, USA

    Suzan Dziennis, Sarah Mader, Kozaburo Akiyoshi, Xuefang Ren, Patricia Ayala, Paco S. Herson, Patricia D. Hurn & Halina A. Offner

  3. Department of Neurology, Oregon Health & Science University, Portland, OR, 97239, USA

    Gregory G. Burrows, Arthur A. Vandenbark & Halina A. Offner

  4. Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, 97239, USA

    Arthur A. Vandenbark

  5. Neuroimmunology Research R&D-31, Portland V.A. Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR, 97239, USA

    Halina A. Offner

  6. Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland, OR, 97239, USA

    Gregory G. Burrows

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  1. Suzan Dziennis
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  3. Kozaburo Akiyoshi
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Correspondence to Halina A. Offner.

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Dziennis, S., Mader, S., Akiyoshi, K. et al. Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice. Metab Brain Dis 26, 123–133 (2011). https://doi.org/10.1007/s11011-011-9241-2

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  • DOI: https://doi.org/10.1007/s11011-011-9241-2

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