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Animal Models
Hartmut Wekerle, MD,” Kimikazu Kojima, MD, Joseli Lannes-Vieira, PhD, Hans Lassmann, MD,T
and Christopher Linington, PhD
Different models of experimental autoimmune encephalomyelitis(EAE) have been successfully applied to investigate
and manifold aspects of the autoimmune pathogenesis of multiple sclerosis. Studies using myelin-specific T-cell lines
that transfer EAE to naive recipient animals established that only activated lymphocytes are able to cross the endothelid blood-brain barrier and cause autoimmune disease within the local parenchyma. All encephalitogenic T cells are
CD4+ Thl-type lymphocytes that recognize autoantigenic peptides in the context of MHC class I1 molecules. In the
case of myelin basic protein (MBP) specific EAE in the Lewis rat, the T-cell response is directed against one strongly
dominant peptide epitope. The encephalitogenic T cells preferentially use one particular set of T-cell receptor genes.
Although MBP is a strong encephalitogen in many species, a number of other brain protein are now known to induce
EAE. These include mainly myelin components (PLP, MAG, and MOG), but also, the astroglial Sloop protein.
EncephalitogenicT cells produce only inflammatory changes in the central nervous system, without extensive primary
demyelination. Destruction of myelin and oligodendrocytes in these models requires additional effector mechanisms
such as auto-antibodies binding to myelin surface antigens such as the myelin-oligodendrocyte glycoprotein.
Wekerle H, Kojima K, Lannes-Vieira J, Lassmann H, Linington C.
Animal models. Ann Neurol 1994;36:S47-S53
Ten years ago a symposium was held in Seattle that
addressed the question, “How good a model of MS is
EAE today?” [l]. Despite the intervening decade the
research community remains divided over this question. To the present day there are “believers,” who are
convinced that experimental allergic encephalomyelitis
(EAE) provides an excellent animal model of multiple
sclerosis (MS); and at the same time there are the
“skeptics,” who point out that profound differences exist between the clinical course and pathology of these
cwo diseases.
Beyond any doubt, MS remains a extremely complex disease of unknown etiology for which there is no
spontaneous animal equivalent representing all aspects
of pathogenesis. Thus, perhaps the question should be
modified to ask, “Which EAE model can be used to
investigate which aspect of MS!”
Studies of EAE have led to the concept that pathogenesis of MS involves dysregulation of myelin-specific
autoimmune T lymphocytes [27. The ultimate expression of this as yet hypothetical autoimmune response
is the MS lesion, which reflects three distinct but interrelated aspects inflammation, demyelination, and eventually, gllal scar formation. These pathological changes
can be mimicked in the appropriate EAE models.
Thus, autoimmune-mediated central nervous system
(CNS) inflammation can be studied in acute mouse and
rat models of EAE induced by either active immunization with myelin basic protein (MBP), or the adoptive
transfer of MBP-specific T-cell lines or clones 131. In
contrast, chronic relapsing models of EAE in susceptible strains of mice and guinea pig have proved useful
to establish models for primary autoimmune demyelination and glial scar formation, but possibly also for the
immunoregulatory events that lead to encephalitic relapses 141. Induction of relapses in autoimmune CNS
disease has been furthermore achieved in cyclosporine
release variants of actively induced EAE [ S , 67, in
transgenic mice carrying MBP-specific T-cell receptor
genes in their germ line 17’1.
The key to understanding the pathogenesis of MS,
and hopefully to designing new specific therapies, is to
better understand the basic immunoregulatory mechanisms that are involved in maintenance and loss of tolerance to myelin antigens. This concerns especially the
potential function of regulatory cell circuits that are
required to maintain immunological self-tolerance.The
presence of regulatory T cells has been indicated initially by studies involving T-cell line vaccination 18lo], CD8 T-cell depletion [ll], and finally, genetically
engineered CD8 knock-out mice 1121.
It is undisputed that studies using the mouse have
certain advantages, such as the availability of many congeneic strains, mutants, and an increasing variety of
From ‘Abteilung Neuroimmunologie, Max-Planck-Institute, Martinsried-Munchen, Germany;and ?Institute for Brain Research, Austrim Academy of Sciences, Vienna, Austria.
Address correspondence to Dr Wekerle, Max-Planck-Institut fiir
Psychiacrie, D-82 152 Martinsried-Munchen, Germany.
Copyright 0 1994 by the American Neurological Association a 7
useful transgenic a n d s and biological reagents. Yet,
we have concentrated on analyzing the immunopathogenesis of EAE in the Lewis rat. EAE in this species
has the great advantage that this rat strain is hlghly susceptible to both actively induced and passively transferred EAE; its histopathological changes and functional
deficits are predictable and clearly definable. Although
Lewis EAE does not show primary demyelination, it can
be combined with demyelinating antibodies to produce
demyelinating lesions strikingly resembling the MS
plaque [131. It thus appears that EAE in the Lewis rat is
an optimal model for the early, inflammatory phase of
the generation of the MS lesion [141.
Myelin Basic Protein-specific T
Cell-mediated EAE in the Lewis Rat
Acute EAE can be induced in the Lewis rat by either
active immunization with purified myelin autoantigens
in Freund's complete adjuvant, or by the adoptive
transfer of MBP-specific T cells. In both cases the disease is characterized by an ascending paralytic disease,
which first affects the tail and hind limbs and subsequently forelimbs and brain. Histologically, clinical disease is associated with perivascular and parenchymal
inflammation, but demyelination is minimal. Clearly
the etiology of these models of EAE is far removed
from that of MS; in particular, induction of the encephalitogenic T-cell response requires the use of a potent
immune adjuvant. However, the histopathology of
MBP-mediated EAE in the rat closely resembles many
of the inflammatoryaspects of the MS lesion and it was
this model that led to the demonstration that EAE is
mediated by an autoaggressive, myelin-specific T-cell
response [41.
The examination of MBP-specific T-lymphocyte
lines isolated in many laboratories has identified a nunber of obligatory properties the T-cell lines must express to be encephalitogenic in vivo. Without exception all encephalitogenic MBP-specific T-cell lines
express the CD4+CD8-, T-cell receptor (TCR) - ctp
membrane phenotype and their response to MBP is
class I1 major histocompatibility locus (MHC) restricted. The T-cell lines must also express the appropriate cell adhesion molecules and enzymes to permit
their migration across the blood-brain barrier. It is
interesting that all those encephalitogenic T-cell lines
that have been analyzed express and secrete
interferon-y, tumor necrosis factor (TNF-a), and interleukin-2 (IL-2), but not IL4 [15, 161, indicating that
they may be members of the T h l subpopulation of
CD4+ T cells that was first described in the mouse
[17]. Remarkably, despite their CD4' phenotype, all
encephalitogenic MBP-spec& T cells are cytotoxic
and will lyse syngeneic astrocytes, or other antigenpresenting cells, in vitro in an antigendependent manner 1181.
s48 Annals of Neurology Supplement
T-cell Receptor Vp8.2 Gene Usage Is an
Intrinsic Property of the Lewis Rat T-cell
Response to MBP
The most striking characteristic, however, of the encephalitogenic T-cell response in the Lewis rat, and
also the PWJ mouse, is the immunodominance of single MBP epitopes that induce the encephalitogenic
T cell response. Moreover, this is associated with a
highly preferential usage of particular Vp TCR genes
Several groups reported almost simultaneously that
almost all encephalitogenic MBP-specific T-cell lines
derived from the Lewis rat 120, 211 and PL/J mouse
[22, 231 use Vp8.2 TCR genes in preference to other
Vp elements. This observation led to the construction
of new therapeutic strategies based on the specific neutralization or ablation of T cells expressing Vp8.2
TCRs [24-261. This strategy worked extremely well
in the two animal models and raised hopes that this
form of immunotherapy could be adapted to treat MS.
Although more recent studies have confirmed that
both MBP epitope and TCR Vp usage are relatively
restricted in the Lewis rat and PWJ mouse, this restriction is not absolute. Sampling the MBP-specific T-cell
repertoire at different time points indicates that the
T-cell response to MBP evolves to recognize additional
MBP epitopes [27-291 and use additional TCR Vp
elements during the course of EAE [30, 311, particularly as the animals enter recovery. It is interesting that
a broad repertoire of Vp usage, rather than the preferential usage of Vp8.2, is seen in T-cell lines derived
from Lewis rats immunized with minor, encephalitogenic determinants of MBP 132, 331.
It seems now that the Lewis rat and PLIJ mouse
seem to be special cases, as in other strains, such as
the SJUJ mouse, the T-cell response to MBP uses a
considerably broader repertoire of Vp elements [34,
351. The same is also true for the human MBP-specific
T-cell response, which, whether the donor has MS or
is healthy, is directed against multiple MBP epitopes
and uses a wide variety of TCR variable genes C36-381.
These observations indicate that in most patients immunotherapies for MS based on either the elirmnation
of particular TCR Vp families, or the T-cell response
to defined MBP epitopes, will probably be unsuccessful. However, it is interesting that there does appear
to be a limited restriction of T-cell receptor variable
gene usage in some MS brain samples. At present,
however, it is not possible to determine whether the
T cells using these elements were specific for MBP,
some other autoantigen, or even an infectious agent
Although it is unknown whether the restriction of
the primary MBP-specific T-cell response in the Lewis
rat is a rare exception, or is of real importance with
respect to anti-myelin autoimmune response, it is of
Volume 36, 1994
interest to determine what is responsible for this dominance. It is perhaps a trivial consequence of immunization protocol used that preferentially selects for the
immunodominant determinant MBP6,,
and responsive T cells using Vp8.2 TCR genes. Alternatively, it
may be a characteristic of the ~ N aMBP-specific
Tcell repertoire generated by positive selection within
the thymus.
We have approached this question directly by using
a primary limiting dilution technique 1401 to isolate
MBP-specific T-cell clones directly from the thymus of
naive Lewis rats, which had never been immunized
before with MBP. Using this primary limiting dilution
technique to clone naive thymus-derived T cells, a
panel of “naive” MBP-specific T-cell clones was isolated and analyzed. It is surprising that the examination
of the T-cell receptor usage by these T cell lines revealed that more than 93% of the naive MBP-specific
T-cell lines also use Vp8.2. A more detailed comparison of the complementary determining V D J sequences
obtained from these T-cell lines revealed the presence
of motives that are also regularly used by MBP-specific
T-cell clones derived from MBP-primed Lewis rats.
The preferential usage of the TCR Vp8.2 gene by
MBP-specific T cells thus seems to be an intrinsic property of the T-cell repertoire of the Lewis rat rather
than an epiphenomenon related to the immunization
protocol. The physiological/genetic basis of this
skewed response is still under investigation but involves an antigendependent interaction between the
differentiating T-cell and the thymic microenvironment. Obviously this observation has consequences for
understanding individual immune reactivity against
myelin proteins.
Self-Tolerance and Autoimmune Encephalitis:
MBP Is Not the Only Culprit!
For many years it was generally believed that MBP was
the one and only encephalitogenic autoantigen involved in the pathogenesis of EAE. Although it was
somewhat reluctantly accepted in the late 1970s that
purified myelin proteolipid protein (PLP) could also
induce EAE 1411, MBP remained at the center of interest with respect to the immunopathogenesis of EAE,
and by extrapolation MS. It was generally just not considered that other components of the brain may be
able to elicit an autoimmune-mediated inflammatory
disease of the CNS.
What then were the particular molecular characteristics of MBP that made it such a potent encephalitogen?
A few years ago it appeared that the basic criteria could
be summarized as follows: (1) An encephalitogenic
protein must be able to elicit a very strong T-cell response. ( 2 ) The encephalitogenic protein must be expressed in the CNS in a proper cellular and molecular
context to promote T-cell activation. ( 3 ) The encephalitogenic T-cell response must be cytotoxic 1427.
These are, obviously, minimal criteria, and a large
number of CNS components other than MBP should
fulfill them. Indeed, in the last few years evidence has
accumulated suggesting that contrary to our original
beliefs, MBP is by no means the only encephalitogen
in the CNS. It is now completely accepted that other
myelin proteins may be of similar encephahtogenic potential to MBP. This is definitely true for PLP and it
has more recently been demonstrated that there are
encephalitogenic T-cell responses to the myelin oligodendrocyte glycoprotein (MOG) 1431. In a similar
manner in the peripheral nervous system (PNS),
T cells responding to both the P2 [44] and PO myelin
proteins 1451 transfer experimental autoimmune neuritis. It is interesting that these myelin autoantigens all
exhibit very different physicochemical properties and
are members of different gene families, indicating that
myelin proteins of completely different molecular
characteristics can be encephalitogenic. More recently,
we extended this concept to include nonmyelin proteins that are major components of the CNS and once
again have molecular properties strikingly different
from MBP, PLP, or MOG. The two proteins studied
were the astrocyte-specific intermediate filament protein, dial fibrillary acidic protein (GFAP), and S l o o p ,
an astrocyte-derived calcium-binding protein 1461. In
both cases we found that T lymphocytes specific for
either of these astrocyte components efficiently induce
an inflammatory response in the CNS in a manner similar to that seen following the transfer of MBP-specific
T cells.
These experiments were initiated following the demonstration that encephalitogenic, myelin-specific T cells
are a normal component of the immune repertoire of
healthy Lewis rats. This observation raised the question
of how the pathogenic potential of these cells is suppressed in vivo, as the Lewis rat never develops spontaneous EAE.
Our present understanding of immunological selftolerance has been shaped by studies using transgenic
mice that maintain that the character, concentration,
and localization of autoantigens determine the mechanism(s) responsible for the generation of self-tolerance.
Thymic expression of autoantigens is thought to result
in the clonal deletion of the complimentary selfreactive T cells 1471. In contrast, self-tolerance to autoantigens expressed exclusively outside the thymus is
maintained predominantly by mechanisms resulting in
the functional paralysis of self-reactive T cells’ (anergy)
148). However, a thud category of autoantigens is out
of reach of the circulating immune system, sequestered
in immunoprivileged tissues such as the eye, testis, and
nervous system. It has been firmly believed that selftolerance to such tissue-specific autoantigens is mainWekerle
et al:
Animal Models S49
tained by the principle of “immune ignorance.” In
other words, self-antigens that the immune system cannot “see,” cannot promote an immune response and
can therefore be safely ignored and nor be removed
from the normal healthy immune repertoire.
It was generally accepted that this was the case for
myelin autoantigens, they are sequestered behind the
blood-brain barrier and self-tolerance to myelin was
obviously maintained by immune ignorance. However,
we have now been able to demonstrate that this concept is definitely not applicable to all CNS autoantigens. Moreover, our most recent data suggest that the
importance of immune ignorance as a dominant mechanism in the maintenance of self-tolerance to CNS
autoantigens must be reviewed. This conceptual revision resulted from the new model of autoimmune
encephalomyelitis induced by the adoptive transfer of
S100P-specific T cells.
As stated before, we selected Sloop as a control
nonmyelin CNS autoantigen to investigate whether
brain proteins radically different from MBP could also
elicit an encephalitogenic autoimmune response. The
chances that this protein would prove to be encephalitogenic were not very high, as earlier studies had
shown that the encephalitogenic activity of CNS homogenates was localized in the myelin membrane,
Moreover, in striking contrast to MBP, PLP, or MOG,
Sloop is also expressed outside of the nervous system
in adipocytes, Miiller cells in the retina, and, most important, also in the thymus and peripheral immune organs. This tissue distribution led us to believe that tolerance to Sloop would be very tlghtly controlled. The
thymic expression of the protein should result in the
deletion of S 100P-reactive T cells, while expression of
Sloop in the periphery should anergize those Sloopspecific T cells that may avoid thymic deletion.
However, after immunization of Lewis rats with
Sloop, we were able to isolate a total of around 50
different S100P-specific T-cell lines, all of which were
CD4+ and MHC class I1 restricted. The adoptive
transfer of these S 1006-specific T-cell lines induced
definite CNS disease in naive syngeneic recipients, extensive parenchymal and perivascular infiltrates of inflammatory cells being observed throughout the CNS,
as well as to a lesser extent in the PNS. These observations demonstrate that autoaggressive S 1006-specific
T-cell clones can be primed and expanded in vivo following immunization with the purified antigen indicating that tolerance to Sloop is at best leaky.
As a step toward understanding this phenomenon it
was necessary to determine whether the naive thymus
contains the clonal T-cell precursors required to establish this pathogenic T-cell response. Using the previously described limiting-dilution technique it was possible to isolate S100P-specific T cells from naive Lewis
rat thymus. Much to our surprise we found that such
clones are indeed a normal component of the naive
thymic T-cell repertoire. Adoptive transfer of such naive CD4+ CD8- S100P-specific T-cell lines initiated
an inflammatory response in the CNS of naive recipients demonstrating their pathogenic potential.
These results, which were highly unexpected, clearly
demonstrated that potentially pathogenic T-cell clones
specific for an autoantigen present in the thymus, periphery, and CNS are present in the normal immune
repertoire. The importance of these observations is
that they demonstrate immune ignorance is unlikely to
be the mechanism responsible for silencing myelinspecific T cells present in the immune repertoire. The
presence of other counter-regulatory or regulatory
mechanisms must be postulated to prevent such cells
mounting a spontaneous immune response directed
against the CNS.
Generation of the Inflammatory Lesion in EAE
The evolution of the inflammatory lesion in EAE involves several distinct steps. Activated T cells first cross
the blood-brain barrier irrespective of their antigen
specificity. This is followed by the antigen-specific interaction of the invading CD4+ T cell with an MHC
class 11-positive antigen-presenting cell within the
CNS, perivascular ED2+ cells, microgha, and possibly
astrocytes. This local antigen-specific interaction
primes the immedate microenvironment for the subsequent induction of a full-blown inflammatory response [497. The expression of cell adhesion molecules
on the vascular endothelium is up-regulated, and chemotactic and proinflammatory cytokines are released,
the ultimate consequence of these changes being the
antigen-independent recruitment of mononuclear cells
into the CNS, including CD4+ T cells of all specificities and monocytes, and an increased permeability of
the blood-brain barrier to serum proteins. This inflammatory pathology is associated with a severe neurological dysfunction, characterized by an ascending
Typically, EAE in the Lewis rat is an acute disease
and both the clinical signs of disease and the associated
histopathological abnormalities resolve after a predictable period. We do not fully understand the mechanisms that limit the course of EAE, or know what happens to the effector T-cell population. However,
thanks to the work of Hans Lassmann and Michael
Pender, apoptosis has been identified as an important
mechanism responsible for the elimination of infiltrating T cells in the CNS [50, Sl}.
This scenario is, however, derived from studies of
MBP-mediated EAE and it was assumed that regardless
of the identity of the target encephalitogen, the adoptive transfer of autoreactive T cells would trigger the
same sequence of events. Analysis of S100P-mediated
Annals of Neurology Supplement to Volume 36, 1994
EAE has revealed that this is not necessarily the case;
the identity of the target autoantigen has a profound
influence on the clinical course and histopathology of
Comparison of the MBP- and S100P-mediated models of EAE revealed that they differ radically with respect to the severity of disease and the composition
and tissue distribution of the inflammatory infiltrates.
In the SlOOP model, large inflammatory lesions are
observed throughout the CNS; lesions of this size and
density are rare in MBP-mediated EAE.However, despite this intense inflammatory response in the CNS,
the animals do not develop severe clinical disease. This
is in striking contrast to MBP-mediated EAE, in which
a correspondingly severe inflammatory response would
result in paralysis or death.
We were intrigued by this curious discrepancy between clinical and histopathological disease severity
and have investigated two potential causes. In MBPmediated EAE the clinical deficit is mediated by activated macrophages invading the CNS. It is intriguing
that quantitative morphological studies revealed that
macrophages are underrepresented in the inflammatory infiltrates induced in the CNS by the adoptive
transfer of S100P-specific T cells. In contrast to MBPmediated EAE in which macrophages are the predominant component of the inflammatory infiltrates, in the
new SlOOP model of EAE, T cells predominate. The
physiological basis for this observation is unclear but
may reflect a deficit in chemokine production within
the lesions. However, the encephalitogenic potential of
MBP-specific T-cell lines is also associated with CD4
T cell-mediated cytotoxicity. It is surprising that none
of the encephalitogenic S100P-specific T-cell lines examined were found to be cytotoxic in vitro, although
both Sloop- and MBP-specific T-cell lines are of the
T h l subtype. Whether these two observations are related is at present under investigation.
The tissue distribution of the inflammatory infiltrates
in SlOOP EAE also differs drastically from that seen in
MBP-induced EAE. In the latter, lesions are first seen,
and are most severe in the caudal spinal cord 141. In
contrast, in S100P-induced EAE,lesions occur simultaneously throughout the spinal cord, as well as in the
brain and optic nerve and to a lesser extent the PNS.
Indeed many brain regions (medulla, telencephalon,
and cerebellum) are involved that are generally spared
in the MBP model. Perhaps even more exciting for
the MS researcher, a profound involvement of the eye
is also seen in Sloop-mediated EAE,with virtually all
animals developing uveitis and more rarely retinitis.
This pathology reflects the expression of Sloop in both
the uvea and retina, tissues that are not myelinated
and are therefore not inflamed in animals injected with
MBP-specific T-cell lines. It is interesting that inflammatory changes in the retina and uvea are also rela+
tively common in MS, although as in the rat these
tissues are not myelinated in humans 1521. Our observations in the S 100P-mediated EAE raise the possibility that retinal abnormalities of these MS patients may
indeed represent an antigen-specific, myelin-independent event.
The major lesson from these studies is that a large
number of brain proteins may qualify as potential encephalitogens, even if they are also expressed outside
of the nervous system. The histopathology and clinical
course of the encephalitis triggered by such diverse
autoantigens, however, may be very different. It is now
crucial to establish the molecular basis for these differences if we are to understand their involvement in human disease. With respect to EAE induced by the
adoptive transfer of S100P-specific T cells, it appears
this may be a better model of the initial inflammatory
events that occur in MS, rather than the MBPmediated model. In particular, the lesion distribution
and the minimal neurological deficit seen in the Sloop
model are very similar to that seen in the human disease. This would be compatible with the possibility that
the initiating event in MS may be not be directed
against a myelin autoantigen, but rather an astrocyteor endothelialderived component. We predict that this
may also be the case in other, so far ill-characterized,
human inflammatory CNS diseases, such as the paraneoplastic syndromes.
Demyelination in Inflammatory Autoimmune
Central Nervous System Disease
The major feature in which T cell-mediated models
of EAE in the Lewis rat differ from MS is the virtual
absence of demyelination. At least the following four
autoimmune mechanisms have been discussed as accounting for the extensive loss of myelin that is characteristic of MS: (1) myelin destruction mediated by cytokines released at the site of CNS inflammation 1531,
(2) demyelination mediated by the nonspecific action
of plasma proteins (proteolytic enzymes, complement,
etc) that can enter the CNS in MS as a consequence
of blood-brain barrier damage 1541, (3) CD8'
T cell-mediated killing of oligodendrocytes 1121, and
(4) autoantibody-mediated demyelination I131.
The observation that demyelination is not associated
with autoimmune-mediated inflammation in the rat
tends to undermine the first two of these hypotheses.
In both MBP and Sloop variants of adoptively transferred EAE,extensive inflammation of the CNS is associated with minimal demyelination, despite the local
production of potentially myelinotoxic cytokines and
disruption of the blood-brain barrier. As for third possibility, there is as yet no direct evidence for the
involvement of CD8+ T cells in immune-mediated
demyelination. Only in the case of autoantibodyWekerle et al: Animal Models
mediated demyelination is there formal proof that this
may lead to the formation of large confluent demyelinated lesions similar to those seen in MS.
Although the immunopathogenesis of demyelination in MS is obscure, even less is known about the
mechanisms responsible for the induction of relapses
in EAE and multiple sclerosis. As stated earlier, there
are CREAE models based on genetically susceptible
strains, such as SJL. mice that can spontaneously relapse, as well as PUJ CD8 knock-out mouse mutants
that also show propensity to develop spontaneous relapses after a priming with MBP in adjuvant [12).
These models together with pharmacological models
of CREAE are at present the only tools available for
studying the mechanisms involved in relapse induction.
We anticipate, although it is not proven, that dysregulation of a subset of regulatory T lymphocytes, which
could perhaps be termed suppressor T cells, is involved
in the generation of relapses in these models.
In summary, it can be stated we have learned many
lessons from studies on the classical model of MBPmediated EAE. These include the revision of the concept of CNS immunological privilege to include T-cell
traffic through the blood-brain barrier and antigen
presentation by glia cells, the realization that autoaggressive T cells exist in the normal immune repertoire,
and the development of potential immune therapies
based on T-cell receptor gene usage, epitope specificity, and T-cell vaccination. It is now apparent, however,
that MBP is not the only encephalitogen present in the
CNS. A large variety of other CNS autoantigens can
also induce T cell-mediated autoimmune responses in
the CNS. The past concentration of interest on MBP
as the key encephalitogen must now be qualified.
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