Anti-Lysophosphatidic Acid Antibodies Improve Traumatic Brain Injury Outcomes

BACKGROUND: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury. FINDINGS: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes. CONCLUSIONS: This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction

Characterising type-1 interferon signalling following traumatic brain injury

© 2015 Dr. Ila Prasad KarveThe widespread consequences of traumatic brain injury (TBI) apply to individuals, their carers and society. The total cost of TBI in 2009 to the Victorian economy was $8.6 billion (Access Economics report), a figure which encompassed costs from individuals with both severe and mild TBI. Death is a common occurrence in individuals that have sustained severe TBI. Compounding the problem is that individuals who survive after TBI are more susceptible to mental illness, long-term disability, inability to return to work and overall, suffer a reduced quality of life. TBI leads to structural and biochemical alterations within the brain, affecting not only individual cells, but also synaptic and cell-cell connections. This can lead to an overall loss of functional tissue and impairment of cerebral function. Central nervous system (CNS) inflammation is a common occurrence following brain injury. While inflammation is an important response when it comes to combating infection within the body, persistent and uncontrolled inflammation can lead to cellular degeneration. Following TBI, disruption of the blood-brain barrier can cause infiltration of inflammatory leukocytes, initiating a complex molecular cascade of events including activation of resident microglia and astrocytes, secretion of inflammatory cytokines and chemokines and neuronal cell loss. Important players in the inflammatory cascade, the type-1 interferons (IFNs) are considered crucial in mounting an immune and inflammatory response. Type-1 IFNs bind their cognate receptor, the interferon α receptor (IFNAR), consisting of IFNAR1 and IFNAR2 receptor chains. Receptor activation initiates downstream pathways, leading to the production of type-1 IFNs and IFN-regulated genes. Importantly, knockout of the IFNAR1 receptor chain is effective at blocking downstream signalling, a property that has been exploited by researchers to study this signalling system in various peripheral and CNS pathologies. This thesis has explored type-1 IFN signalling using a murine TBI model. Type-1 IFN signalling has been ablated using an IFNAR1 receptor knockout mouse, as well as a neutralising monoclonal antibody targeted to IFNAR1. Abrogating the type-1 IFN response after TBI elicited neuro-protection, improved behavioural outcome and diminished the secretion of pro-inflammatory cytokines. The activation status of microglia and macrophages was also studied using markers for M1 (neurotoxic) and M2 (neuro-protective) cells. Interestingly, ablation of the type-1 IFN response resulted in a predominant M2 response. The M1/M2 markers reflected changes in the whole brain environment, an environment comprised of a heterogeneous population of both resident and infiltrating cells. This finding of a changed neuro-inflammatory environment suggested that type-1 IFNs were potentially binding to and signalling through central and peripheral cells. To investigate the source of type-1 IFN signalling after injury, bone marrow chimeric mice were generated, with IFNAR1 deleted in either hematopoietic cells or in the brain. Using the chimeras, we determined that type-1 IFN signalling in peripheral cells was critical in driving neuro-inflammatory events and potentiating tissue damage after TBI. The findings from this thesis build on our understanding of neuro-inflammatory events in TBI. Furthermore, this thesis has identified a novel therapeutic target in the treatment of TBI, and provides a foundation for implementing further studies that investigate the intricacies of anti-IFNAR1 therapy following brain injuries

Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes

BACKGROUND:Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.FINDINGS:Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes.CONCLUSIONS:This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes

BACKGROUND:Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.FINDINGS:Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes.CONCLUSIONS:This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]