Innate immune response in traumatic Spinal Cord Injury (SCI), a beneficial regulatory role for MIS416 — ASN Events
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  3. Innate immune response in traumatic Spinal Cord Injury (SCI), a beneficial regulatory role for MIS416

Innate immune response in traumatic Spinal Cord Injury (SCI), a beneficial regulatory role for MIS416 (#245)

Masoud Hassanpour Golakani 1 2 , Gill Webster 3 , Mohammad G Mohammad 4 , Hui Li 1 2 , Samuel N Breit 1 , Marc J Ruitenberg 5 , David A Brown 1 2
  1. St Vincent's Centre for Applied Medical Research (AMR), Darlinghurst, NSW, Australia
  2. Neuroinflammation Research Group, Westmead Institute for Medical Research (WIMR), Sydney, NSW, Australia
  3. Innate Immunotherapeutics, Auckland, New Zealand
  4. Department of Medical Laboratory Sciences, University of Sharjah, Sharjah, UAE
  5. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia

The precise temporal dynamics of inflammatory responses post spinal cord injury (SCI), and its significance for recovery, remain largely unknown. We aimed to define various peripheral and infiltrating myeloid cells in the injured spinal cord and determine their relationship to functional outcomes. We also investigated the role of MIS416, a novel immunomodulatory drug in clinical development that specifically targets myeloid cell responses, in SCI.

Severe contusive SCI (70 kilo dyne) was induced in mice and locomotion was assessed on day 1,7,14, 21 and 28 post SCI using the Basso Mouse Scale. MIS416 (6mg/kg) was administered intravenously 24hr following SCI and weekly thereafter. Immune cells were isolated from peripheral blood and the whole spinal cord, phenotyped using FACS, immunohistochemistry, and immunofluorescence, and correlated with functional recovery.

In untreated mice, peripherally-derived infiltrating immune cells progressively increased over the course of recovery from SCI, most of which being CD8+ and CD4+ T-cells and mDCs. CD11c+ and CD3+ cells infiltrated the injury core, GFAP+ astrocytes surrounded the core; Iba-1+ microglia were dispersed throughout the entire cord. Macrophages numbers were negatively correlated with functional recovery at 7-14 dpi, while positively correlated at 21-28 dpi. CD11c+B220+ cells showed positive correlation at 7-14 and negative correlation at 21-28 dpi. MIS416 treated mice showed significantly augmented functional recovery compared to untreated mice. MIS416 expanded the non-inflammatory CD115+ bone marrow-derived peripheral monocyte pool at 7 dpi, which showed positive correlation with recovery at 28 dpi, and reduced the number of circulating inflammatory GR1+ leukocytes at 7 dpi, showing negative correlation with recovery at 28 dpi. Additionally, MIS416 treatment promoted CD11c+ tissue protecting microglia in the injured spinal cord at 28 dpi.

These findings highlight that the dynamics of the innate immune responses post-SCI might be therapeutically manipulated to augment functional recovery and identifies MIS416 as a novel therapeutic candidate.

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