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responses, as well as inflammation-induced changes in tryptophan-ky-
nurenine pathway in a rabbit pediatric TBI model. On postnatal day
5–7 (P5-7), New Zealand white rabbits from the same litter were
randomized into three groups, naı¨ve (no injury), sham (craniotomy
alone) and TBI (controlled cortical impact [CCI]: 6 mm impactor tip;
5.5 m/s, 2 mm depth, 50 msec duration). Animals were sacrificed
at 6h, 1, 3, 7 and 21 days post-injury for evaluating mRNA and
protein expressions of pro- and anti-inflammatory cytokines, as well
as the major components in the tryptophan-kynurenine and gluta-
mate pathways. Myelination was evaluated by myelin basic protein
(MBP) staining. We found that the pro- and anti-inflammatory cy-
tokines levels were differentially regulated in a time-dependent
manner post-injury. Peak expression of TNF-
a
and IL-10 occurred 3
days after injury. However, IL1-
b
expression was upregulated
throughout the evaluation period. This was associated with increased
expression of Indoleamine 2,3 dioxygeenase (IDO) the rate limiting
enzyme in the tryptophan-kynurenine pathway, that is up-regulated
by pro-inflammatory cytokines, suggesting the shift of tryptophan
metabolism away from serotonin towards the kynurenine pathway. A
decrease in myelination in both ipsilateral and contralateral hemi-
spheres was noted 21 days after TBI and may be related to the
ongoing pro-inflammatory microglial presence in the white matter
tracts in the developing brain leading to secondary axonal or oli-
godendrocyte injury. A better understanding of the timing of the
inflammatory response and its role in injury and repair following
TBI is crucial for appropriately designing and evaluating neuro-
protective therapies in pediatric TBI.
Keywords: traumatic brain injury, Neuroinflammation, rabbit, cy-
tokines
C7-08
ACCUMULATING BETA-AMYLOID ALTERS THE POST-
INJURY INFLAMMATORY RESPONSE
Olga Kokiko-Cochran
1
, Lena Ransohoff
1
, Mike Veenstra
1
, Sungho
Lee
1
, Matt Sikora
1
, Ryan Teknipp
1
, Guixiang Xu
1
, Shane Bemiller
1
,
Gina Wilson
2
, Samuel Crish
2
, Kiran Bhaskar
3
, Yu-Shang Lee
1
,
Richard Ransohoff
4
, Bruce Lamb
1,5
1
Lerner Research Institute, Neurosciences, Cleveland, USA
2
Northeast Ohio Medical University, Pharmaceutical Science,
Rootstown, USA
3
University of New Mexico, Molecular Genetics, Microbiology, and
Neurology, Albuquerque, USA
4
Biogen Idec, Multiple Sclerosis & Related Disorders, Cambridge, USA
5
Case Western Reserve University, Genetics and Neurosciences,
Cleveland, USA
Traumatic brain injury (TBI) has acute and chronic sequelae, including an
increased risk for the development of Alzheimer’s disease (AD). Recent
studies have implicated beta-amyloid as a major manipulator of the in-
flammatory response. To examine neuroinflammation following TBI and
development of AD-like features, these studies examined the effects of
TBI in the presence and absence of beta-amyloid. The R1.40 mouse model
of cerebral amyloidosis was utilized. Unexpectedly, in R1.40 mice the
acute neuroinflammatory response to TBI was strikingly muted, with re-
duced numbers of CNS myeloid cells acquiring a macrophage phenotype.
However, at chronic time points, R1.40 mice exhibited enhanced brain
cavitation, relatively unchanged levels of macrophage activation with
enhanced genotype-dependent cytokine expression, and task-specific
worsening of cognitive function compared to Non-Tg mice. These find-
ings suggest that accumulating beta-amyloid in the R1.40 mouse model
leads to a reduced post-injury macrophage response, persistent neuro-
pathological deficits, and altered cognitive status. Together, these studies
emphasize the role of post-injury neuroinflammation in modulating long-
term sequelae following TBI and also support recent studies implicating
beta-amyloid as a modulator of the neuroinflammatory response.
Keywords: beta-amyloid, macrophage, Alzheimer’s disease, neu-
roinflammation
C7-09
THE ADAPTIVE IMMUNE RESPONSE IN THE BRAIN
CORRELATES WITH LONG-TERM NEUROLOGICAL DYS-
FUNCTION IN A MOUSE MODEL OF TBI
Maria Daglas
1
, Adam Galle
1
, Dominik Draxler
1
, Rachael Borg
2
,
Zeyad Nasa
3
, Amanda Au
4
, Frank Alderuccio
3
, Maithili
Sashindranath*
1
, Robert Medcalf *
1
1
Monash University, Australian Centre for Blood Diseases, Mel-
bourne, Australia
2
Monash University, Central Clinical School, Melbourne, Australia
3
Monash University, Department of Immunology, Melbourne, Aus-
tralia
4
WEHI, Cancer and Haematology, Melbourne, Australia
Traumatic brain injury (TBI) causes a cascade of neuroinflammatory
and pathophysiological events typically resulting in long-lasting phys-
ical and cognitive disabilities. The immune response has been described
as a ‘double-edged sword’ as it is important for tissue repair and pre-
vention of invading pathogens early after injury however it can be
harmful when prolonged or intensified. It is not known why an esti-
mated 60% of people with a sustained TBI experience moderate to
severe long-term disability a year later. Whether the chronic immune
response could be responsible for these long-term deficits has not been
explored in detail. Hence, we sought to determine the role of the im-
mune system following TBI using the cortical controlled impact model
in mice. Mice exhibited a progressive neurological decline over a 32
week period including slow mobility, unilateral movement, uneven gait,
tail weakness and spasms. Gait impairment was further confirmed using
the DigiGait apparatus which measures changes in motor function and
coordination. Interestingly, immunophenotyping using flow cytometry
revealed a rapid increase in inflammatory cells and CD4 T-cells within
the first week post-TBI, as expected. Remarkably, we discovered that a
chronic/adaptive immune response occurs at 8–32 weeks post-TBI. In
particular, activated effector cytotoxic CD8 T-cells and activated B-
cells were increased in the injured brain at this time period. Surpris-
ingly, a concomitant elevation of circulating antibodies specific to
myelin was observed in TBI mice, a typical feature of demyelinating
diseases. These results indicate that there is a significant change in
immune cell infiltration up to 32 weeks post-TBI coinciding with
neurological deterioration. This is consistent with the hypothesis that
there is a causal relationship between the cellular immune response and
late onset neurodegeneration following brain injury.
Keywords: Neuroimmunology, Neurodegeneration, Inflammation,
Traumatic Brain Injury
C7-10
INCIDENCE OF EARLY FEVER IN TBI VERSUS MAJOR
TRAUMA
Holly Hinson
1,2
, Dennis Bourdette
1
, Mary Stenzel-Poore
3
, Amber
Laurie
2
, Martin Schriber
4
1
Oregon Health & Science University, Neurology, Portland, USA
*Co-corresponding authors
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