Book of abstracts - British Neuroscience Association

10.10
Immuno-regulatory T cell function in patients with multiple
sclerosis undergoing autologous hematopoietic stem cell
transplantation
Abrahamsson S, Packer A, Oh U, Burt R K, Muraro P A
Department of Cellular and Molecular Neuroscience, , Division of
Neuroscience and Mental Health, , Imperial College Faculty of
Medicine, , Charing Cross Hospital, , St. Dunstan`s Road,, London W6
8RP, UK, and , , Neuroimmunology Branch, NINDS, National Institutes
of Health, Bethesda, MD 20892 USA
Autologous hematopoietic stem cell transplantation (HSCT) is a novel
experimental approach to treat multiple sclerosis (MS). Clinical trials
have shown promising results, with prolonged suppression of brain
inflammation. The positive clinical outcome of HSCT is likely to be due
to the reprogramming of the immune system and its substitution with a
new repertoire of cells, originated from precursors that repopulate the
bone marrow. However, since autoreactive cells may also be
regenerated in susceptible individuals, we hypothesize that
reconstitution of immune regulatory circuits could be an important
contributing factor to the positive clinical outcome of HSCT. Regulatory
cells that keep self-reactive cells under control to prevent autoimmune
reactions include a T cell subset identified by a CD4+CD25+
phenotype and intracellular expression of FoxP3. Regulatory
properties have also been suggested for CD8+ T cell subpopulations.
We assessed numerical recovery of immune cells in the peripheral
blood of patients with severe MS who underwent HSCT and observed
significant increases in the frequency of CD4+FoxP3+ and of
CD8+CD28-CD57+ cells, with demonstrated or suggested regulatory
properties. FoxP3-expressing CD4+ T cells were transiently upregulated
in patients at 6 months post-transplant. CD28-CD57+ T cells
were massively increased, constituting up to >80% of the CD8+ T cell
repertoire and persisting at high frequency for the entire duration of a
2-year follow-up post-transplantation. This suggests that these cells
may have a role in determining the positive clinical outcome of HSCT
therapy. We are examining the suppressive functions of CD8+CD28-
CD57+ T cells by in vitro co-culture and cytotoxicity assays.
10.11
Small molecule VLA-4 antagonist suppresses MOG-EAE in the DA rat
Papadopoulos D, Rundle J L, Patel R, Gonzalez I M, Reynolds R
Cellular & Molecular Neuroscience, Imperial College London, Charing
Cross Hospital, W6 8RF
Interaction of VLA-4 (α4β1 integrin) with its ligand vascular cell adhesion
molecule-1 (VCAM-1) is required for CNS migration of encephalitogenic T-
cells in EAE. Blockade of VLA-4 has been shown to be a beneficial target
for therapeutic intervention in Multiple Sclerosis (MS) both in preclinical
trials in EAE and in clinical trials in MS. This study sought to investigate the
efficacy of a small molecule VLA-4 antagonist (BIO5192) in a relapsingremitting
model of antibody-mediated inflammatory demyelination.
Chronic-relapsing EAE was induced in female DA rats by immunization with
recombinant mouse MOG. A group of 25 rats was treated from day 7 postimmunization
with BIO5192 and a control group of equal size was treated
with vehicle. Demyelination was assessed with LFB staining and
inflammatory activity, neuronal and axonal loss were assessed with CD45,
OX-42, NeuN and neurofilament immunostaining respectively.
BIO5192 ameliorated EAE reducing disease severity, relapse rate and
cumulative disease index. Pathological examination revealed that BIO5192
treatment prevented demyelination and CD45+ and OX-42+
immunoreactivity was reduced by 81% and 58% respectively in BIO5192-
treated rats. In addition, BIO5192 treatment decreased the extent of axonal
loss in the medial dorsal funiculus by 35% and neuronal loss in the upper
lumbar cord by 16.8%. No post-treatment exacerbation was observed
following BIO5192 withdrawal.
Our data suggests that WBC trafficking in MOG-EAE in the DA rat is VLA-4
dependent. Along with all other similarities with MS in pathology, this
common immunopathogenetic mechanism renders MOG-EAE in the DA rat
a valid and useful model for testing potential MS therapies.
10.12
TNF-alpha blockade by etanercept reduces neutrophil
recruitment into the injured brain through attenuation of the
acute phase response
Jiang Y, Campbell S J, Farrands R, Anthony D C
Experimental Neuropathology, Department of Pharmacology,
University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK
The release of inflammatory mediators by recruited leukocytes after
head injury is a significant cause of secondary damage to neurons.
An important local mediator of the host response to injury is the
cytokine TNF-alpha, which has proven to be a good target for
treatment of peripheral inflammatory disease. However, the blood
brain barrier restricts the access of high molecular weight TNF-alpha
inhibitors and limits their use for CNS pathologies. Our recent data has
shown that the liver produces TNF-alpha as part of the acute phase
response to CNS injury, and it may overcome the need for inhibitors to
cross the blood brain barrier. Here we show that microinjection of IL-
1beta into the brain results in the acute upregulation of TNF-alpha in
the liver, but not in the brain. The subcutaneous administration of
etanercept, a TNF-alpha antagonist, inhibited the production of hepatic
TNF-alpha and of TNF-alpha- induced genes, including chemokines
CCL-2, CXCL-5 and CXCL-10. There was also a significant reduction
in the number of neutrophils in the liver and in the circulation. As a
consequence, the number of neutrophils recruited to the liver, and
more importantly to the IL-1beta- challenged brain were markedly
reduced in our brain injury model. In summary, our findings suggest
that therapeutics which target hepatic TNF-alpha have a potential to
inhibit CNS inflammation without the necessity to cross the blood brain
barrier.
10.13
Inflammatory stimuli exert a more profound effect in tissue prepared
from IL-4 knockout mice
Mc Quillan K, Lyons A, O`Connell F, Lynch M A
Trinity College Institute of Neuroscience, Department of Physiology, Trinity
College Dublin, Dublin 2, Ireland
Among the changes that occur in the brain in response to stressors is an
increase in microglial activation, resulting in the release of proinflammatory
cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor α
(TNFα). IL-1β is the most studied cytokine in the brain and its actions are
known to be mediated through the signaling receptor IL-1R1. Recent
investigations have indicated that IL-4 down-regulates microglial activation
and therefore decreases release of proinflammatory cytokines. Previous
data from this laboratory have indicated that IL-4 acts as a negative
regulator of IL-1 and lipopolysaccharide (LPS) signaling. In this study, we
prepared mixed glial cultures from wild-type IL-4-/- mice to establish
whether the absence of IL-4 resulted in a more pronounced inflammatory
response to lipopolysaccharide (LPS). We report that LPS increased
expression of several markers of microglial activation including TNF-α and
CD86 and that this activation was more pronounced in mixed glia prepared
from IL-4-/- compared with wild-type mice. The evidence suggests that a
similar inflammatory phenotype exists in vivo. Data will be presented which
indicates that, at least in the case of some measures, amyloid β also
induces a more profound response in tissue prepared from IL-4 knockout
animals.
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