Multiple
sclerosis
(MS)
affects
around
2.5
million
people
worldwide,
making
it
one
of
the
most
common
neurological
conditions
in
young
adults.
Experimental
autoimmune
encephalomyelitis
(EAE)
has
been
the
standard
animal
model
for
MS
where
antigens
are
introduced
alongside
powerful
T
cell
polarising
adjuvants
to
induce
disease.
This
general
protocol
has
been
both
helpful
and
sometimes
limiting
in
modelling
T
cell
events
as
the
immune
adjuvants
make
interpretation
of
mechanism
more
difficult.
There
is
a
need
for
more
relevant
mouse
models
lacking
the
inherent
biases
of
immune
adjuvants
and
providing
a
human
context
for
disease
initiation
and
progression.
For
this
thesis,
I
have
characterized
the
disease
and
cellular
dynamics
in
a
humanized,
T
cell
receptor
(TCR)
transgenic
mouse
model,
termed
Line7.
The
mice
develop
spontaneous,
ascending
paralysis.
T
cell
responses
defined
in
these
transgenics
have
direct
relevance
to
the
human
setting
since
they
are
by
definition
HLA-­‐DR15
restricted
and
are
allowed
to
progress
without
interference
from
modifying
adjuvants.
I
have
focused
on
the
dynamics
of
Th1
and
Th17
cells
in
both
the
initiation
and
progressive
phase
of
disease
and
the
role
that
regulatory
T
cells
play
in
affecting
this
balance.
Initial
observation
of
naturally
progressing
disease
showed
that
in
this
model
IFNγ+
cells
dominate
through
disease
initiation
and
IL-­‐17+
cells
are
only
observed
in
the
affected
tissue
once
disease
is
established.
The
cytokine
milieu
favours
Treg
differentiation
over
Th17
cells
and
regulatory
T
cells
accumulate
in
the
central
nervous
system
(CNS)
but
are
ineffective
at
halting
progression
or
initiating
recovery.
Through
removal
of
the
Tregs,
severe
acceleration
of
symptoms
developed
with
uncontrolled
infiltration
of
lymphocytes
into
the
CNS.
IFNγ
production
by
CD4
and
CD8
cells
is
upregulated
at
the
expense
of
IL-­‐17
but
reconstitution
of
the
Treg
population
halts
disease
progression,
illustrating
the
roles
of
Tregs
in
regulating
autoreactive
T
cell
activity
and
controlling
cellular
infiltration
across
immunological
barriers.
Therefore
the
use
of
this
model,
without
the
introduced
biases
of
immune
adjuvants,
has
highlighted
the
importance
of
the
Th1/Treg
balance
in
disease
initiation
over
Th17
cells
whilst
underlining
the
critical
role
for
Tregs
in
preventing
autoimmune
conditions
or
halting
ongoing
disease
even
in
highly
susceptible
individuals.