Novel Humanized Recombinant T Cell Receptor Ligands Protect the Female Brain After Experimental Stroke

Jie Pan, Julie Palmateer, Timothy Schallert, Madison Hart, Arushi Pandya, Arthur Vandenbark, Halina Offner, Patricia D. Hurn

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Transmigration of peripheral leukocytes to the brain is a major contributor to cerebral ischemic cell death mechanisms. Humanized partial major histocompatibility complex class II constructs (pMHC), covalently linked to myelin peptides, are effective for treating experimental stroke in males, but new evidence suggests that some inflammatory cell death mechanisms after brain injury are sex-specific. We here demonstrate that treatment with pMHC constructs also improves outcomes in female mice with middle cerebral artery occlusion (MCAO). HLA-DR2 transgenic female mice with MCAO were treated with RTL1000 (HLA-DR2 moiety linked to human MOG-35-55 peptide), HLA-DRa1-MOG-35-55, or vehicle (VEH) at 3, 24, 48, and 72 h after reperfusion and were recovered for 96 h or 2 weeks post-injury for measurement of histology (TTC staining) or behavioral testing. RTL1000- and DRa1-MOG-treated mice had profoundly reduced infarct volumes as compared to the VEH group, although higher doses of DRa1-MOG were needed for females vs. males evaluated previously. RTL1000-treated females also exhibited strongly improved functional recovery in a standard cylinder test. In novel studies of post-ischemic ultrasonic vocalization (USV), as measured by animal calls to their cage mates, we modeled in mice the post-stroke speech deficits common in human stroke survivors. The number of calls was reduced in injured animals relative to pre-MCAO baseline regardless of RTL1000 treatment status. However, call duration was significantly improved by RTL1000 treatment, suggesting benefit to the animal's recovery of vocalization capability. We conclude that both the parent RTL1000 molecule and the novel non-polymorphic DRα1-MOG-35-55 construct were highly effective immunotherapies for treatment of transient cerebral ischemia in females.

Original languageEnglish (US)
Pages (from-to)577-585
Number of pages9
JournalTranslational Stroke Research
Volume5
Issue number5
DOIs
StatePublished - 2014

Fingerprint

T-Cell Antigen Receptor
Stroke
Ligands
Middle Cerebral Artery Infarction
HLA-DR2 Antigen
Brain
Animal Vocalization
Cell Death
Peptides
Transient Ischemic Attack
Therapeutics
Myelin Sheath
Major Histocompatibility Complex
Ultrasonics
Immunotherapy
Brain Injuries
Transgenic Mice
Reperfusion
Histology
Leukocytes

Keywords

  • Cerebral ischemia
  • Gender
  • Immunotherapy
  • Partial MHC class II constructs
  • Sex
  • Stroke
  • Ultrasonic vocalization

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)
  • Cardiology and Cardiovascular Medicine
  • Medicine(all)

Cite this

Novel Humanized Recombinant T Cell Receptor Ligands Protect the Female Brain After Experimental Stroke. / Pan, Jie; Palmateer, Julie; Schallert, Timothy; Hart, Madison; Pandya, Arushi; Vandenbark, Arthur; Offner, Halina; Hurn, Patricia D.

In: Translational Stroke Research, Vol. 5, No. 5, 2014, p. 577-585.

Research output: Contribution to journalArticle

Pan, Jie ; Palmateer, Julie ; Schallert, Timothy ; Hart, Madison ; Pandya, Arushi ; Vandenbark, Arthur ; Offner, Halina ; Hurn, Patricia D. / Novel Humanized Recombinant T Cell Receptor Ligands Protect the Female Brain After Experimental Stroke. In: Translational Stroke Research. 2014 ; Vol. 5, No. 5. pp. 577-585.
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