Recombinant T cell receptor ligand treats experimental stroke

Sandhya Subramanian, Bing Zhang, Yasuharu Kosaka, Gregory G. Burrows, Marjorie Grafe, Arthur Vandenbark, Patricia D. Hurn, Halina Offner

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Background and Purpose - Experimental stroke induces a biphasic effect on the immune response that involves early activation of peripheral leukocytes followed by severe immunodepression and atrophy of the spleen and thymus. In tandem, the developing infarct is exacerbated by influx of numerous inflammatory cell types, including T and B lymphocytes. These features of stroke prompted our use of recombinant T cell receptor ligands (RTL), partial major histocompatibility complex Class II molecules covalently bound to myelin peptides. We tested the hypothesis that RTL would improve ischemic outcome in the brain without exacerbating defects in the peripheral immune system function. Methods - Four daily doses of RTL were administered subcutaneously to C57BL/6 mice after middle cerebral artery occlusion, and lesion size and cellular composition were assessed in the brain and cell numbers were assessed in the spleen and thymus. Results - Treatment with RTL551 (I-A b molecule linked to MOG-35-55 peptide) reduced cortical and total stroke lesion size by approximately 50%, inhibited the accumulation of inflammatory cells, particularly macrophages/activated microglial cells and dendritic cells, and mitigated splenic atrophy. Treatment with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide) similarly reduced the stroke lesion size in HLA-DR2 transgenic mice. In contrast, control RTL with a nonneuroantigen peptide or a mismatched major histocompatibility complex Class II moiety had no effect on stroke lesion size. Conclusions - These data are the first to demonstrate successful treatment of experimental stroke using a neuroantigen-specific immunomodulatory agent administered after ischemia, suggesting therapeutic potential in human stroke.

Original languageEnglish (US)
Pages (from-to)2539-2545
Number of pages7
JournalStroke
Volume40
Issue number7
DOIs
StatePublished - Jul 1 2009

Fingerprint

T-Cell Antigen Receptor
Stroke
Ligands
HLA-DR2 Antigen
Peptides
Major Histocompatibility Complex
Thymus Gland
Atrophy
Spleen
Middle Cerebral Artery Infarction
Brain
Myelin Sheath
Inbred C57BL Mouse
Immunosuppression
Dendritic Cells
Transgenic Mice
Immune System
Leukocytes
B-Lymphocytes
Ischemia

Keywords

  • Autoreactive T cells
  • Immunotherapy
  • Recombinant TCR ligands
  • Stroke

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing

Cite this

Recombinant T cell receptor ligand treats experimental stroke. / Subramanian, Sandhya; Zhang, Bing; Kosaka, Yasuharu; Burrows, Gregory G.; Grafe, Marjorie; Vandenbark, Arthur; Hurn, Patricia D.; Offner, Halina.

In: Stroke, Vol. 40, No. 7, 01.07.2009, p. 2539-2545.

Research output: Contribution to journalArticle

Subramanian, S, Zhang, B, Kosaka, Y, Burrows, GG, Grafe, M, Vandenbark, A, Hurn, PD & Offner, H 2009, 'Recombinant T cell receptor ligand treats experimental stroke', Stroke, vol. 40, no. 7, pp. 2539-2545. https://doi.org/10.1161/STROKEAHA.108.543991
Subramanian, Sandhya ; Zhang, Bing ; Kosaka, Yasuharu ; Burrows, Gregory G. ; Grafe, Marjorie ; Vandenbark, Arthur ; Hurn, Patricia D. ; Offner, Halina. / Recombinant T cell receptor ligand treats experimental stroke. In: Stroke. 2009 ; Vol. 40, No. 7. pp. 2539-2545.
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AU - Hurn, Patricia D.

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