A Novel Partial MHC Class II Construct, DRmQ, Inhibits Central and Peripheral Inflammatory Responses to Promote Neuroprotection in Experimental Stroke

Jea Young Lee, Vanessa Castelli, Brooke Bonsack, Alexandreya B. Coats, Lisset Navarro-Torres, Julian Garcia-Sanchez, Chase Kingsbury, Hung Nguyen, Arthur A. Vandenbark, Roberto Meza-Romero, Halina Offner, Cesar V. Borlongan

Research output: Contribution to journalArticle

Abstract

Recognizing that the pathologic progression of stroke is closely associated with aberrant immune responses, in particular the activation of peripheral leukocytes, namely T cells, we hypothesized that finding a treatment designed to inhibit neuroantigen-specific T cells and block cytotoxic monocytes and macrophages may render therapeutic effects in stroke. We previously reported that subcutaneous administration of partial MHC class II constructs promote behavioral and histological effects in stroke mice by centrally promoting a protective M2 macrophage/microglia phenotype in the CNS and peripherally reversing stroke-associated splenic atrophy. Here, we employed a second species using adult Sprague-Dawley rats exposed to the middle cerebral artery occlusion stroke model and observed similar therapeutic effects with a mouse partial MHC class II construct called DRmQ, as evidenced by reductions in stroke-induced motor deficits, infarcts, and peri-infarct cell loss and neuroinflammation. More importantly, we offered further evidence of peripheral sequestration of inflammation at the level of the spleen, which was characterized by attenuation of stroke-induced spleen weight reduction and TNF-ɑ and IL-6 upregulation. Collectively, these results satisfy the Stroke Therapy Academic Industry Roundtable criteria of testing a novel therapeutic in a second species and support the use of partial MHC class II constructs as a stroke therapeutic designed to sequester both central and peripheral inflammation responses in an effort to retard, or even halt, the neuroinflammation that exacerbates the secondary cell death in stroke.

Original languageEnglish (US)
JournalTranslational Stroke Research
DOIs
StateAccepted/In press - Jan 1 2019

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Stroke
Middle Cerebral Artery Infarction
Therapeutic Uses
Spleen
Macrophages
Inflammation
T-Lymphocytes
Neuroprotection
Microglia
Atrophy
Sprague Dawley Rats
Weight Loss
Monocytes
Interleukin-6
Industry
Leukocytes
Cell Death
Up-Regulation
Therapeutics
Phenotype

Keywords

  • Cerebral ischemia
  • Cytokines
  • DRmQ
  • Immune response
  • Middle cerebral artery occlusion
  • Regenerative medicine
  • Spleen

ASJC Scopus subject areas

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

Cite this

A Novel Partial MHC Class II Construct, DRmQ, Inhibits Central and Peripheral Inflammatory Responses to Promote Neuroprotection in Experimental Stroke. / Lee, Jea Young; Castelli, Vanessa; Bonsack, Brooke; Coats, Alexandreya B.; Navarro-Torres, Lisset; Garcia-Sanchez, Julian; Kingsbury, Chase; Nguyen, Hung; Vandenbark, Arthur A.; Meza-Romero, Roberto; Offner, Halina; Borlongan, Cesar V.

In: Translational Stroke Research, 01.01.2019.

Research output: Contribution to journalArticle

Lee, Jea Young ; Castelli, Vanessa ; Bonsack, Brooke ; Coats, Alexandreya B. ; Navarro-Torres, Lisset ; Garcia-Sanchez, Julian ; Kingsbury, Chase ; Nguyen, Hung ; Vandenbark, Arthur A. ; Meza-Romero, Roberto ; Offner, Halina ; Borlongan, Cesar V. / A Novel Partial MHC Class II Construct, DRmQ, Inhibits Central and Peripheral Inflammatory Responses to Promote Neuroprotection in Experimental Stroke. In: Translational Stroke Research. 2019.
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AU - Kingsbury, Chase

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