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Autoimmune inflammation of astrocyte transplants.

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Autoimmune Inflammation
of Astrocyte Transplants
Fred D. Lublin, MD," Joseph C. Marini, BA,' Marielle Perreault, BS," Christina Olender, BS,'
Concetta DImperio, BS,* Jeymohan Joseph, PhD," Robert Korngold, PhD,t
and Robert L. Knobler, MD, PhD*
--. -..
Astrocytes have been shown to be capable of serving as antigen-presenting cells and as targets for encephalitogenic
cytotoxic T lymphocytes. The role of astrocytes in central nervous system (CNS) autoimmune inflammation is unclear.
To study this further, we transplanted astrocyte aggregates into the anterior eye chamber of the mouse. The astrocytii
nature of these transplants was confirmed by immunohistochemical detection of glial fibrillary acidic protein and the
inability to detect oligodendrocyte or microglial markers. When mice bearing transplants were induced to develop
experimental allergic encephalomyelitis by either passive or active protocols, the astrocyte transplants developed a
perivascular inflammatory response similar to that seen in the host CNS during the course of the encephalomyelitis.
The data suggest that astrocytes could serve as targets for the autoimmune attack of experimental allergic encephalomyelitis and support the possibility that the pathogenesis of this disease may involve an autoimmune reaction against
a site other than the myelin sheath.
Lublin FD, Marini JC, Perreault M, Olender C, DImperio C, Joseph J, Korngold R, Knobler KL.
Autoimmune inflammation of astrocyte transplants. Ann Neurol 1992;31:519-524
The site of antigen recognition and presentation within
the central nervous system (CNS) during the course
of the autoimmune inflammatory disease experimental
allergic encephalomyelitis (EAE) has not been clearly
identified. This disease can be produced by autoimmunization with myelin proteins and their peptides [ 1-31.
However, these antigens are not necessarily expressed
in locations that allow an interface with immune effectors. For example, myelin basic protein (MBP), the
most encephalitogenic of the myelin proteins, is normally localized to an internal site on the cytoplasmic
surface of the myelin membrane and not expressed
on the surface of the myelin sheath [4}. The actual
mechanism of tissue damage in EAE has not been conclusively determined. Although there is convincing evidence that this disease is mediated by specific populations of T lymphocytes [3, 5-71, it is not yet
understood how these cells produce dysfunction within
the CNS. Some have suggested that the disease is produced by CNS-specific cytotoxic cells that directly attack myelin [ S ] , while others have implicated damage
of the CNS vasculature [c)], recruitment of macrophages [lo], or local edema formation [ l I] as important factors. In contrast, it has been proposed that the
disease results from the proximity of neural tissue
ro lymphokines and other factors secreted during a
From the Division of Neuroimmunology, Departments of *Neurology and of ;Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA.
delayed-type hypersensitivity response (a bystander response) [11-13}. In support of this argument is a study
on chimeric animals suggesting that the tissues of the
CNS need not be syngeneic with the sensitized lyinphocytes that mediate disease [ 141. This latter study
raises the possibility that the site of attack within the
CNS in EAE may be directed against a component
other than the myelin sheath.
Astrocytes can serve as antigen-presenting cells
C15-17) and as targets for immune responses (18, 19j.
Sun and Wekerle showed that an Ia antigen-restricted
encephalitogenic T-lymphocyte cell line capable of mediating EAE is also able to mount a cytotoxic response
against MBP-presenting astrocytes [ 191. This observation suggests that an interaction between sensitized
lymphocytes and astrocytes may be involved in the
pathogenesis of EAE.
In previous studies we demonstrated that brain cissue transplanted into the anterior eye chamber can dcvelop the pathological signs of EAE following imriiunlzation of the transplant recipient C20, 21). In order to
determine the role of isolated components of the CNS
in inflammatory conditions, we transplanted aggregates
of cultured mouse astrocytes into the anterior chamber
of the eye, using a modification of our protocol for
transplanting brain tissue into the eye 12 1). The trans7 '
__ _-
___ -
Address correspondence to D r Lublin, Division of Neurulrninunuogy, Depdrtment of Neurology, Thomas Jefferson University, Philadelphia, PA 19107-5083
Received AUK5 , 1991, and in revised form Sep 0. Accepted for
publication 6 c t 13, 1991.
Copyright 0 1992 by the American Neurological Association 5 19
plantation paradigm allows us to treat cells u n d e r conditions that simulate both t h e simplicity of in vitro tissue culture conditions and the complexity of t h e in
vivo milieu. Thus, w e can investigate t h e responses of
a purified population of cells in t h e environmenr of a
living organism.
Materials and Methods
M iii.
SJLiJ mice were obtained from the Jackson Laboratory (Bar
Harbor, ME) and utilized when 4 to 6 weeks old. They were
housed in micro-isolator cages and fed ad libitum.
Brain tissue from mouse embryos at gestational day 1I was
mechanically dissociated through a Nitex 2 10-Fm mesh bag
(Tetko, Elmsforci, N Y j into Dulbecco's modified Eatgle'sHam's F I2 media (lrvine Scientific,) containing antihiotics
and 100; heat-inactivareJ fetal calf serum. The cell suspension was centrifuged at 800 rpm for 5 minutes. The pellet
was resuspended i n the same medium, counted, checked for
viability bv trypan blue dye exclusion, and plated at a concentration of 2 x 10' cells/cm' of culture vessel. The culture
flasks were incubated at 37'C in a 5c4 carbon dioxide--W%
air atmosphere. The flasks were checked every 3 to Cs days
for confluence. When confluent, the cells were hanested
acid (EDTA) and
using trypsin-ethylenedia~~inetetr~cetic
passaged at a dilution of 1 : 2. The cultures were enriched for
astrorytes b y serial subculturing. Astrocytic homogeneity was
assessed by markers l o r glial fibrillary acidic protein (GFAP)
1221. Contamination by oligodendrocytes and microglia was
assessed by indicators of 2',3'-cyclic nucleotide-3-phosphohydrolase ( C N P j 123, 2'rI and MAC-1 [ 2 5 ] , respecrively.
Astmc yte AgKreKdtzon
Four inilliliters o f medium containing 2 3 x 10" viable cells
was inoculated into A 25-ml Erlenmeyer screw-cap flask and
Incubated ,it V " C in ,I rotatory shaker water bath, constantly
rotating 'it 7 0 rpm, following the method of Lu and colle'tgucs ( 2 0 ) After 5 to 7 davs, dggregates of cells that were
1 to 2 mm i n size were harvtsted These astrocyre aggrcgates
were then tran\planted into the anterior eye chamber T h e
aggregates were alloxveci to develop in olzdo for 4 to 6 Reeks
The .imoi) tic iinture of the ,iggregates was confirmed before
and after transplantation by the detection of GFAP and the
inability t o tietect CNP .inti MAC-1 [23-251
Adult male and female SJL mice were used as hosts for transplanted tissue. Mice were anesthetized during the transplant
procedure. With a small pipette. the astrocyte transplants
were inserted into the anterior cye chamber, through an incision in the cornea, utilizing the same procedure we described
for transplants of whole CNS tissue C2 1). Transplants matured for ,'1 to 6 weeks before mice were immunized. IYJ
transplants were examined for vascularization and viatiility,
anti were measurctl ic)r growth every 2 weeks with the .iiJ
of ,i dissecting microscope.
Vol 31
Mice were immunized with either muuse spinal cord homogenate (MSCH) ( 5 mg) or porcine MBP (0.4 mg) emulsified in
complete Freund's adjuvant (CFA) with atldeii Mycobat-rerinm
tuberczdosis H37Ra (Mtb) (0.2 mg), in a volume of 0.05 ml
in each hind footpad. Pertussis vaccine (Commonwealth of
Massachusetts Department of Public Health, Division of Biologic Laboratories) (2.7 X 10" organisms) was injected inrravenously into a tail vein on the day of immunization and 48
hours later. A control group of mice was immunized in a:
similar fashion with an emulsion containing CFA, saline solution, Mtb, and intravenous pertussis vaccine.
Adoptive Transfer Protocol
Trchniqne of Astroqtr Czrltuw
520 A n m i \ of Neurology
Induction of Acute Experimental Allergi
No 5
M q 1992
Donor mice were immunized with either the MSCH-CFA
emulsion, as outlined above for induction of EAE, or the
saline-CFA emulsion, as a control. Nine days after immunization, the mice were killed and draining lymph nodes excised
under sterile conditions [27]. T h e lymph nocics were minced
to produce a single cell suspension, washed, and resuspended
in RPMI tissue culture media. Recipient mice received a total
of 10' cells injected via the tail vein.
Clinicul Assessment
Mice were (observed daily for signs of EAE. An animal was
considered co have a clinical episode of EAE if it developed
paraparesis, hemiparesis, quadriparesis, atrutia, abnormal
righting response, or incontinence.
Histological' Assessment
When mice developed clinical signs of EAE, or within 21
days after active immunization or 11 days after passive transfer, they were deeply anesthetized and perfused with 4 9
paraformaldehyde. Transplants and surrounding ocular tis-sues, brain, and spinal cord were rclmoved from the host
animal. Tissues were postfixed overnight and processed for
embedding in paraffin. Embedded tissue was sectioned using
a microtome and stained with hematoxylin-eosin. Specimens
of host brain and spinal cord were c-onsidered indicative of
EAE if they demonstrated perivascular mononuclear infiltration. Astrocyte transplants were graded for the presence of
perivascular cuffing and mononuclear cell intiltration.
The antibodies were used as indictors for the
immunohistochemical procedures: rat anti-GFAP ( 1 : 1 0 0
dilution, gift of Dr Virginia Lee, University of Pennsylvania), rabbit anti-CNP ( 1 : 2 5 0 dilution, gift of Dr Arthur
McMorris, Wistar Institute), rat anti-MAC:-1, M l / 7 0
( 1 : 1,000 dilution, Boehringer-Mannheim, Indianapolis, IN),
and rabbit anti-MBP ( 1 : 100, gift of D r John Whitaker, University of Alabama, Birmingham). Antibodies were detected
with an indirect immunofluorescence technique. Histological
sections were deparaffinized, incubated for 30 minutes i n 0.1
M phosphate buffered saline solution (PBSj with 5% normal
goat serum, and then incubated overnight in the primary
antibody. After rinsing in PBS, the sections were incubated
for 1 hour with the appropriate secondary antibody gear
anti-rat-rhoclamine. 1 : 100 dilution, or goat anrirabbit-Huo-
rescein isothiocyanate [FITC}, 1: 100 dilution, Accurate Scientific, Westbury, NY). After a final rinse in PBS, sections
were mounted in Hydromount (Polysciences, Warrington,
PA) and examined with a darkfield fluorescence microscope.
Transplants of astrocyte aggregates can be grown in the
anterior chamber of the eye. Figure 1 demonstrates the
histological features of an astrocyte transplant grown in
the eye for 4 weeks. The astrocytic nature of these
transplants was confirmed by the immunohistochemical detection of GFAP [ 2 2 f (Fig 2). W e did not detect
the presence of CNP, an oligodendrocyte marker {23,
a microglial marker C251, in these %gregates, using reagents that readily labeled Positive
control specimens. Also, we did not detect the presence of MBP in the astrocyte aggregates prior to immunization.
The presence of astrocyte transplants in the eye did
not affect the expression of clinical or pathological
signs of EAE in the host, which followed the usual
course for this illness. The results of these experiments
are summarized in the Table.
Astrocyte transplants grafted into mice subsequently
immunized with the saline-CFA emulsion or into unimmunized mice did not show the pathological changes
of EAE (see Fig 1).
In contrast, astrocyte transplants in mice immunized
for EAE using whole C N S (MSCH) showed perivascular cuffing and mononuclear cell infiltrates extending
into the parenchyma (Fig 3 ) , similar to those seen in
the brain of animals with EAE. As shown in the Table,
the incidence of pathological signs of EAE in the
astrocytes was similar to that seen in the host CNS.
In order to better define the antigen responsible for
inducing inflammation in these astrocyte transplants,
we immunized a series of mice with MBP rather than
whole CNS tissue. Mice immunized with MBP did not
develop the clinical signs of EAE, but demonstrated
pathological signs of disease both in the CNS and in
the astrocyte transplants. The incidence of pathological
changes was similar for both the C N S and the astrocyte
To eliminate the possibility that C N S antigens present in the immunizing emulsion were being adsorbed
onto the astrocyte transplants, we employed an adoptive transfer protocol to induce EAE. In these adoptive
transfer experiments, pathological signs of EAE were
observed in the C N S of mice receiving lymph node
cells from MSCH-immunized donors. Inflammatory
changes of EAE were also found in the astrocyte transplants. Control mice, receiving lymphocytes from animals immunized with the saline-CFA emulsion, did not
demonstrate any pathological changes in the C N S or
astrocyte transplants.
The nature of the inflammatory response in both the
Fig 1. Photomicrograph of an astrocyte aggregate in the anterior
chamber of the eye of a mouse that was immunized with a
saline-complete Freund's adjuvant emulsion. The aggregate matured for 4 weeks prior t o immunization. The tissue was obtained on day 21 after immunization. (Parafin-embedded section, hematoxylin-eosin; X 165 before 32% reduction.)
F ig 2 . Photomicrograph of an SJL astrocyte aggregate grown in
the anterior eye chamber of an unimmunized SJL mouse. I t is
labeled for glial jbrillary acidic protein, indicated with Puoresrein isothiocyanate. (Paraffin-embedded section, no counterstain;
x 165 before 32% reduction.)
Incidence of Clinical and Pathological Signs of Actively
Induced and Adoptively Transferred Experimental Allergic
Encephalomyelitis (EAE) in Mice with Astrocyte Transplants
"Tissues from one specimen were unsuirable for pathologid assessment.
bAdoptive transfer of lymph node cells from mice immunized with
CDA = complete Freund's adjuvant; MSCH
homogenare; MBP = myelin basic protein.
mouse spinal cord
Lublin et al: Astrocyte Transplants 521
<INS and the astrocyte transplants, as assessed by the
histological techniques employed in this :;tudy, did not
differ i n the MSCH, MBP, and MSCH-derived adoptive transfer experimental groups. T h e extent of inflammation tended to be greater in the CNS of mice
immunized with MSCH. There was no difference in
t h e degree of infl;unmation seen in the asrrocyte aggregates from the groups of mice immunized with MSCH
or MBP or in the MSCH-derived adoptive transfer
recipient group.
We have been able to grow and maintam transplants
o f astrocyte aggregates in the anterior eye chamber of
the mouse. The astrocytic nature of these transplarits
WAS assessed by the iminunohistocheniicai cietectiori of
astroc-ytic markers and the absence of oligociendrocyte
or microglial markers. When these mice are immunized with an encephalitogenic emulsion, the astrocyte
transplants develop an inflammatory response similar
to that seen in the host CNS during the course of EAE.
There is considerable evidence demonstrating that
astrocytes have inimunoconipetent properties. Astrocytes can cxpress major histocompatibility complex
(MHC) class I1 antigens in response to various cytokines and can serve as antigen-presenting cells 16,
1 7 , 2%--31 1. Astrocytes can secrete immunoreactive
molecules (e.g., interleukin-1, -3, and -6, i:urnor necrosis fa-tor, interferon C Y / @ and comp1emc:nt proteins)
{32-4 1). Sun and Wekerle [ l y ] demonstrated that
astrocyes cultured in vitro may serve as targets for
encephalitc.,genic cytotoxic ?’ lymphocytes. Lymphocvtes from mice immunized with either whole CNS
antigen or MBP show strong proliferative responses
when cultured with astrocytes 142). Two studies reported an increased immunological competence of
astrocytes isolated from EAE-susceptible strains of rats
and mice as compared t o EAE-resistant strains [4:3,
441. T h e actual immunological role of astrocytes in
C.NS inflammation is unclear, but they possess the POtetritial properties to serve both as mediators of am immune response and as targets. Other cells within the
C N S also have potential immunological functions.
most norably the microglia (451.
Studies are underway to determine the types ( I o r
11) of astrocytes present in the grafts. W e also are undertaking studies to determine whether M B P can be
detected on the astrocyte transplants after immunization with M B P and after the onset of EAE.
T h e inflammatory response detected in our astrocytc
transplants may represent a direct attack o n the astrocgtes themselves. A similar phenomenon was suggested by the in vitro cytotoxic lymphocyte studies (:I$
Sun and Wekerle [ 191. There are several other possible causes for the inflammation observed in these
astrocyte transplants. First, immunization with wholt:
C N S tissue could potentially induce an autoimmunt!
“astrocytitis,” as astrocytes in the CNS tissue emulsion
could act as an immunogen. Pekovic and colleagues
reported development 4,f antiastrocyte a n t i t d i e s in
guinea pigs immunized with whole CNS emulsion butnot in those immunized with M B P [46].This possibility is less likely in that in our experiments, inflamma-.
tion of the astrocyte transplants occurred after immunization with MBP. Second, astrocytes may express an
an.tigen that crossreacts with MBP 142, 471 and thus
respond to both immunization with MBP and piissive
transfer of MBP-reactive lymphocytes. Finally, it is
possible that during the course of EAE i n the host
CNS, M B P o r other CNS-immunoreactive molecules
are released into the circulation and adsorbed by the
astrocytes in the transplant, which could then present
the MBP antigen to circulating anti-MBP lymphocytes.
Any of these possibilities could allow the astrocyte to
serve a pathophysiolo~gical rolc in mediating EAE.
The astrocyte, on reacting with ‘ictivated lymphocytes,
could secrete cytokines (e.g., tumor necrosis factor-alpha) that could lead t o myelin damage as a bystander
reaction 1 1- 1J J. Given the paucity of evidence for
MHC class 11 expression o n oligodendrocytes anci my-elin sheaths [48--51} and the fact that MBP is not expressed on the surface of these structures, a primary
response against one of the immunoreactive cells of
the C N S becomes a reasonable possibility. O u r data
suggest that astrocytes could be a target for the autoim-mime attack o f EAE and supports the possibility that
the pathogenesis of EAE may initially involve an auto-.
immune reaction against a site other than t h c myelin
This work was supported by research grants RG1801 and RG1722
from the National Multiple Sclerosis Society and NS23081,
NSOO961, and NS22145 from the National Institutes of Health.
Presented ar the 114th Annual Meeting of the American Neurological Association, New Orleans, September 25, 1989.
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