Blood, Vol. 94 No. 8 (October 15), 1999:
pp. 2915-2922
Viral Hyperinfection of the Central Nervous System and High
Mortality After Hematopoietic Stem Cell Transplantation for
Treatment of Theiler's Murine Encephalomyelitis Virus-Induced
Demyelinating Disease
By
Richard K. Burt,
Josette Padilla,
Mauro C. Dal Canto, and
Stephen
D. Miller
From the Department of Medicine, the Department of
Microbiology-Immunology and Interdepartmental Immunobiology Center, the
Department of Pathology, and Robert H. Lurie Cancer Center,
Northwestern University Medical School, Chicago, IL.
 |
ABSTRACT |
Theiler's murine encephalomyelitis virus (TMEV) establishes a
persistent infection in the central nervous system (CNS) leading to an
inflammatory demyelinating disease of the CNS in which the histology
and clinical course is similar to multiple sclerosis (MS). Disease
pathogenesis is primarily due to T-cell-mediated destruction of
myelin, which has been attributed to cytopathic effects of the virus,
but immune-mediated destruction of myelin mediated via both
virus-specific and myelin-specific T cells appear to play the major
role. To determine if bone marrow transplantation would be an effective
therapy for a virus-initiated autoimmune disease and to better separate
viral cytopathic effects from immune-mediated demyelination, we ablated
the immune system of TMEV-infected animals with 1,100 cGy total body
irradiation, and then the animal's immunity was reconstituted by
transplantation of disease-susceptible SJL/J mice with syngeneic marrow
or disease-susceptible DBA/2J with marrow from disease-resistant
(C57Bl/6 × DBA/2)F1 (B6D2) donors. Hematopoietic transplant performed
after onset of disease resulted in 42% mortality in SJL/J syngeneic
transplants, 47% mortality in diseased DBA2 recipients restored with
marrow from naive B6D2 donors, and 12% in diseased DBA2 recipients
receiving marrow from B6D2 donors previously infected with TMEV.
Delayed type hypersensitivity (DTH) to both virion and myelin proteins
was decreased in surviving mice that underwent transplantation;
however, CNS viral titers were significantly elevated compared with
nontransplanted controls. We conclude that a functional immune system
with appropriate T-cell responses are important in prevention of lethal
cytopathic CNS effects from TMEV. Relevant to the clinical use of bone
marrow transplantation, attempts to ablate the immune system in
viral-mediated immune diseases or virus-initiated autoimmune disease
may have acute and lethal consequences. Our results raise concern about the attempted use of autologous hematopoietic transplantation in
patients with MS, an autoimmune disease with a suspected virus etiology, particularly if the graft is aggressively
depleted of lymphocytes.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THEILER'S MURINE encephalomyelitis virus
(TMEV) is a naturally occurring enteric murine
picornavirus.1 Infection of susceptible mouse strains leads
to a biphasic disease that is first manifest as an acute gray matter
inflammation followed by chronic, immune-mediated white matter
demyelination of the central nervous system (CNS) that serves as a
model for multiple sclerosis (MS).2 Virus persists within
the CNS throughout a susceptible host's life.3 Target
cells for early infection are neural, glial, and endothelial cells,
whereas cells harboring virus during chronic demyelination are
predominately CNS macrophages and, to a lesser extent,
oligodendrocytes.4,5 The neurologic consequences of TMEV
arise from early acute viral cytopathic effects on gray matter neurons
that evolve into chronic immune T-cell-mediated demyelination of CNS
white matter.6,7 The immune system's role in preventing
acute disease is supported by the effective clearance of TMEV from the
CNS of disease-resistant murine strains and abrogation of this
resistance by either immunosuppressive total body irradiation (TBI) or
infection of athymic mice that would otherwise be
disease-resistant.8-10 The immune system's role in causing
chronic disease is documented by prevention of demyelination in
disease-susceptible strains of mice after treatment with
immunosuppressive agents such as cyclophosphamide, antithymocyte globulin, irradiation, or anti-major histocompatibility complex (MHC) class II or anti-CD4 monoclonal antibody
therapy.7,11-14
After infection of SJL mice with the BeAn 8386 strain of TMEV,
demyelination is initiated by CD4+ T cells specific for
virus epitopes that arise within 7 to 10 days postinfection and target
CNS-persistent virus leading to macrophage-mediated bystander
destruction of myelin.7,15,16 Approximately 4 weeks after
onset of clinical disease, T-cell responses to myelin epitopes arise in
an ordered temporal progression17 consistent with a role
for both virus- and myelin-specific responses in the chronic phase of
disease. The latter appearance of myelin-specific responses and the
lack of cross-reactivity between TMEV and myelin epitopes indicate that
CNS autoimmunity arises by epitope spreading and is not due to shared
virus and myelin epitopes.17-19
Hematopoietic stem cell transplantation has been proposed as a therapy
for immune-mediated disorders such as multiple
sclerosis.20,21 Because inflammatory cells such as
autoreactive lymphocytes and activated macrophages arise from the
hematopoietic progenitor stem cell compartment, the rationale is to
ablate the immune system, followed by immune reconstitution with
hematopoietic stem cells from an unaffected animal in the hopes of
ablating autoreactive lymphocytes and re-establishing tolerance to
self-epitopes. The efficacy of this is supported by experiments
demonstrating that either syngeneic or allogeneic hematopoietic stem
cell transplantation from an unaffected animal is capable of
preventing, ameliorating, and/or curing experimental autoimmune
encephalomyelitis (EAE), another autoimmune animal model of
MS.22-26 Recent short-term outcome studies on limited
numbers of patients with MS suggest that immune ablation and
hematopoietic stem cell reconstitution with autologous hematopoietic
stem cells may prevent progression of and in some cases improve the
pathogenesis of MS.22,23
Because the histology and clinical course of TMEV are similar to human
MS and because epidemiological studies suggest MS may be initiated
and/or exacerbated by virus infections,27 we evaluated the
outcome of hematopoietic stem cell transplantation in TMEV-induced demyelinating disease. The results demonstrate that stem cell transplantation of mice with ongoing TMEV-induced demyelinating disease
results in a high incidence of mortality concomitant with a significant
elevation of CNS virus titers. Thus, attempts to ablate the immune
system in viral-mediated immune diseases or virus-initiated autoimmune
diseases associated with persistent infection may have acute and lethal consequences.
| |
MATERIALS AND METHODS |
Animals.
Six-week-old female SJL mice were obtained from Harlan Laboratories
(Madison, WI). DBA/2J and B6D2 F1 mice were obtained from Jackson
Laboratories (Bar Harbor, ME). Animals were maintained on standard
mouse chow and water ad libitum in a containment animal facility.
Neomycin sulfate (0.7 mmol/L), tetracycline (0.1 mmol/L), and
trimethoprim/sulfamethoxazole (0.4 mmol/L) were added in the drinking
water for 2 weeks after bone marrow transplantation (BMT) to prevent infections.
Induction of TMEV-induced demyelinating disease.
BeAn 8386 virus was plaque purified and amplified in BHK-21
cells. A working stock was prepared by passage in BHK-21 cells. Female
mice were anesthetized with methoxyflurane and intracerebrally inoculated in the right cerebral hemisphere with approximately 2.9 × 106 PFU of BeAn virus in 30 µL. All animals were
examined several times per week for the first 4 weeks and at least once
weekly thereafter. Sham-infected control animals received 30 µL
Dulbecco's modified Eagle's medium (DMEM).
Treatment.
By definition, day 0 was the day of intracerebral inoculation. At 2 time points after infection (day between days 70 and 90), mice were
divided into control and treatment groups. Control mice received no
further therapy. The treatment groups underwent myeloablation and
marrow rescue from same-sex animals using 107 nucleated
bone marrow cells from either (1) syngeneic disease-susceptible naive
mice, (2) allogeneic naive but disease-resistant B6D2 mice, or (3)
allogeneic healthy disease-resistant B6D2 mice previously inoculated
with TMEV. Myeloablation consisted of TBI at a dose of 1,100 cGy in 2 fractions of 550 cGy administered 6 hours apart 1 day before marrow infusion.
Clinical evaluation.
TMEV was scored clinically according to neurologic deficit using the
following numerical scores: 0, asymptomatic; 1, mild waddling gait; 2, more severe waddling gait, righting reflexes normal to mildly impaired,
able to right itself in under 3 seconds; 3, spastic paralysis, righting
reflexes severely impaired, unable to right itself in under 3 seconds;
4, dehydration; 5, total hind limb paralysis, dehydration,
malnutrition; and 6, death. All clinical scoring was performed by the
same observer.
Histology.
Ten to 12 1-µm-thick, Epon-embedded sections stained with toluidine
blue were examined from each spinal cord and scored as follows:
+/
, mild inflammation without demyelination; +, inflammation with focal demyelination; ++, inflammation with multiple foci of
demyelination; and +++, marked inflammation with bilateral, converging
areas of demyelination. Glial scarring was characterized according to
the majority of sections involved as follows: absent, mild (focal glial
bands in the margin of the cord); moderate (gliosis extending to at
least 50% of the thickness of the anterior and/or lateral columns); or
severe (glial scarring covering the entire thickness of the anterior
column). Mice selected for histologic examination had clinical
scores that represented the average for their group. The
neuropathologist performing histologic scoring was blinded to animal
treatment and clinical score.
Delayed type hypersensitivity (DTH).
Virion peptide-specific (VP1 233-250, VP2 70-86, and VP3 24-37) and
myelin epitope-specific (PLP 139-151) DTH responses were quantitated
using a 24-hour in vivo ear swelling assay. Three mice from each group
were challenged with 5 µg of the indicated VP or 10 µg of
proteolipid protein (PLP) peptide in 0.01 mL saline. Twenty-four hours
after challenge, the increase in ear swelling was quantitated with an
engineer's micrometer (Mitutoyo Model 7326; Schlesinger Tools,
Brooklyn, NY). Results were corrected for prechallenge ear thickness.
CNS cytokine analysis.
Analysis of cytokine mRNA levels in the CNS was performed by
homogenizing phosphate-buffered saline (PBS) perfused
spinal cord from 3 mice in each group in guanidium isothiocyanate and isolating total RNA by CsCl gradient. First-strand cDNA synthesis was
performed using 2 µL (0.5 µg/µL) of RNA in 10.5 µL
of diethyl pyrocarbonate (DEPC)-treated water, 1 µL of oligo-(dT)
primer, and 6.5 µL of a master mix (4 µL of 5× reaction
buffer, 1 µL of dNTP mix [10 mmol/L each], 0.5 µL RNAse
inhibitor, and 1.0 µL of Moloney murine leukemia virus
[M-MLV] reverse transcriptase). Polymerase chain
reaction (PCR) primers for interferon-
(IFN-), interleukin-10
(IL-10), and tumor necrosis factor-
(TNF-) encompass 234, 324, and 240 bp of wild-type cDNA, respectively. First-strand cDNA was
amplified 35 cycles (Perkin Elmer Thermocycler; Perkin Elmer, Norwalk, CT).
Virus plaque assays.
Standard plaque assays (previously described28) were
performed for quantification of virus titers in the spinal cord, brain, and spleen. Organs from 3 mice per group were homogenized with a Virtis
tissue homogenizer (Virtisher-Gardiner, New York, NY) into a 10%
solution and the homogenate was layered over BHK-21 cells. After 96 hours of incubation, live cells were stained using a 0.015% neutral
red. Plates were incubated for 4 hours and plaques were enumerated.
Statistical analyses.
Student's t-tests were used to determine the statistical
significance of clinical scores, DTH, and virus titers between
experimental groups.
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RESULTS |
Syngeneic transplantation of TMEV-susceptible SJL mice.
Syngeneic hematopoietic stem cell transplantation was performed on 2 separate groups of SJL mice with established TMEV-induced demyelinating
disease at days 70 and 92 postinfection. Thirteen of 31 (42%) of these
mice transplanted 70 days postinfection died within 2 weeks
posttransplantation (Fig 1A).
Interestingly, the mortality rate for SJL mice with TMEV-induced
demyelinating disease was significantly greater than we have noted in
similar transplants of SJL mice with established relapsing EAE, in
which a mortality rate of less than 6% was observed in well over 100 mice transplanted at varying times during ongoing
disease.26 There was no significant difference in median
neurologic deficit in surviving transplanted animals compared with
nontransplanted animals (P = .3858) as neurologic deterioration
continued in both the transplanted and control groups (Fig 1B). Despite
the progression of clinical disease, the myeloablation was apparently
successful, because DTH responses to both virus epitopes (VP2 70-86 and
VP3 24-37) and to the immunodominant epitope on proteolipid protein
(PLP 139-151) were abrogated in transplanted mice assayed approximately
30 to 40 days postreconstitution (Fig 2).
Evaluation of the CNS for Th1-associated (IFN- and TNF-) or
Th2-associated (IL-10) cytokine mRNA levels using a semiquantitative PCR analysis showed no significant differences between transplanted and
nontransplanted mice assayed approximately 40 days postreconstitution (Fig 3).
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| Fig 1.
Syngeneic BMT using naive SJL donor marrow for SJL/J
disease-susceptible TMEV-infected recipients. (A) Survival curve. (B)
Mean clinical score. Ir = 1,100 cGy TBI.
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| Fig 2.
DTH responses to viral-specific (VP1 233-250, VP2 70-86, and VP3 24-37) and myelin-specific (PLP 139-151) epitopes in SJL/J mice
inoculated with TMEV. The horizontal line indicates average response in
3 normal noninfected animals. DTH assays were performed on day 132. PLP, proteolipid protein; VP, viral peptide.
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| Fig 3.
Cytokine RNA levels by PCR. Rows 1, 2, and 3 are IFN-;
rows 4, 5, and 6 are TNF- ; and rows 7, 8, and 9 are IL-10. Naive
controls never inoculated with TMEV are rows 3, 6, and 9. TMEV diseased
but untransplanted animals are rows 1, 4, and 7. Mice with TMEV treated
by transplantation are rows 2, 5, and 8. Assays were performed on day
128.
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Interestingly, transplanted animals exhibited significantly higher
titers of infectious TMEV within the spinal cord than did untreated
controls (Fig 4). In transplanted mice,
approximately 4-fold more infectious virus was present in the spinal
cords than in the nontransplanted mice (12.6 × 103
PFU/mg v 3.1 × 103 PFU/mg, P = .004).
No viral plaques were found in the brain or spleen of either
TMEV-infected group or in any tissues in the uninfected controls.
Histologic examination of the spinal cords showed an acute inflammatory
infiltrate with less glial scarring in transplanted mice versus a
prominent chronic demyelination and gliosis with minimal residual
infiltration in nontransplanted mice (Fig
5).
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| Fig 4.
Viral titer within the spinal cord of animals infected
with TMEV. Naive mice were never inoculated with TMEV. Control mice
were inoculated with TMEV but had no further treatment. Ir/BMT,
treatment with TBI and BMT from uninfected healthy syngeneic animals.
Assays were performed on day 128. These results are representative of 2 assays.
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| Fig 5.
(A) Histology of SJL/J spinal cords from mice infected
with TMEV. Section of spinal cord of an SJL/J mouse, 130 days after
infection with TMEV. The right anterior column is completely
demyelinated and numerous large lipid-laden macrophages are present
close to the central sulcus. The gray uniform background reflects
conspicuous gliosis in the demyelinated area (1-µm-thick,
Epon-embedded section, stained with toluidine blue; original
magnification × 220). (B) Section from spinal cord of an SJL/J mouse
130 days after infection with TMEV and after treatment with radiation
and BMT. Inflammatory cells are still around the large venule in the
parenchyma of the left anterior column, indicating active disease, but
many axons are still surrounded by myelin sheaths and gliosis is less
prominent (1-µm-thick, Epon-embedded section, stained with toluidine
blue; original magnification × 220).
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Allogeneic transplantation using TMEV-resistant donors.
To determine if the efficacy of the transplantation may be increased by
using marrow from disease-resistant donors, disease-susceptible DBA/2J
mice were treated with TBI and infused with marrow from either naive or
TMEV-infected disease-resistant B6D2 mice. At day 20 postinfection,
before the onset of clinical disease, susceptible DBA/2J mice were
treated with TBI and infused with marrow from either naive or TMEV
infected disease-resistant B6D2 mice (Fig 6). Control mice developed chronic progressive disease with no mortality (0/9). There was 50% mortality (5/10) in DBA/2J mice transplanted with bone marrow from naive disease-resistant B6D2 mice
and 20% mortality (2/10) in DBA/2J mice receiving allogeneic marrow
from B6D2 donors that had previously been infected with TMEV. Mortality
was secondary to progressive neurologic disability, with most animals
dying between 60 and 90 days posttransplant. In a second experiment
(data not shown) performed after disease onset (day 94 postinfection),
DBA/2 mice transplanted with allogeneic marrow from naive
disease-resistant B6D2 donors had a 43% mortality (3/7), whereas only
1 of 14 (7%) mice transplanted with marrow from a TMEV-infected B6D2
donor died. Therefore, the combined mortality from 2 different
experiments was 8 of 17 (47%) for recipients of naive B6D2 marrow and
3 of 24 (12%; P = .029) for recipients of marrow from
TMEV-infected, but healthy, B6D2 donors.
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| Fig 6.
Allogeneic BMT using naive or TMEV-infected B6D2
disease-resistant donor marrow for DBA/2J disease-susceptible
recipients inoculated with TMEV. (A) Percentage of animals surviving.
(B) Neurologic score of surviving mice.
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| |
DISCUSSION |
Resistance and susceptibility to demyelination after TMEV infection are
both immune-mediated processes. Susceptibility/resistance to
TMEV-induced demyelinating disease is controlled by multiple loci,
including Tmevd-1 on chromosome 6 near the genes encoding the 
chain
of the T-cell receptor29; Tmevd-2 on chromosome 3 near the
Car-2 locus30; and the MHC class I H-2D region on chromosome 17.31-34 Disease susceptibility correlates with
development of strong virus-specific Th1 responses, as exemplified by
expression of DTH reactivity31,35,36 and predominant
production of Th1-derived cytokines37 and IgG2a-predominant
antivirus antibody responses.38 Disease-susceptible mice
also display a lifelong persistent CNS virus infection.3 In
contrast, disease resistance is associated with clearance of virus from
the CNS within 2 to 3 weeks postinfection36,39 and
development of only low levels of virus-specific DTH.36 Recent evidence indicates that virus clearance is largely mediated by
an abundant MHC class I-restricted CD8+ CTL response
arising within the first 10 days postinfection.40 Studies
have shown that depletion of CD8+ T cells can confer
susceptibility to some otherwise resistant inbred
strains.41
In disease-susceptible strains, TMEV-induced demyelinating disease is a
2-stage process. Infection with the DA strain of TMEV leads to early
inflammatory infiltration within the CNS gray matter that leads to a
limited amount of neuronal necrosis that is consistent with lytic
infection of neurons in cell culture.42 The gray matter
inflammation is cleared within 2 weeks postinfection and is replaced by
mononuclear inflammation and demyelination of white matter. Use of the
BeAn strain of TMEV that was employed in these studies obviates much of
the gray matter pathology. Relatively weak CTL responses in susceptible
strains40 result in the inability to clear virus from the
CNS and lead to establishment of persistent infection.3
White matter damage is initiated by virus-specific CD4+ T
cells that lead to macrophage-mediated bystander destruction of
myelin.7,15,16 Myelin-specific T-cell responses do not play
a role in disease initiation as responses to immunodominant epitopes on
MBP and PLP are not detected before disease onset,17,18 and
peripheral tolerance to myelin components before virus infection fails
to affect the course of demyelination.16 However, chronic disease is associated with the development of T-cell responses to
multiple myelin epitopes that arise via epitope
spreading.17 Taken together with the fact that
TMEV-specific T-cell responses persist throughout the disease course in
susceptible SJL mice,35 the data are consistent with a role
for both anti-virus-specific and anti-myelin-specific T-cell
responses in chronic disease.
Because MS27 and perhaps other T-cell-mediated autoimmune
diseases may be initiated as a secondary consequence to a virus infection, we have attempted to use hematopoietic stem cell
transplantation as a tool to separate the overlapping roles of direct
virus cytopathology, virus-specific immunity, and myelin
epitope-specific autoimmunity in TMEV-induced demyelinating disease.
The results clearly show that transplantation of syngeneic marrow from
naive TMEV-susceptible donors to diseased SJL/J recipients resulted in
40% mortality within 10 to 15 days after transplantation (Fig 1).
Although the deaths may have been due to radiation induced CNS injury,
the mortality rate was significantly higher than that of SJL mice undergoing BMT for the treatment of relapsing EAE, a purely autoimmune inflammatory demyelinating disease, in which we and others have historically observed an approximate 6.0% mortality
rate.22-26
Surviving mice displayed significantly diminished immune DTH responses
to both virus and myelin epitopes, indicating the effectiveness of the
myeloablative therapy (Fig 2). The acute neurologic deterioration correlated with an increased CNS viral load (Fig 4). Histologic evaluation (Fig 5) showed a predominance of acute gray matter inflammation in transplanted mice compared with predominant white matter demyelination in untreated animals. The slightly exacerbated clinical disease course, increased CNS virus levels, and pattern of
histology are consistent with an exacerbation of direct viral cytopathology, not immune-mediated CNS damage. This finding is similar
to that previously reported by Lipton and Dal Canto,11 who
showed that high-dose cyclophosphamide or antithymocyte serum administered shortly after virus infection prevented TMEV-induced immune-mediated demyelination, but resulted in a mortality rate of 77%
to 88%. Thus, severe immunosuppression of TMEV-infected animals is
capable of causing fatal neurologic consequences that were also likely
due to uncontrolled virus growth.
To reconstitute viral immunity more rapidly, we attempted allogeneic
transplantation of marrow from naive disease-resistant B6D2 mice into
diseased DBA/2J mice. This resulted in an equally high early mortality
of 50%, although death was delayed to 60 to 70 days posttransplant.
Therefore, we attempted allogeneic transplantation using
disease-resistant but previously inoculated B6D2 donors rather than
naive B6D2 donors. This resulted in a mortality rate (20%) that was
substantially lower than that of mice receiving bone marrow from naive
allogeneic or syngeneic donors. Lower mortality may have been due to
adoptive transfer of viral-specific cytotoxic lymphocytes infused with
the donor marrow.43 Because mouse bone marrow contains
relatively few lymphocytes, adoptive transfer of both splenocytes and
marrow from previously infected disease-resistant mice may prevent or further decrease exacerbation of viral cytopathic effects after transplantation.
BMT is currently being investigated in clinical trials as therapy for
human autoimmune diseases. Whereas the experimental results in
autoimmune disorders such as EAE indicate amelioration or cure after
transplantation, the current results in TMEV-induced demyelinating
disease suggest that this therapy may be dangerous in virus-associated
autoimmune diseases. Transplantation did improve the autoimmune
component of TMEV by decreasing immune responses to viral and PLP
peptides. However, nonspecific attempts to suppress this
virus-initiated autoimmune process also suppress viral immunity and can
apparently result in lethal consequences.
Further advances in transplant of viral-associated autoimmune diseases
should recognize the importance of controlling viral cytotoxicity after
transplantation with either peritransplant antiviral drugs and/or
virus-specific adoptive immunotherapy at the time of graft infusion.
This is particularly true in MS, in which an infectious etiology is
strongly suspected based on a variety of observations, including
epidemiological data,44-49 abnormal humoral and/or cellular
responses to viruses,50-55 isolation of virus or presence
of viral proteins within CNS plaques,56-58 and animal
models of virus-initiated, inflammatory CNS demyelinating diseases that
mimic MS clinically and histologically.1,2 The rationale
for treating MS by hematopoietic stem cell transplantation is based on
the unproven assumption that MS is an autoimmune disease targeting
myelin proteins and that the procedure will ablate activated autoreactive T cells and also lead to the re-establishment of self-tolerance to myelin epitopes. This theory is supported by cure or
amelioration of disease after transplantation of autoimmune diseases
such as EAE,22-26 collagen-induced arthritis,59
and adjuvant arthritis,60 which are induced by active
immunization with self-proteins/peptides in adjuvant. However, the
current data clearly show that stem cell transplantation of an
autoimmune-like disease initiated by infection with TMEV, a natural
mouse pathogen, although dampening autoimmune responses, also inhibits
antiviral responses, resulting in virus reactivation and significant mortality.
It should be pointed out that TMEV-induced demyelinating disease may be
an exception, because the virus establishes a lifelong persistent CNS
infection. Hematopoietic stem cell transplantation may be perfectly
appropriate for treating virus-induced autoimmune diseases in which the
initial virus infection has been cleared, thus alleviating the danger
of virus reactivation. Current results from transplantation of MS
patients have not shown undue mortality,1,2,6 perhaps
suggesting that the disease etiology is diverse, with only a subset
being virally mediated, or that a potential virus infection may have
already been cleared or is relatively noncytopathic. However, given the
limited number of patients transplanted to date, the potential for
virus reactivation is a real concern and may depend on the level of
immunosuppression of the recipient and/or the degree of lymphocyte
depletion of the graft.
| |
FOOTNOTES |
Submitted November 4, 1998; accepted June 6, 1999.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Richard K. Burt, MD, Department of
Medicine, Northwestern University Medical School, 250 E Superior St,
Room 1456, Wesley Pavilion, Chicago, IL 60611.
| |
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TOP
ABSTRACT
INTRODUCTION
