close

Вход

Забыли?

вход по аккаунту

?

Chronic remitting-relapsing experimental allergic encephalomyelitis induced in monkeys with homologous myelin basic protein.

код для вставкиСкачать
Chronic Remitting-Relapsing
Experimental Allergic Encephalomyelitis
Induced in Monkeys with Homologous
Myelin Basic Protein
Cheng-Mei Shaw, MD, Ellsworth C. Alvord, Jr, MD, and Sarka Hruby, MS
A chronic remitting-relapsing form of experimental allergic encephalomyelitis (EAE) has been produced in monkeys
sensitized to homologous myelin basic protein in Freund’s complete adjuvants by the technique of suboptimal treatment after the onset of disease. Not only does the clinical course resemble that of human multiple sclerosis more closely
than does the clinical course of acute EAE, but so also does the histological reaction, with more-nearly pure demyelination, rather than the hyperacute hemorrhagic-necrotic lesions that occur so commonly in untreated monkeys with
ordinary acute EAE.
Shaw C-M, Alvord EC Jr, Hruby S. Chronic remitting-relapsing experimental allergic encephalomyelitis
induced in monkeys with homologous myelin basic protein. Ann Neurol 1988;24:738-748
Although examples of chronic relapsing neurological
syndromes in experimental allergic encephalomyelitis
(EAE) in monkeys have been reported {1-6], they
have generally occurred only sporadically, not under
the investigator’s experimental control, and have required sensitization to whole central nervous system
tissues. Similar syndromes have been observed in mice
17-91, guinea pigs [lo-151, rabbits {16], and rats {17191, in some models following sensitization to purified
encephalitogens, such as myelin basic protein (BP) or
proteolipid protein. In the most recent models in adult
guinea pigs {lo] and rats {20] two antigens have been
required to elicit adequate sensitization: one (BP) to
sensitize T cells, and the other (a non-BP myelin antigen) to induce B cells to make demyelinating antibodies. In immature guinea pigs {I 1-15], however,
sensitization to whole central nervous system tissue is
still necessary to induce chronic relapsing EAE.
About 20 years ago, anticipating that a similar treatment might be extended to humans with multiple
sclerosis (MS), we were asked to perform masked experiments to evaluate the claim 121) that EAE in
nonhuman primates could be treated successfully with
BP. Our analyses of this therapy showed that in addi-
tion to BP a species-specific adjunctive factor” was
necessary, namely an antibiotic in Maraca mzrlatta and a
steroid in M. fasricularis {22-2411. A serendipitous result was the production of relapsing EAE following
otherwise effective treatments that were not continued
long enough to prevent subsequent relapses. At autopsy, instead of the acute hemorrhagic-necrotic lesions typical of untreated EAE in the monkey, or the
healed lesions following successful treatment, or an
absence of lesions altogether, a variety of lesions was
seen, including severely gliotic and purely demyelinated plaques.
Since the balance between the inductive and therapeutic mechanisms {25] can now be manipulated at
will, these “treatment failures” present an experimental
model that not only resembles MS both clinically and
pathologically but also has the advantage of being induced by a purified, chemically defined antigen in a
setting of well-defined pathogenesis.
This report concerns the clinicopathological correlations derived from studies of our first 228 monkeys
that developed EAE after sensitization to monkey BP
or peptide fragments of BP. It does not include more
recent animals that were studied with (1) evoked corti-
From the Laboratory of Neuropathology, Department of Pathology,
University of Washington School of Medicine, Seattle, WA.
*Adjunct or adjunctive factor is used to connote a helpful additive
component of the treatment, not necessarlly a synergistic or multiPlicative factor, and should not be confused with dy.WUnt, as the
term is typically used in an immunological experimental context
(ex., Freund’s adjuvants).
Received Aug 6 , 1987, and in revised formJan 26 and
1, 1988,
Accepted for publication Jun 16, 1988.
Address correspondence to Dr Alvord, Laboratory of Neuropathology (RJ-O5), University of Washington School of Medicine, Sedttle,
WA 98195.
738 Copyright 0 1988 by the American Neurological Association
cal potentials to define the onset of subclinical disease
f261, o r (2) monoclonal antibodies to define changes in
lymphocyte subsets at the onset of EAE [271, o r (3)
treatments with monoclonal antibodies {28}, since
these experiments had slightly different goals that
made the clinicopathological correlations in these animals not comparable with the ones under consideration.
Methods
Each animal, both sexes of M . mulutta (75 animals) and M .
fasciculuris (15 3 animals) weighing 2.5 to 4 kg, was obtained
from the University of Washington Regional Primate Center, where the animals were also quarantined and housed.
The Center conforms to the National Institutes of Health
standards for the care and use of experimental animals.
EAE was induced in most of these animals by a single
sensitization with homologous (M. nemestrinu) BP in complete Freund’s adjuvants, as previously reported C22-24,
261. In some animals the sensitization was repeated once or
twice at intervals of 1 (14%), 3 ( l l % ) ,or 4 and 6 weeks
( 2 1%) when no sign of clinical EAE developed following the
first sensitization. No animal received more than three sensitizing injections.
Each animal was handled essentially the same way, being
observed twice daily for signs of EAE 1241. The blind experimental design permitted an unbiased determination of the
onset of EAE by a diagnostician who decided when treatment should be begun and when it should be ended as either
successful or unsuccessful, but who remained uninformed as
to just what treatments were being investigated either in the
group as a whole or in individual animals. Following successful treatments, any relapse in a particular animal was treated
in the same way with the same therapy.
Each experiment contained 8 to 12 monkeys to be treated
with particular substances randomly assigned in the order in
which the animals became sick. In general, each treatment
contained two components, BP and an adjunct, either or
both of which could be randomly substituted by physiological saline as a placebo control. The BP was monkey BP that
was dissolved in saline in Freund’s incomplete adjuvant and
injected intramuscularly daily [24], dissolved in saline and
injected subcutaneously every 2 hours 1221, or dissolved in
10% dimethylsulfoxide and released from subcutaneously
implanted osmotic minipumps 1263 designed to release for 7
days. Substitutions for BP included Cop I, a synthetic copolymer of four amino acids (alanine, glutarnic acid, lysine,
and tyrosine) with a molecular weight of 23,000 daltons [22],
and the synthetic tryptophan nonapeptide [24].The adjuncts
were procaine penicillin G (200,000 units daily IM),
cephalothin sodium (125 mg every 12 hours IM), or dexamethasone (0.7 mg every 12 hours IM or in osmotic minipumps). The use of osmotic minipumps [26} implanted subcutaneously greatly simplified the treatment schedules, since
the pumps could be removed at any time or replaced at
weekly intervals as indicated.
At varying intervals after apparent recovery the animals
were sacrificed by an overdose of pentobarbital. Some animals died of EAE or its complications or were sacrificed
when moribund following an unsuccessful treatment, but
most were sacrificed when they were free of active clinical
EAE. Perfusion through the left cardiac ventricle with 10%
buffered formalin or 2.5% glutaraldehyde in cacodylate buffer following a brief perfusion with normal saline was performed whenever possible.
A complete autopsy was performed on each animal. The
specimens of brain and spinal cord were immersed in 10%
formalin for 2 weeks or more before gross dissections were
made. Multiple transverse sections of the cerebrum were
usually made in the coronal plane, and horizontal sections of
the brainstem and cerebellum; horizontal and longitudinal
sections of the spinal cord were also made. Representative
blocks of these tissues were embedded in paraffin, sectioned,
and stained with hematoxylin-eosin and either Luxol fast
blue, periodic acid-Schiff (PAS), and hematoxylin 1271, or
gallocyanin and Darrow red [30]. On selected blocks
Holmes’ axon stain {31), Luxol fast blue and Holmes’ stain
1291, Holzer’s astroglial stain, and Gomori’s trichrome stain
were also applied to paraffin sections, and oil red 0 and
hematoxylin 132, 331 were applied to frozen sections.
Results
Clinicotherapeutic Correlations
T h e time of onset, severity of clinical signs, and duration of clinical course varied widely among these animals, but there was no correlation between these factors and the total amounts of BP and mycobacteria
used for sensitization or the number of sensitizing
challenges given, even though the incidence of EAE
varied widely depending o n the amounts of BP and
mycobacteria incorporated in the emulsion { 34}. Several different patterns of the clinical course of each
attack of EAE could be recognized in these animals:
(1)progression to death or a moribund state requiring
sacrifice, (2) fluctuation with transient partial improvement but without a definite period of remission, ( 3 )
definite improvement, or (4)recovery. Typical examples of the courses of EAE that we have observed in
untreated or treated monkeys are graphicaily displayed
in Figures 1 to 4;the first two figures show the courses
in M. mzlkztta and the next two show the courses in M .
fascicularis.
The incidence of each of the clinical patterns is
shown in Table 1, which correlates the clinical courses
of 280 attacks of EAE with the types of treatments
given these 228 monkeys. We have included in the
untreated group not only all of the monkeys who actually received n o treatments because they were the subjects of bioassays for encephalitogenic activity of BP
peptides f35}, but also all of those who received saline
placebos as part of the blind experimental design and
all of those who received what proved to be inadequate therapy (i.e., C o p I o r tryptophan nonapeptide
but no BP). Combining all of these subgroups leaves
64 attacks not treated with either BP or a speciesspecific adjunctive factor. Of these, 49 attacks (77%)
were acute, progressive, and generally fatal o r required
sacrifice of the animal in a moribund state.
Shaw et al: Remitting-Relapsing EAE 739
:
i
F i g 1 . Representatit~ecounes of aczrte experimental allergic encephalomyelitis(EAE) in 2 rhesus monkeys (Macaca mulatta:
N p 521 5 , 52 19) sensitized t o myelin basic protein peptide 4590 in complete Freund's adjuvant and given no treatments. S =
sacrifce: D = died.
s-,
$>
--T
ii
3
:
00
10
20
30
40
1
50
Doys
Fig 3. Typical courses of experimental allergic encephalomyelitis
(EAE) in 2 monkeys (Macaca fascicularis: N p j743. 5742)
sensitized to myelin basic protein in complete Freunds adjuvant
and treated with myelin basic protein and steroid srme.rsfully on
each of t w o occasions. S = .iacrzfice.
7
++1
"
I
0
I0
20
io
40
Doys
50
do
70
Fig 2. Tyfiiizl c0urse.i of experimental allergic eniephalomyelitis
(EAE) in 2 rhesus monkeys (Macaca mulatta: Np -5650. 36521
sensitized t o myelin basic protein in complete Freunds adjuvant
and treated t w o (top) or three (bottom) times wirh myelin basic
protein and penicillin. Complete recoveyfollowed each of the five
treatments, but relapses followed treatments of suboptimal duration. S = sac-rzfice.
By contrast, if BP alone was given as treatment, only
50% of the attacks were progressive, and if only an
appropriate adjunct (antibiotic in M . mulatta or steroid
in M . fascicukzris) was given, only 48 to 589; were
similarly progressive (see Table 1). If both BP and the
adjunct appropriate for each species were given, only
21% of attacks ended fatally.
Table 1 also shows the converse of these observations: Complete remissions of EAE in monkeys can
occur without therapy, but only in about 8% of the
attacks. If either BP or an adjunct was given, only a
few more (25, 31, or 32%') of attacks remitted, but
69% remitted if both BP and the adjunct were given.
(it should be noted that this last result averages the
results in both M . mulatta and M. fa..rcicularis. The
study of the former species was incomplete because
740 Annals of Neurology
Vol 24
Fig 4. Typical courses of experimental allergic encephalomyelitis
(EAE) in 3 monkeys (Macaca fascicularis: N p 57.39, 6327.
6276) sensitized to myelin basic protein in complete Fveund'J
adjuvant and treated with myelin basic protein and steroid. D
= died:S = sacrifice.
the supply of M. mdatta disappeared with our last
therapeutic experiments showing recovery in only
56% of cases 1241. The study of M. fascicularis was
more complete and showed recovery in 92%) of cases
when both BP and the adjunct were given [22 1.)
Table 2 indicates what could be expected following
treatments of different durations of the first attack of
EAE with what should have been a successful therapy
(i.e., BP and antibiotic for M. mukztta or BP and
steroid for M. fascicularis). If the attack could be re-
No 6 December 1088
Table I . Correlation of Types of Treatments w i t h Patterns of Clinical Courses of 280 A t t a c h of E A E in 228 M o n k t y
Courses Following Treatment
Progressive (%)
Treatment
Nonea
BP only
Adjunctb
Antibiotic
Steroid
BP adjunctb
Total
+
~
Fluctuating
Recovery (%I
Improvement
Total Treated
49 (77)
8 (50)
8
3
2
1
5 (8)
4 (25)
64
16
15 (58)
19 (48)
28 (21)
119 (42)
1
4
3
19
2
4
10
19
8 (31)
13 (32)
93 (69)'
123 (44)
26
40
134
280
~~~
"Saline, Cop I, or tryptophan nonapeptide but no BP or adjunct.
bAntibiotic in Macaca muhtta, steroid in Macuca fascicukaris.
'The average of recovery in 56% of cases in M . mulattu [24} and 92% of cases in M . fascicukzrzi 1221.
EAE = experimental allergic encephalomyelitis; BP
=
(myelin) basic protein.
Table 2. Results of First Treatments w i t h Myelin Basic Protein and Adjunct"
No. with Remission
Duration of
Treatment (days)
No. Treated
Partial
Complete (%)
No. with
Relapse (%)
0- 3
4-6
7-9
2 10
Total
5
19
25
20
69
0
0
1
2
3
5 (100)
19 (100)
24 (96)
18 (90)
66 (96)
4 (80)
14 (74)
12 (50)b
10 (55)b
40 (61)b
"Antibiotic in Macaca mulatta, steroid in Macuca fascicufaris
bPercentage with relapse following complete remission.
versed within 6 days, as it could be in about a third of
these cases, about 75% of the animals relapsed. If 7 or
more days of treatment were required or given, the
relapse rate dropped to about 50%.
Failares afer Adequate Therapy
Figures 5 to 7 summarize some of the clinical features
of the failures of generally adequate therapy of EAE,
that is, death during therapy or relapse following cessation of therapy, the latter being the major subject of
this report. Most of the deaths (see Fig 5A) and most
of the relapses (see Fig 5B) occurred after only 7 days
of treatment, but deaths could occur after 20 days of
treatment and relapses after 21 days of treatment. For
comparison, in a smaller number of animals Eylar 1361
and Eylar and colleagues 121, 371 observed relapses
that required a progressive lengthening of treatments
from a period of 8 to 10 days 1361, a period of 10 to 12
days (211, and eventually to a period of 16 days 1371 to
yield a completely satisfactory treatment.
As shown in Figure 6, most relapses in our monkeys
occurred within 10 days of stopping treatment, but
relapse occurred as long as 30 days after stopping treatment, and might have occurred even later if we had
allowed recovered animals to live longer before terminating the experiment (see Fig 7).
Parenthetically, following successful treatment with
monoclonal antibodies against the CD4 antigen on T
lymphocytes (281, 5 out of 6 monkeys relapsed within
3 to 27 days. Although the treatments were given for
10 days, the development of antimouse immunoglobulins after 7 days undoubtedly shortened the effective
duration of treatment. Since retreatment was also precluded by the presence of the circulating antimouse
antibodies, these animals were not included in the
present analysis.
Histopathological Correlations
Some of the various histological patterns of different
durations observed in typical monkeys whose clinical
courses were illustrated in Figures 2 and 4 are shown
in Figures 8 and 9. More chronic lesions observed in
another monkey whose clinical course is illustrated in
Figure 10 are shown in Figure 11. Although it was not
possible to correlate each anatomical lesion with a
specific clinical neurological deficit, it was possible to
correlate acute, subacute, and chronic lesions with each
of the relapses noted following several relatively short
treatments. These lesions of different durations were
also visible in frozen sections stained with oil red 0,
each of the small perivascular lesions being relatively
homogeneous with respect to the sizes of the lipid
Shaw et al: Remitting-Relapsing EAE 741
$@
135
8h
a
AAA
A
A
6
A
30
25
A
A Sacrifice
Relapse
A
A
A
A
O
A@
A
A
20
Y
3
a
AA
15
A
.fp
e
10
2
4
8
10 12
5
B
.he
e A
e
Fig 5 . Failures of treatments of experimental allergic encephalomyelitis in terms of the number of monkeys that died (A) and the
number of monkeys that relapsed (B) as a function of the duration of what otherwise should have been adequate therapy.
0
A
A
mep -
e
14 16 18 20 22
Duration of treatment (days)
6
e
ee
ee
eeo
oee
m
A
CIQ
o
A
e
0
~
oo
I
5
I
I
A
10
15
20
Days of treatment
I
25
Fig 7. Interval of time between cessation of treatment and relapse
or sacrifice (at end of the experiment) as a function of the duration of treatment.
-8
$6
54
4
O2
S O
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30
Days until relapse
Fig 6. Interval of time between cessation of treatment and onset
of relapse.
droplets, and in paraffin sections stained with Luxol
fast blue-PAS-hematoxylin, where Luxol fast bluestained droplets preceded the development of PASpositive droplets of myelin debris in macrophages.
Monkeys with remitting-relapsing EAE tended to
show resorbing lesions, such as pure demyelination
and gliosis (see Figs 8C, 9A, and l l ) , less commonly
showed necrosis (see Fig 8A, B) with or without cyst
formation, and rarely showed evidence of hyperacute
EAE if they were sacrificed during remission. Occasional animals showed early or mild focal hyperacute
EAE with many polymorphonuclear leukocytes (see
Figs 8E and 9D) with or without hemorrhages 1381,
but these animals might have been developing early
signs of a relapse at the time of sacrifice. By contrast, as
previously reported 1231, most of the fatal cases of
EAE of short duration showed the hyperacute form.
742 Annals of Neurology
Discussion
Previous investigators have generally used whole central nervous system tissues to sensitize monkeys in the
induction of EAE, some observing remissions and exacerbations 11-61 and others not 121, 36, 37, 39-43].
These remissions and exacerbations have been relatively rare and generally not reproducibly under the
investigator’s control, although Ravkina and colleagues
[5] stressed the need for low doses of homologous
spinal cord for sensitization. The present study is the
first report of remitting-relapsing EAE in monkeys
given only purified myelin BP, an antigen that should
permit more detailed examination of the pathogenesis
of remissions and relapses of EAE.
Based on the clinicopathologicalcorrelations that we
have presented in this report, the following hypotheses
summarize our current understanding of the various
courses of EAE that can occur in nonhuman primates:
1. Hyperacute EAE occurs in about 15% of monkeys
Vol 24 N o 6 December 1988
in which EAE has been induced 1341 and is usually
fatal, being characteristic of animals dying after a
disease course of only a few days. Ordinary acute
EAE in the monkey is usually not fatal unless vital
centers in the brainstem are severely involved.
Since EAE can be successfully treated with therapy of sufficiently long duration 122-241 without
A
B
D
Fig 8. Lesions of diffent durations from the monkey (Macaca
mulatta: N p 3650) illustrated in Figure 2 (top). (A, B, C)
Cerebellum shows old cystic necrosis (A, B) and adjacent demyelination (C).(Luxolfast blue-Holmes’; x 30 {A}, X 120 {B},
and x 30 {C), all before 30% reduction.)(D, E) The lateral
genicukate nucleus shows intermediate demyelination and acute
perivacukar inflammation. (Luxolfast blue-PAS-hemutoxylin;
x 30 {D}and x I20 {E).)
c
B
744 Annals of Neurology Vol 24 No 6 December I988
D
evidence of old hyperacute EAE detectable at autopsy, hyperacute EAE probably does not represent an early stage in the evolution of EAE, but is
rather a different type of reaction {38) that may or
may not complicate or be superimposed upon ordinary EAE.
2. Progression of EAE is due to the development of
additional lesions of ordinary EAE or the appearance of hyperacute EAE within preexisting ordinary
EAE.
3. If the multiplication of EAE lesions stops (spontaneously or, more commonly, following treatment), the existing lesions will be resorbed and the
animals will recover or improve clinically until the
next wave of new lesions of ordinary or hyperacute
EAE appears.
4. Animals will continue to show remissions and relapses as long as (a) hyperacute EAE does not develop and kill the animal, (b) sensitized lymphocytes remain active, and (c) lesions, even those of
ordinary EAE, do not destroy vital centers.
The simplest explanation for the wide variations in
severity of EAE is that there is a balance between
inductive and suppressive mechanisms of delayed-type
hypersensitivity [25}. In modern immunological terms
these mechanisms are generally identified as related to
T helper cells and T suppressor cells, respectively [27,
28, 44, 451. Manipulations of either or both of these
mechanisms should lead to hyperacute, acute, chronic,
or subclinical forms of EAE, as well as to remissions,
which may be complete (total and permanent) or incomplete (partial or temporary). Repeated incomplete
remissions of EAE should lead to relapsing forms of
the disease in which demyelination becomes the intermediate stage between necrosis and pure inflammation, as Hurst {46} speculated decades ago.
In view of the demonstration that both T and B cells
and two different antigens (BP and non-BP myelin
components) are involved in demyelination in guinea
pigs {lo] and rats [ZO}, one must wonder whether
both T and B cells are involved in monkeys and rabbits
1471, in both of which BP or BP fragments suffice to
induce demyelination. Since we have not seen EAE
develop in monkeys without concomitant anti-BP anti-
1Figfascicularis:
9. Lesions of different durations from the
(Macaca
N p 6327) illustrated in Figure 4 (middle). (A)
monkey
Cerebellar white matter shows intermediate demyelination.
(Luxolfast blue-PAS-hematoxylin; X 120.) (B) Midbrain
(brachium conjunctivum) shows intermediate demyelination and
perivascular inJfammtion. (Luxolfast blue-Holmes'; X 120.)
(C) Amygdzloid nuclem shows subacute perivascular injammation diffusing out into parenchyma. (H 0 E; X 120.) (Dl Occipital cortex shows acute perivascular injammation. (Luxolfast
blue-PAS-hematoxylin; x 120.)
++
1I
3
v1
h
1
r-
?I
5227
1
O?
Challenges
'
60
'
f
-
8'0
100
120 220
240
Days
Fig 10. Course ofa monk0 (Macaca fascicularis: Np 10834)
who received three sensitizing injections and developed three major attach of experimentalallergic encephalomyelitis (EAE) that
were treated successfully, sacrijice being 227 days after the first
sensitization. S = sacri$ce.
bodies [27], we suspect that the two-cell model will
apply to monkeys and rabbits, although the two antigens may merely be different epitopes on BP. However, one argument against this suspicion is that Seil
and colleagues {48} could not demonstrate myelination-inhibiting (demyelinating) activity in antibodies,
including anti-BP antibodies, in sera of monkeys developing acute EAE after sensitization with only BP.
The resolution of this discrepancy is important, but
must await other studies.
It may be just as treacherous as it is easy to extend
to MS the above concept of a two-cell model of EAE
in which either cell can be affected by appropriate
treatments. The spontaneous remissions that characterize most cases of MS can most easily be interpreted
as caused by as yet unidentified endogenous host factors of resistance, factors that even now can be slightly
augmented by steroid treatments {49] but that may
some day be more completely augmented by a more
specific and effective exogenous therapy once we
understand the etiopathogenesis of MS. That monkeys
with acute EAE have some comparable endogenous
resistance is suggested by the spontaneous improvements that occasionally occur, albeit in less than 10%
of our animals (see Table 1).The observation that rats
with acute EAE may improve with stress [17} also
suggests that endogenous resistance can be manipulated favorably.
In addition to these endogenous factors, exogenous
therapeutic factors have been identified in EAE, and in
monkeys include not only the specific antigen BP, but
also an adjunct, which in M.fascz'cdaris is a steroid that
conceivably augments host endogenous steroids. Thus,
although one may see many external differences in the
experimental therapeutic manipulations of EAE animals as compared with the manipulations of MS patients, the actual mechanisms being affected could be
remarkably similar. One merely needs to treat the
Shaw et al: Remitting-Relapsing EAE
745
C
F i g 11. Demyelinated and gliotic focus in the cerebellum o j the
monkey illustrated in Figure 10: (A) Demyelinated focus. (Luxol
fast blue-PAS-hematoxylin; x 7.1 (Bi Cowesponding gliosis.
D
(Holzer; x 7.) (C, D ) Demyelinated axons (Luxolfast blueHolmes; X 30 {C}, x 120 {D).)
EAE monkey suboptimally to produce a relapse following a temporary remission.
Supported in part by research grants RG-805-E-20 and RG-1708-A2 1 from the National Multiple Sclerosis Society and RR-00166 from
the National Institutes of Health.
References
1. Ferraro A, Cazzullo CL. Chronic experimental allergic encephalomyelitis in monkeys. J Neuropathol Exp Neurol 1948;7:2352 60
2. Ferraro A, Roizin L. Neuropathologic variations in experimental allergic encephalomyelitis, hemorrhagic encephalomyelitis,
perivenous encephalomyelitis, diffuse encephalomyelitis, patchy
gliosis. J Neuropathol Exp Neurol 1954;13:60-89
3. Hayreh SS, Massanari RM, Yamada T, Hayreh SMS. Experimental allergic encephalomyelitis: 1. Optic nerve and central
nervous system manifestations. Invest Ophthalmol Vis Sci
1981;2 1:256-269
4. %bat EA, Wolf A, Bezer AE. The rapid production of acute
disseminated encephalomyelitis in rhesus monkeys by injection
of heterologous and homologous brain tissue with adjuvants. J
Exp Med 1947;85:117-130
5. Ravkina L, Rogova V, Lazarenko L. Chronic experimental allergic encephalomyelitis in rhesus monkeys and its modification
by treatment. J Neurol Sci 1978;38:281-293
6. Wolf A, Kabat EA, Bezer AE. The pathology of acute disseminated encephalomyelitis produced experimentally in the
rhesus monkey and its resemblance to human demyelinating
disease. J Neuropathol Exp Neurol 1947;6:333-359
7. Brown AM, McFarlin DE. Relapsing experimental allergic encephalomyelitis in the SJVJ mouse. Lab Invest 1981;45:278284
8. Lublin FD, Maurer PH, Berry RG, Tippett D. Delayed, relapsing experimental allergic encephalomyelitis in mice. J Immunol
1981;126:819-822
9. Tabira T, Endoh M, Kunishita T. Acute and relapsing EAE in
Balb/c mice sensitized with DM-20. Can J Neurol Sci 1986;
13:377
10. Driscoll BF, Kira J, Kies MW, Alvord EC Jr. Mechanism of
demyelination in the guinea pig: separate sensitization with encephalitogenic myelin basic protein and nonencephalitogenic
brain components. Neurochem Pathol 1986;4:11-22
11. Fujiwara S, Ohtani S. Experimental allergic encephalomyelitis
(EAE) in two inbred guinea pigs: 1. Strain differences in developing chronic relapsing form of EAE. Jpn J Exp Med
1980;50:173-1 7 8
12. Keith AB, McDermott JR. Optimum conditions for inducing
chronic relapsing experimental allergic encephalomyelitis in
guinea pigs. J Neurol Sci 1980;46:353-364
13. Lassmann H, Wisniewski HM. Chronic relapsing experimental
allergic encephalomyelitis: morphological sequence of myelin
degradation. Brain Res 1979;169:357-368
14. Raine CS, Traugott U, Nussenblatt RB, Stone SH. Optic neuritis and chronic relapsing experimental allergic encephalomyelitis. Relationship to clinical course and comparison with multiple
sclerosis. Lab Invest 1980;42:327-335
15. Stone SH, Lerner EM 11. Chronic disseminated allergic encephalomyelitis in guinea pigs. Ann N Y Acad Sci 1965;122:22724 1
16. Sobel RA, van der Veen RC, Lees MB. Chronic experimental
allergic encephalomyelitis (cEAE) induced in rabbits by proteolipid protein: characterization of blood and in siru inflammatory cells. J Neuropathol Exp Neurol 1985;44:320
17. Levine S, Sowinski R, Steinetz B. Effects of experimental al-
lergic encephalomyelitis on thymus and adrenal: relation to remission and relapse. Proc SOCExp Biol Med 1980;165:218224
18. McFarlin DE, Blank SE, Kibler RF. Recurrent experimental
allergic encephalomyelitis in the Lewis rat. J Immunol 1974;
113:712-715
19, Panitch H, Ciccone c, Induction of recurrent experimental allergic encephalomyelitis with myelin basic protein. Ann Neurol
1981;9:433-438
20. Lassmann H , Linington C. Demyelination in vivo mediated by a
monoclonal antibody specific for a minor myelin glycoprotein.
Can J Neurol Sci 1986;13:376
2 1. Eylar EH, Jackson J, Rothenberg B, Brostoff SW. Suppression
of the immune response: reversal of the disease state with antigen in allergic encephalomyelitis. Nature 1972;236:74-76
22. Alvord EC Jr, Shaw C-M, Hruby S. Myelin basic protein treatment of experimental allergic encephalomyelitis in monkeys.
Ann Neurol 1979; 6:469-473
23. Shaw C-M, Alvord EC Jr. Treatment of experimental allergic
encephalomyelitis in monkeys: 11. Histopathological studies. In:
Shiraki H , Yonezawa T, Kuroiwa Y, eds. The aetiology and
pathogenesis of the demyelinating diseases. Tokyo: Japan Science Press, 1976:377-395
24. Shaw C-M, Alvord EC Jr, Hruby S. Treatment of experimental
allergic encephalomyelitis in monkeys: I. Clinical studies. In:
Shiraki H , Yonezawa T, Kuriowa Y, eds. The aetiology and
pathogenesis of the demyelinating diseases. Tokyo: Japan Science Press, 19761367-376
25. Alvord EC Jr. Pathogenesis of experimental allergic encephalomyelitis: introductory remarks. Ann NY Acad Sci 1965;122:
245-255
26. Alvord EC Jr, Shaw C-M, Hruby S, et al. The onset of experimental allergic encephalomyelitis as defined by clinical, electrophysiological and immunochemical changes. In: Alvord EC Jr.
Kies MW, Suckling AJ, eds. Experimental allergic encephalomyelitis: a useful model for multiple sclerosis. New York: AR
L~ss,
1984x461-466
27. Rose LM, Clark EA, Hruby S, Alvord EC Jr. Fluctuations of the
T- and B-cell subsets in basic protein-induced experimental allergic encephalomyelitis (EAE) in long-tailed macaques. Clin
Immunol Immunopathol 1987;44:93-106
28. Rose LM, Alvord EC Jr, Hruby S, et al. In vzvo administration of
anti-CD4 monoclonal antibody prolongs survival in long-tailed
macaques with experimental allergic encephalomyelitis. Clin
Immunol Immunopathol 1988;45:405-423
29. Margolis G, Pickett JP. New applications of the Lux01 fast blue
myelin stain: I. A myelo-angio-cytoarchitectural method. 11. A
myelin-neuroglia method. 111. A myelin-fat method. IV. A myelin-axis cylinder method. Lab Invest 1956;5:459-474
30. Augulis V, Sepinwall J. Use of gallocyanin as a myelin stain for
brain and spinal cord. Stain Technol 1971;46:137-143
31. Holmes W. Silver staining of nerve axons in paraffin sections.
Anat Rec 1943;86:157-187
32. Chiffelle TL, Putt FA. Propylene and ethylene glycol as solvents
for Sudan IV and Sudan black B. Stain Technol 1951;26:51-56
33. Kil E. Block-face application of a 7:3 propylene glycol-water
mixture to facilitate cutting of large frozen sections. Stain Techno1 1972;47:271-272
34. Alvord EC Jr. Rose LM, Hruby S, et al. Experimental allergic
encephalomyelitis in non-human primates: an excellent model
of multiple sclerosis. In: Jonker M, ed. Biomedical research in
primates. Amsterdam: Elsevier, 1988 (in press)
35. Alvord EC Jr, Shaw C-M, Hruby S, et al. Neuro-allergic reactions in primates. In: Shiraki H, Yonezawa T, Kuroiwa Y, eds.
The aetiology and pathogenesis of the demyelinating diseases.
Tokyo: Japan Science Press, 1976:203-216
36. Eylar EH. Structure-function relationships of the basic protein
from myelin membranes. In: Field EJ, Bell TM, Carnegie PR,
Shaw et al: Remitting-Relapsing EAE 747
37.
38.
39.
40.
41.
42.
43.
44.
eds. Multiple sclerosis, progress in research. Amsterdam:
North-Holland 1072:90- 104
Eylar EH, Jackson JJ, Kniskern PH. Suppression and reversal of
allergic encephalomyelitis in rhesus monkeys with basic protein
and peptides. Neurochem Res 1979;4:249-258
k v i n e S, Wenk E. A hyperacute form of allergic encephalomyelitis. Am J Pathol 1365;47:61-88
Behan PO, Kies MW, Lsak RP, et al. Immunologic mechanisms
in experimental encephalomyelitis in nonhuman primates. Arch
Neurol 1973;29:4-9
Ferraro A, Jervis GA. Experimental disseminated encephalopathy in the monkey. Arch Neurol Psychiatry l940;43:19'j-209
Morgan IM. Allergic encephalomyelitis in monkeys in response
to injection of normal monkey nervous tissue. J Exp Med
1947;85:131- 140
Rivers TM, Schwentker FF. Encephalomyelitis accompanied by
myelin destruction experimentally produced in monkeys. J Exp
Med 1935;61:689-702
Rwers TM, Sprunt DH, Berry GP. Observations on attempts to
produce acute disseminated encephalomyelitis in monkeys. J
Exp Med 1933;58:39-53
Ben-Nun A, Cohen IR. Spontaneous remission and acquired
748 Annals of Neurology
Vol 24
45.
46.
47.
48.
49.
No 6 December 1988
resistance to autoimmune encephalomyelitis (EAE) are associated with suppression of T cell reactivity: suppressed EAE effector T cells recovered as T cell lines. J Immunol 1982;128:14501457
Welch AM, Holda JH, Swanborg RH. Regulation of expenmental allergic encephalomyelitis: 11. Appearance of suppressor
cells during the remission phase of the disease. J Immunol
1780;125: 186- 188
Hurst EW. A review of some recent observations of demyelination. Brain 1944;67:103-124
Kira J, Bacon ML, Martenson RE, er al. Experimental allergic
encephalomyelitis in rabbits: a major encephalitogenic determinant within residues 1-44 of myelin basic protein. J Neurommunol 1986;12:183-193
Seil FJ, Rauch HC, Einstein ER, Hamilron AE. Myelinatiorr
inhibition factor: its absence in sera from subhuman primates
sensitized with myelin basic protein. J Immunol 1 9 7 3 ; l l l : q L
100
Rose AS, Kuzma JW, Kurtzke JF, et al. Cooperative study in
the evaluation of therapy in multiple sclerosis. ACTH vs.
placebo. Final report. Neurology 1970;20(no 5 , part 2). 1-
59
Документ
Категория
Без категории
Просмотров
3
Размер файла
1 203 Кб
Теги
experimentov, remitting, allergic, homologous, induced, monkey, relapsing, basic, protein, myelin, encephalomyelitis, chronic
1/--страниц
Пожаловаться на содержимое документа