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The Journal of Neuroscience, January 1, 2001, 21(1):136-142
Vaccination for Neuroprotection in the Mouse Optic Nerve:
Implications for Optic Neuropathies
Jasmin
Fisher1,
Hanna
Levkovitch-Verbin1,
Hadas
Schori1,
Eti
Yoles1,
Oleg
Butovsky1,
Joel F.
Kaye2,
Avraham
Ben-Nun2, and
Michal
Schwartz1
Departments of 1 Neurobiology and
2 Immunology, The Weizmann Institute of Science, Rehovot,
Israel
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ABSTRACT |
T-cell autoimmunity to myelin basic protein was recently
shown to be neuroprotective in injured rat optic nerves. In the present study, using the mouse optic nerve, we examined whether active immunization rather than passive transfer of T-cells can be beneficial in protecting retinal ganglion cells (RGCs) from post-traumatic death.
Before severe crush injury of the optic nerve, SJL/J and C3H.SW mice
were actively immunized with encephalitogenic or nonencephalitogenic peptides of proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein (MOG), respectively. At different times after the injury,
the numbers of surviving RGCs in both strains immunized with the
nonencephalitogenic peptides pPLP 190-209 or pMOG 1-22 were
significantly higher than in injured controls treated with the
non-self-antigen ovalbumin or with a peptide derived from  -amyloid,
a non-myelin-associated protein. Immunization with the encephalitogenic
myelin peptide pPLP 139-151 was beneficial only when the disease it
induced, experimental autoimmune encephalomyelitis, was mild. The
results of this study show that survival of RGCs after axonal injury
can be enhanced by vaccination with an appropriate self-antigen.
Furthermore, the use of nonencephalitogenic myelin peptides for
immunization apparently allows neuroprotection without incurring the
risk of an autoimmune disease. Application of these findings might lead
to a promising new approach for treating optic neuropathies such as glaucoma.
Key words:
vaccination; neuroprotection; myelin; T-cells; CNS
injury; autoimmunity; optic nerve
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INTRODUCTION |
Injury to the CNS of adult
mammals results in primary damage to the directly affected neurons and
is often compounded by a gradual secondary loss of undamaged neurons in
the vicinity (Faden and Salzman, 1992 ; Faden, 1993; McIntosh, 1993;
Yoles and Schwartz, 1998). The primary lesion causes changes in
extracellular ion concentrations, increased circulation of free
radicals, release of neurotransmitters, depletion of growth factors,
and local inflammation (Liu et al., 1994). These changes trigger a
cascade of intracellular destructive events leading to delayed neuronal
death (Villegas-Perez et al., 1993; Berkelaar et al., 1994;
Garcia-Valenzuela et al., 1994).
In the case of the optic nerve, primary injury of the nerve fibers
leads to death of the corresponding cell bodies, the retinal ganglion
cells (RGCs) (Villegas-Perez et al., 1993). In the adult rat, for
example, >90% of RGCs die within 2 weeks of optic nerve axotomy
performed close to the eye (Villegas-Perez et al., 1988). In mice, RGCs
undergo apoptosis after trauma to the axon (Li et al., 1999),
decreasing to 50-80% of their original number by 30 d after
intraorbital optic nerve transection (Allcutt et al., 1984).
It was recently shown in our laboratory that optic nerve injury in the
rat is followed by a transient accumulation of activated T-cells at the
lesion site, irrespective of their antigenic specificity. Although the
accumulation is nonselective (Hirschberg et al., 1998; Moalem et al.,
1999a), only T-cells that are specific to myelin basic protein (MBP)
were found to reduce secondary degeneration (i.e., the spread of damage
to neurons that had escaped the primary lesion) (Moalem et al., 1999b).
These findings indicated that specific autoimmunity in the CNS may not
always be detrimental and, under certain circumstances, might have a
physiological role in protecting the damaged CNS.
The aim of the present study was to determine whether immune
neuroprotection can promote post-traumatic survival of RGCs with damaged axons, and whether this can be achieved by active immunization. The model chosen for the study was the mouse optic nerve, which offers
the possibility of examining various knock-out mice and thus gaining
insight into the genetic control of immune neuroprotection.
The myelin sheath of the nerve is composed mainly of proteolipid
protein (PLP) and MBP (Wucherpfennig, 1994). Some glycoproteins are
also present in the myelin sheath but constitute only a minor fraction
of the total protein. Among these, myelin oligodendrocyte glycoprotein
(MOG) comprises 0.01-0.05% of the total myelin protein (Amiguet et
al., 1992). A large body of evidence indicates that MBP, PLP, and MOG
are all encephalitogenic proteins capable of causing experimental
autoimmune encephalomyelitis (EAE), an animal model for multiple
sclerosis (Zamvil and Steinman, 1990; Linington et al., 1993).
The MOG peptide encompassing amino acids 35-55 (pMOG 35-55) of the
mouse MOG sequence is encephalitogenic in
H-2b (C3H.SW, C56BL/6J) mice (Kerlero de
Rosbo et al., 1995; Mendel et al., 1995) but not in
H-2k mice, and the disease in
H-2b mice is similar to the chronic EAE
induced by MBP or PLP. Histologically, the perivascular inflammatory
foci seen in the CNS of C3H.SW mice with EAE induced by pMOG 35-55 are
equivalent in number and intensity to those seen in mice with EAE
induced by MBP or PLP (Kerlero de Rosbo et al., 1995). Whereas pPLP
139-151 and pMOG 35-55 are known to induce EAE in SJL/J (Bebo et al.,
1998) and C3H.SW (Mendel et al., 1995) mice, respectively, the peptides
pPLP 190-209 and pMOG 1-22 are not encephalitogenic in these strains
(Mendel et al., 1995; Nicholson et al., 1995).
In this study, using the injured mouse optic nerve as a model, we
demonstrate that active immunization with the encephalitogenic PLP
peptide leads to neuroprotection only in cases in which the induced EAE
is mild; the immunization has no beneficial effect in mice that develop
severe EAE. Immunization with nonencephalitogenic myelin-associated
peptides derived from PLP or MOG leads to neuroprotection. The
unexpected finding that the post-traumatic death of RGCs might be
slowed down by immunization, and especially by immunization with an
autoimmune antigen, compels us to reassess the relationship between the
immune system (in particular autoimmunity) and the injured CNS.
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MATERIALS AND METHODS |
Animals. Adult female C3H.SW and SJL/J mice (8-12
weeks old) were purchased from The Jackson Laboratory (Bar Harbor, ME). The mice were housed in a light- and temperature-controlled room and
matched for age in each experiment.
Antigens. MOG peptides 1-22 (GQFRVIGPGHPIRALVGDEAEL) and
35-55 (MEVGWYRSPFSRVVHLYRNGK) of rat origin, PLP peptides 190-209 (SKTSASIGSLCADARMYGVL) and 139-151 (HSLGKWLGHPDKF) of mouse origin, and AP peptides 1-20 (DAEFGHDSGFEVRHQKLVFF) and 10-30
(EVRHQKLVFFAEDVGSNKGA) of rat and mouse origin were synthesized in the
laboratory of Prof. M. Fridkin, at the Department of Chemistry of the
Weizmann Institute of Science, using the
fluorenylmethoxycarbonyl amino acids by automatic multiple
peptide synthesizer (AMS422; Abimed, Langenfeld, Germany). Ovalbumin
(OVA), fraction V, was purchased from Sigma Israel (Rehovot, Israel).
Active immunization. For EAE induction, mice were injected
subcutaneously in the flank with 200 µl of an emulsion containing either 300 µg of rat MOG peptide (35-55) or 200 µg of rat PLP peptide (139-151) in complete Freund's adjuvant (CFA) supplemented with 500 µg of Mycobacterium tuberculosis H37RA (Difco,
Detroit, MI). In the mice injected with pMOG 35-55, an identical
injection was given in the other flank as a booster 1 week later.
Immunization with nonencephalitogenic myelin peptides was done as
follows. Mice were injected subcutaneously at one site in the flank
with 200 µl of emulsion consisting of MOG 1-22 or OVA (C3H.SW mice, 300 µg/mouse) or PLP 190-209, AP 1-30, or OVA (SJL/J mice, 200 µg/mouse), emulsified in CFA supplemented with 500 µg of M. tuberculosis. In the mice injected with pMOG 1-22, an identical
injection was given in the other flank as a booster 1 week later.
Control mice were injected only with PBS and CFA.
After encephalitogenic challenge, the mice were observed daily, and
clinical manifestations of EAE were scored on a scale of 0-5 (0, no
clinical signs; 1, flaccid tail; 2, hind-leg paralysis; 3, hind-leg
paralysis with lower-body paresis; 4, hind-leg and foreleg paralysis;
5, death).
Preinjury application of stereotactic dye. For baseline
labeling of RGCs, a stereotactic dye was applied before the crush injury. Eleven days after the first active immunization, mice were
deeply anesthetized by intraperitoneal injection of xylazine (14 mg/kg;
Vitamed, Bat Yam, Israel) and ketamine (60 mg/kg; Fort Dodge
Laboratories, Fort Dodge, IA) and placed in a small stereotactic instrument. The skull was exposed and kept dry and clean using 3%
hydrogen peroxide. The bregma was identified and marked. A hole was
drilled above the superior colliculus of each hemisphere (0.292 mm
behind and 0.05 mm lateral to the midline). Using a stereotactic
measuring device and a Hamilton injector, the mice were injected with
FluoroGold (3% in saline; ; 1 µl; Fluorochrome, Denver, CO) at one
point in the superior colliculus of each hemisphere, at a depth of 0.16 mm (in C3H.SW mice) or 0.175 mm (in SJL/J mice) from the bony surface
of the brain. After completion of the injection, the wound was sutured.
Retrograde uptake of the dye provides a marker of the living cells.
Three days after dye application, the right optic nerve of each mouse
was subjected to a crush injury severe enough to cause primary damage
to most of the axons. After such an injury, the number of labeled cell
bodies at a given time provides an indication of the rate of primary
degeneration and cell body death.
RGC survival was assessed 1, 2, and 4 weeks after the crush injury.
Mice were killed, eyes showing signs of ischemia or infection were
discarded, and only eyes that looked healthy were used. Each retina was
detached from the eye, prepared as a flattened whole mount in 4%
paraformaldehyde solution, and examined for labeled RGCs by
fluorescence microscopy. Labeled RGCs from five to six fields of
identical size (0.196 mm2), located 1 mm
from the optic disk, were counted under the fluorescence microscope and
averaged. Calculation of the number of labeled RGCs per square
millimeter in the right retina provided a quantitative measure
of the total degeneration.
Crush injury of the mouse optic nerve. Three days after
stereotactic dye application (14 d after the first active
immunization), the mice were deeply anesthetized by intraperitoneal
injection of xylazine (14 mg/kg) and ketamine (60 mg/kg). Using a
binocular operating microscope, the conjuctiva of the right eye was
incised, and the optic nerve was exposed. With the aid of cross-action forceps, the optic nerve was subjected to a severe crush injury 1-2 mm
from the eyeball. The uninjured contralateral nerve was left
undisturbed. Anterograde labeling of RGCs revealed no continuity of
fibers beyond the site of injury, indicating that the crush was severe
enough to cause primary damage to most of the axons (E. Yoles and M. Schwartz, unpublished observations). This model has yielded a high
degree of reproducibility with minimal variation among animals in the
same group. Thus, significant results can be obtained even when the
number of mice used in each group is small.
Immunocytochemistry of T-cells. Longitudinal cryosections of
the excised nerves (10 µm thick) were placed on gelatin-coated glass
slides and frozen until preparation for fluorescence staining. Sections
were fixed in ethanol for 10 min at room temperature, washed twice in
double-distilled water, and incubated for 3 min in PBS containing
0.05% polyoxyethylene-sorbitan monolaurate (Tween 20). Sections were
then incubated for 1 hr at room temperature with rat antibody to human
CD3 (Serotec, Oxford, UK) or mouse antibody to mouse glial fibrillary
acid protein (GFAP) (PharMingen, San Diego, CA), diluted (1:50) in PBS
containing 3% fetal calf serum and 2% bovine serum albumin. The
sections were washed three times with PBS containing 0.05% Tween 20 and incubated with either fluorescein isothiocyanate-conjugated goat
anti-mouse IgG (Jackson ImmunoResearch, West Grove, PA) or
Cy3-conjugated goat anti-rat IgG (Jackson ImmunoResearch) for 1 hr at
room temperature. The sections were then washed with PBS containing
Tween 20 and treated with glycerol containing 1,4-diazobicyclo-(2,2,2)
octane to inhibit quenching of the fluorescence. Sections were viewed
with either a confocal or light microscope, and cells were observed.
Staining in the absence of the first antibody was negative.
Statistical analysis. The number of RGCs per square
millimeter was calculated for each experiment. Statistical analysis was performed by one-way ANOVA or Student's t test.
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RESULTS |
Establishment of the mouse optic nerve model for the study of
RGC death
Injury of optic nerve axons leads to delayed death of their
corresponding RGCs, mostly by apoptosis (Berkelaar et al., 1994). The
model usually used to study this degenerative process is the rat optic
nerve. However, the availability of a mouse model would confer certain
unique advantages. Unlike the rat model, a model of optic nerve injury
in the mouse will enable us to study post-traumatic death of RGCs in
various transgenic and knock-out mice. It would also allow us to study
autoimmune neuroprotection in mice with different susceptibilities to
EAE. To establish such a model, we developed a method for inflicting
and quantifying well-controlled injuries of the mouse optic nerve,
using a relatively simple technique in which all RGCs are
stereotactically labeled before the injury. This approach yields
reproducible labeling of viable RGCs, with almost no variation among
individuals or among strains. Testing of several mouse strains yielded
similar numbers of RCGs (Table 1). The
efficiency of labeling [i.e., the percentage of RGCs stained after a
single injection of FluoroGold, calculated as the average number of
RGCs observed per square millimeter (Table 1) multiplied by the
approximate size of a mouse retina (24 mm2) divided by the average number of RGCs
per retina (previously shown to be 100,000)] was found to be
80-90%.
Possible link between EAE severity and neuroprotection
Having established a technique for reproducible labeling of RGCs
in the mouse, our objective was to use this method to determine whether
active immunization with myelin-associated peptides in mice would
result in neuroprotection. To ensure that the T-cell response would
reach its peak at the time of injury (which presumably is when it is
needed), we had to suit the timing of the injury to the course of EAE
induced by the encephalitogenic MOG and PLP peptides (pMOG 35-55 and
pPLP 139-151).
EAE was induced in C3H.SW mice (n = 4) by two
inoculations (1 week apart) of pMOG 35-55 in CFA. Clinical signs of
EAE began to develop 12-14 d after the initial challenge, with a
chronic course of ascending paralysis that affected the tail and the
hind legs (Fig. 1a). EAE was
induced in SJL/J mice (n = 5) by a single inoculation
of pPLP 139-151 in CFA. Starting 12-14 d after the initial challenge,
clinical signs of EAE developed in a relapsing-remitting manner (Fig.
1b).
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Figure 1.
Clinical course of EAE, induced by either pMOG
35-55 in C3H.SW mice (n = 4)
(a) or pPLP 139-151 in SJL/J mice
(n = 5) (b). For induction of
disease, mice were injected with pMOG 35-55 or pPLP 190-209 in CFA
supplemented with M. tuberculosis, as described in
Materials and Methods. EAE was evaluated according to a neurological
paralysis scale. The mean ± SEM daily clinical score is shown for
each mouse strain. Note that, in the C3H.SW mice, the induced EAE had a
chronic course, whereas in the SJL/J mice, it was relapsing-remitting
in nature.
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To determine whether the active immunization leads to neuroprotection,
we immunized mice with the encephalitogenic peptide PLP 139-151 and
determined the effect on RGC survival after optic nerve injury. The EAE
score was assessed daily, starting on day 10 after the immunization and
ending on the day of retinal excision. Only those mice (two of five) in
which no further signs of EAE were detectable by day 14 (peak EAE score
of 1) showed significantly larger numbers of surviving RGCs than the
numbers measured in the OVA-injected controls (n = 4).
RGC survival in mice that still had EAE symptoms at the time of retinal
excision (three of five) was no better than in the OVA controls. The
persistence of EAE symptoms 4 weeks after injury is an indication that
the disease had been severe at its peak. RGC survival measured 4 weeks
after immunization was indeed found to be negatively correlated with disease severity 2 weeks after optic nerve injury (Fig.
2). Our interpretation of these findings
is that autoimmunity, although beneficial in terms of neuroprotection,
has a threshold beyond which it is detrimental.
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Figure 2.
Negative correlation between the number of
surviving RGCs of injured nerves from mice immunized with PLP 139-151
and EAE disease severity. Each point indicates the mean
number of labeled RGCs per square millimeter 2 weeks after optic nerve
injury. Two weeks before injury, mice were injected with pPLP 139-151
or OVA. The neurotracer dye FluoroGold was applied stereotactically
3 d before injury. Two weeks after the injury, the retinas were
excised and flat-mounted, and the EAE score was determined. Labeled
RGCs from three to five randomly selected fields in each retina (all
located 1 mm from the optic disk) were counted by fluorescence
microscopy. In mice immunized with PLP 139-151, in which no protection
was observed, the average number of RGCs (563 RGCs/mm2; n = 3) was similar to
that found in OVA-immunized mice (613 RGCs/mm2;
n = 4). The correlation coefficient
(r) was  0.96 according to linear regression;
the p value was 0.009 according to one-way ANOVA.
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Active immunization with nonencephalitogenic myelin-associated
peptides slows down RGC degeneration
In view of the above findings, together with previous findings in
our laboratory that T-cells against nonencephalitogenic myelin-associated peptides have a neuroprotective effect, we examined whether preinjury immunization with the nonencephalitogenic
myelin-associated peptide pPLP 190-209 or pMOG 1-22 would lead to
neuroprotection in SJL/J and C3H.SW mice, respectively. AP was used
as a non-myelin-associated self-peptide control, and OVA was used as a
foreign antigen control. The numbers of labeled RGCs per square
millimeter (reflecting cell bodies that were still viable 2 weeks after
the injury) are shown in Figure 3. The
mean number of surviving RGCs in the retinas of mice immunized with
pPLP 190-209 (1725 RGCs/mm2;
n = 10) was significantly higher than that in the
retinas of OVA-immunized control mice (965 RGCs/mm2; n = 10;
p < 0.001; one-way ANOVA). The mean number of
surviving RGCs in the retinas of AP-injected mice (1240 RGCs/mm2; n = 8) was not
significantly higher than that found in the OVA controls
(p > 0.05; one-way ANOVA).
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Figure 3.
Immunization with pPLP 190-209 slows down death
of RGCs. The histograms record the mean number of labeled RGCs 2 weeks
after optic nerve injury. Two weeks before injury, SJL/J mice were
injected with pPLP 190-209, OVA, or AP. The neurotracer dye
FluoroGold was applied stereotactically 3 d before injury. Two
weeks after the injury, the retinas were excised and flat-mounted.
Labeled RGCs from three to five randomly selected fields in each retina
(all located 1 mm from the optic disk) were counted by fluorescence
microscopy. Survival in each group of injured nerves was expressed as
the mean ± SEM number of labeled RGCs per square millimeter. The
neuroprotective effect of pPLP 190-209 was significant compared with
that of OVA (p < 0.001; one-way ANOVA).
AP did not differ significantly from OVA in its protective effect on
neurons that had escaped the primary injury
(p > 0.05; one-way ANOVA). The results are
a summary of three experiments.
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A similar survival pattern relative to the controls (n = 14) was observed in mice immunized with pMOG 1-22 (n = 12), in which ~1017 RGCs/mm2 were
found to be labeled 2 weeks after injury compared with only 728 in the
retinas of the OVA-immunized controls (n = 14;
p < 0.05; Student's t test).
Because active immunization with pMOG 1-22 or pPLP 190-209
performed 2 weeks before the injury reduced the post-traumatic loss of
RGCs, we were interested in examining the effect of active immunization
performed immediately after the injury. As shown in Figure
4a, in the retinas of mice
immunized immediately after the injury with pMOG 1-22
(n = 5), ~1049 RGCs/mm2
were still viable 2 weeks after the injury, whereas the mean number of
surviving RGCs in the retinas of OVA-injected controls (n = 4) was significantly lower (~777
RGCs/mm2) (p < 0.02; Student's t test).
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Figure 4.
Immunization with pMOG 1-22 slows
down RGC degeneration. The histograms record the mean ± SEM
number of labeled RGCs per square millimeter. a, The
number of labeled RGCs assessed 2 weeks after injury in retinas of mice
before or after injury immunized with pMOG 1-22. For preinjury
immunization, C3H.SW mice were injected with pMOG 1-22 or OVA, 14 d before optic nerve injury. Dye application, preparation, and counting
of RGCs, as well as calculation of RGC survival, were as described for
Figure 3. The number of labeled RGCs in the retinas of mice pretreated
with pMOG 1-22 was significantly higher (p < 0.05; Student's t test) than in mice pretreated with
OVA. The results are a summary of three experiments. For postinjury
immunization, FluoroGold was applied stereotactically 3 d before
optic nerve injury, and the mice were injected with either pMOG 1-22
or OVA immediately after the injury. Two weeks later, the retinas were
prepared and counted as before. The number of labeled RGCs in the
retinas of mice inoculated with pMOG 1-22 after the injury was
significantly higher (p < 0.02; Student's
t test) than in the mice inoculated with OVA before
injury. The results shown are from one experiment only. Each group
contained four to five mice. b, The number of labeled
RGCs in preinjury immunized mice assessed 1 and 4 weeks after the
injury. The histograms record the mean ± SD number of labeled
RGCs per square millimeter. The RGC number in pMOG 1-22-immunized mice
was significantly higher than that of PBS control mice
(p < 0.0001; Student's t
test) either 1 or 4 weeks after the injury. The inset
shows the ratio between the number of surviving RGCs in the retinas of
MOG-immunized mice and the control mice, at each of the time points
tested. The results shown are from one experiment only. Each group
contained five to nine mice.
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To verify that immunization with MOG had indeed slowed down the rate of
RGC death caused by the crush injury, we repeated the experiment and
analyzed the retinas of C3H.SW mice at two additional times, 1 and 4 weeks after the injury. As shown in Figure 4b, in the
retinas of mice preimmunized with pMOG 1-22 (n = 9),
~1323 RGCs/mm2 were still viable 1 week
after the injury, whereas in the retinas of PBS-injected controls
(n = 5), the mean number of viable RGCs was
significantly lower (~610 RGCs/mm2;
p < 0.0001; Student's t test). In
contrast, 4 weeks after the injury, only 422 RGCs/mm2 were still viable in the
preimmunized mice, whereas the mean number of surviving RGCs in the
controls (n = 7) was 296 RGCs/mm2 (p > 0.0001; Student's t test). It thus appeared that at any time point tested, the number of surviving RGCs in the MOG-immunized mice was higher than in the control. These results thus confirm that
the MOG immunization affects the rate of RGC loss and that it has a
long-lasting effect.
T-cell accumulation at the injury site
The finding that adoptively transferred activated T-cells
accumulate at the site of optic nerve injury in rats (Hirschberg et
al., 1998) prompted us to analyze crush-injured optic nerves of mice
for the presence of T-cells after active immunization with pMOG 1-22
or OVA or after injection of PBS with CFA. Staining with GFAP and CD3
antibodies showed that T-cells were present from day 3 after injury
with a peak at day 7 and were restricted to the site of injury. T-cell
accumulation at the site of optic nerve injury in C3H.SW mice after
active immunization with pMOG 1-22 is indicated in Figure
5. Similar patterns were observed in
control mice immunized with either OVA or PBS, in line with a previous
finding of no antigenic selectivity in the post-traumatic accumulation
of T-cells in the rat optic nerve.
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Figure 5.
Confocal microscopy pictures showing T-cell
accumulation at the optic nerve injury site. One week after the injury,
the optic nerves of C3H.SW mice immunized with pMOG 1-22 before injury
were excised and labeled immunocytochemically. Serial optic nerve
sections immunolabeled for GFAP (a) delineate the
site of injury (indicated by the arrows). Immunolabeling
for CD3 (b) indicates the presence of T-cells at
the injury site.
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DISCUSSION |
This work shows that active immunization with myelin-associated
peptides leads to neuroprotection. The neuroprotective effect could be
achieved with either immunodominant encephalitogenic epitopes or with
nonencephalitogenic epitopes. The former were found to be beneficial
only when the disease they caused was mild. These findings support our
contention that beneficial autoimmunity is functionally distinct from
autoimmune disease (Schwartz et al., 1999) and that autoimmunity might
be a benign physiological response as long as it is well controlled
(Cohen and Schwartz, 1999; Schwartz et al., 1999). Thus, autoimmunity,
although beneficial in terms of neuroprotection, has a threshold beyond
which it is detrimental. Accordingly, the autoimmune response induced
here by active immunization with an immunodominant encephalitogenic epitope failed to lead to neuroprotection when it exceeded the upper
limit of benign autoimmunity, becoming what we would define as "out
of control." Such a response would involve substantially more T-cells
and macrophages than the response induced by adoptive transfer of
T-cells (Moalem et al., 1999a). In fact, our studies of active
immunization and passive immunization in the injured spinal cord have
yielded similar results (Hauben et al., 2000a).
Immunization with nonencephalitogenic myelin peptides was shown here to
trigger an immune response that slows down the degeneration of RGCs
after optic nerve injury in mice. This neuroprotective effect is not
restricted to peptides associated with MBP, because nonencephalitogenic
peptides derived from PLP and MOG were similarly neuroprotective. After
passive immunization using the rat optic nerve model, the percentage of
labeled RGCs was about twofold higher in the retinas of rats inoculated
with anti-MBP T-cells than in controls (Moalem et al., 1999b). In the
present study, the retinas of mice actively immunized with pPLP
190-209 or pMOG 1-22 showed ~80 or 40% more surviving RGCs,
respectively, than those of the controls. The differences in degree of
protection between the rat and the mouse might be attributable to the
type of immunization (passive vs active), species differences, or
differences between the parameters examined in the two models. In the
mouse, we examined the effects of different autoimmune responses on the death rate of RGCs of damaged axons, with such death being an inevitable consequence of the primary insult (Berkelaar et al., 1994;
Garcia-Valenzuela et al., 1994). Indeed, although the beneficial effect
of the immunization was long-lasting, it decreased with time; 1 week
after the injury, the neuroprotective effect was higher than the effect
2 and 4 weeks after the injury. In contrast, the parameter measured in
the rat optic nerve model was the effect of passive transfer of
anti-MBP T-cells after partial injury (Moalem et al., 1999b) on the
secondary degeneration of neurons that had escaped the primary lesion
(Yoles and Schwartz, 1998). It should be noted that, unlike passive
immunization, which in our experiments involved only T-cells, active
immunization involves additional immune elements, such as macrophages
and antibodies. Macrophages might affect RGC survival in a way that
influences the potency of active but not of passive immunization
(Hirschberg and Schwartz, 1995). The slight difference in the
degree of protection conferred by immunization with PLP and with MOG in
the mouse might be attributable to the relative abundance of these
proteins in the myelin sheath (Wucherpfennig, 1994); PLP and MBP are
the major constituents of the myelin sheath, whereas MOG comprises only
~0.05% of the total myelin protein (Amiguet et al., 1992).
The neuroprotective effect induced by immunization with myelin peptides
can, in principle, be mediated by either T-cells or antibodies that
were secreted from B-cells and managed to pass through the disrupted
blood-brain barrier as a result of the injury. The previous finding in
the rat model that anti-MBP T-cells accumulate at the injury site
(Konno et al., 1990; Hirschberg et al., 1998; Moalem et al., 1999a) and
are involved in neuroprotection (Moalem et al., 1999b), together with
the present finding that some T-cells "home" to the site of injury,
suggests that the neuroprotective effect seen here is mediated by
T-cells. Moreover, the period between the time of immunization (and
hence the onset of the immune response) and the time when this response
is needed by the damaged nerve is not long enough for the antibodies to
be produced. In a recent study by Huang et al. (1999), it was suggested
that active immunization with a myelin homogenate emulsified in
incomplete Freund's adjuvant promotes nerve regrowth via antibody
activity. Studies in our laboratory have shown that vaccination with
MBP is effective only in neuroprotection, because no recovery could be
demonstrated in the completely transected spinal cord (Hauben et al.,
2000a). Moreover, passive transfer of autoimmune anti-MBP T-cells
(Moalem et al., 1999b; Hauben et al., 2000b), but not of antibodies
against MBP, led to neuroprotection of the partially injured spinal
cord (Hauben et al., 2000a). It is therefore possible that the observed
neuroprotection obtained with autoimmune T-cells represents a
physiological mode of recovery that is spontaneously evoked by the
injury but is apparently insufficient and needs boosting to be
effectively manifested. In contrast, the regrowth obtained by Huang et
al. (1999) represents a pharmacological intervention achieved by
anti-myelin antibodies, similar to that reported previously by
Schnell et al. (1997).
The results of our recent studies, and of the present work, argue in
favor of autoimmunity as a benign physiological response, which, unless
it gets out of control, reduces postinjury degeneration in the CNS.
Other studies have demonstrated an accumulation of T-cells in the
injured CNS (Schnell et al., 1997; Raivich et al., 1998), as well as a
systemic T-cell immune response against MBP in animals with CNS
injuries (Popovich et al., 1996). It was not clear, however, whether
the effect of these T-cells was beneficial or harmful.
The molecular mechanisms by which autoimmune T-cells protect the
injured nerve from degeneration are not yet fully understood. Previous
electrophysiological findings indicated that the anti-MBP T-cells exert
neuroprotection by causing a transient reduction in the
electrophysiological activity of the nerve (Moalem et al., 1999b). It
was suggested recently that the neuroprotection mediated by autoimmune
T-cells might be attributable, at least in part, to antigen-dependent
secretion of neurotrophins by the autoimmune T-cells reactivated at the
lesion site when encountering their specific antigen (Moalem et al.,
2000). The production of neurotrophins by T-cells was reported recently
(Ehrhard et al., 1993; Santambrogio et al., 1994; Besser and Wank 1999;
Kerschensteiner et al., 1999). There is evidence showing that various
neurotrophins exert neuroprotective effects after axotomy (Sawai et
al., 1996). If, however, the effect is indeed exerted via trophic
factors, the therapeutic administration of T-cells would have an
advantage over the administration of any single factor, because the
T-cells are capable of producing a repertoire of factors whose
production can be regulated by signals emanating from the damaged tissue.
In summary, vaccination with CNS myelin-associated self-antigens was
shown here to be capable of leading to post-traumatic neuroprotection
in mice and hence to delayed death of RGCs. The therapeutic window of
the vaccination-induced neuroprotection will be determined by the
choice of peptides and the route of administration. On the basis of
these results, it seems reasonable to suggest that, if an autoimmune
response to specific antigens exposed by CNS injury could be
selectively augmented and well regulated, it might be possible to
achieve neuroprotection without the threat of an autoimmune disease
(Schwartz et al., 1999). Immune activity in general, and autoimmune
activity in particular, have been shown to have conflicting effects
depending on the type of the immune cells, the timing, and the tissue
context. Thus, for example, autoimmunity may be destructive for myelin
in cases in which the axons are intact (Sriram et al., 1989), whereas
in traumatized axons, well-controlled autoimmunity, as shown here and
in previous studies from our laboratory (Moalem et al., 1999b; Hauben
et al., 2000b), is beneficial. Vaccination with myelin-associated
peptides around the time of CNS axonal damage may thus be viewed as a
way of boosting a beneficial physiological response, which is awakened after injury. These findings have promising clinical implications for
the development of a vaccination against optic nerve neuropathies such
as glaucoma, a disease of the optic nerve in which degeneration starts
at the nerve fibers and ends with the death of the RGCs (Jonas and
Budde, 2000). In many cases of optic neuropathy, degeneration continues
to progress even after removal of the primary risk factor(s), and the
end result is RGC death (Yoles and Schwartz, 1998). Neuroprotection might therefore serve as a complementary treatment for optic nerve neuropathies in general and for glaucoma in particular (Schwartz et
al., 1996).
| |
FOOTNOTES |
Received March 10, 2000; revised Sept. 5, 2000; accepted Oct. 17, 2000.
This work was supported in part by a Glaucoma Research Foundation grant
awarded to M.S. A.B.-N. is the incumbent of the Eugene and Marcia
Appelbaum Professorial Chair. M.S. holds the Maurice and Ilse Katz
Professorial Chair in Neuroimmunology. We thank S. Smith for editorial
assistance and A. Shapira for animal assistance.
Correspondence should be addressed to Dr. Michal Schwartz, Department
of Neurobiology, The Weizmann Institute of Science, 76100 Rehovot,
Israel. E-mail: bnschwartz{at}wiccmail.weizmann.ac.il.
| |
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