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Departments of
* Immunology and
Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands;
Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands;
Department of Pathology, Free University Academic Hospital, Amsterdam, The Netherlands;
¶ Netherlands Brain Bank, Amsterdam, The Netherlands;
|| Department of Veterinary Medicine and Primate Husbandry, German Primate Centre, Göttingen, Germany; and
# Tanox Pharma, Amsterdam, The Netherlands
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The CNS has long been regarded as an immune-privileged site sequestered from the immune system by the blood-brain barrier and the lack of lymphatic vessels, but it is now clear that Ags and cells injected into the brain drain to secondary lymphoid organs (14, 15, 16). Outflow of Ags from the brain occurs by interstitial fluid and cerebrospinal fluid drainage to lymphoid organs via various pathways. Ags in these fluids can drain via the blood to the spleen, can escape along cranial nerves into the nasal lymphatics and drain to the cervical lymph nodes (LN), and can escape along spinal nerves to other LN.
The objective of this study was to determine whether myelin Ag-containing APC are present in the cervical LN of monkeys with EAE or individuals with MS and whether they might be involved in modulation of T cell reactivity. Improved insight into these mechanisms will elucidate tolerance induction vs autoimmunity and facilitate the rational development of immunotherapy of demyelinating disease.
We investigated the possible transfer and presentation of myelin Ags in lymphoid organs during a demyelinating inflammatory process in the CNS in nonhuman primates and in MS. The EAE model in common marmoset monkeys (Callithrix jacchus jacchus) mimics human MS in its clinical presentation and in the radiological, neuropathological, and immunological aspects of its brain white matter lesions (17, 18, 19, 20). The close phylogenetic relationship of marmosets and humans makes EAE in this species a unique experimental system for detailed analysis of MS immunopathogenesis. Moreover, this outbred model has several useful features, including 1) a 100% incidence of disease, which results from presentation of an encephalitogenic peptide by a monomorphic MHC class II molecule (21), 2) primary demyelination occurring after immunization with whole human myelin or with recombinant human myelin oligodendrocyte glycoprotein (rhMOG), 3) intramolecular and intermolecular epitope spreading of the cellular and humoral immune response (21, 22), and 4) the complete disease spectrum being based on the intricate interplay between APC, T cells, macrophages, and plasma cells (19, 23). In parallel to lymphoid organs of marmosets, we investigated cervical LN of rhesus monkeys (Macaca mulatta) with acute EAE induced by myelin oligodendrocyte glycoprotein (MOG) immunization (24) and cervical LN from MS and control patients.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Lymphoid organs and brain were isolated from common marmosets, rhesus monkeys (M. mulatta), and cynomolgus monkeys (Macaca fascicularis) raised at the Biomedical Primate Research Center (Rijswijk, The Netherlands), the German Primate Center (Göttingen, Germany), and Inveresk (Tranent, U.K.), as described previously (21, 24), under conditions approved by the Dutch, German, and British law, respectively, on animal experimentation. All experimental procedures were approved by local Institutional Animal Care and Use Committees. Tissues were obtained from animals that were used for studies designed for other purposes, thus avoiding sacrifice of animals for the purpose of the present study only. EAE was induced in marmoset monkeys by immunization with 20 mg human whole myelin or 0.1 mg rhMOG emulsified in CFA as described (17, 21). Adjuvant control marmosets were immunized with 1 mg OVA (Sigma-Aldrich, St. Louis, MO) in CFA. Emulsions were injected into the dorsal skin at four different sites; two injections were given in both the inguinal and axillary LN regions. EAE was induced in rhesus monkeys by immunization with 0.32 mg rhMOG or 0.1 mg MOG34–56 (human MOG peptide (phMOG)) in CFA as described (24). The MOG/CFA emulsion was injected into the dorsal skin at 10 different spots on the back. Adjuvant control rhesus monkeys were immunized with 3–5 mg bovine type II collagen in CFA as described (25). All myelin Ag-immunized animals were examined daily for clinical symptoms of EAE by a trained observer. Brain inflammation was visualized by magnetic resonance imaging and/or (immuno-)histochemistry as described previously (17, 26). According to these examinations, all animals immunized with myelin Ags had clinically active EAE and inflammatory foci in their brain at the time of necropsy. Deep cervical LN and spleens were isolated from animals sacrificed by an i.v. injection of pentobarbital during deep ketamine sedation. In addition, axillary and inguinal LN, draining the immunization sites, were isolated for comparison. All lymphoid tissues were immediately frozen in liquid nitrogen and stored at -80°C until use.
Human tissues
Human cervical LN (one to five per patient) were taken from two patients with chronic MS and two control patients at autopsy, and were provided by the Netherlands Brain Bank. Control patient S01/216 died of cancer of the urinary tract, whereas control patients S01/228 was diagnosed with hereditary motor and sensory neuropathy type 1. After removal, LN were snap frozen in liquid nitrogen and stored at -80°C until use. From each patient, at least five sections were stained for each marker for quantification.
Histochemistry
Myelin degradation products were detected with oil-red O (ORO), which stains neutral lipids, as previously described (27). Neutral lipids as visualized by ORO are not just a marker for degraded myelin, but are relevant to pathogenesis, because self glycolipids are T cell autoantigens in MS (28). Briefly, cryosections (6 µm) were stained with 0.3% (w/v) ORO (Gurr, London, U.K.) in 60% 2-propanol and counterstained with hematoxylin. Acid phosphatase, a marker of macrophages, was detected in acetone-fixed sections, as previously described (29), using naphtol-AS-BI-phosphate (Sigma-Aldrich) as substrate.
Immunohistochemistry
Immunohistochemistry was performed as described previously (26, 30) with slight modifications. Sections were fixed in 4% paraformaldehyde in PBS (pH 7.4) and treated with 0.02% (v/v) H2O2 in PBS to eliminate endogenous peroxidase activity. Any remaining endogenous peroxidase activity was demonstrated with 4-chloro-1-naphthol (dark blue reaction product; Sigma-Aldrich). Sections were incubated with primary Abs overnight in humidified atmosphere, followed by biotinylated-secondary Abs for half an hour and HRP-conjugated avidin-biotin complex (ABC-HRP; DAKO, Glostrup, Denmark) for 1 h. Labeled cells were stained with either 3-amino-9-ethylcarbazole (red reaction product; Sigma-Aldrich) or diaminobenzidine (brown reaction product; Sigma-Aldrich). Finally, sections were counterstained with hematoxylin and embedded in glycerol-gelatin. Double-labeling of cells was performed, as described previously (30), with alkaline phosphatase-conjugated secondary Abs and a substrate solution containing Fast Blue BB Base (blue reaction product; Sigma-Aldrich).
The primary Abs used for immunohistochemistry were polyclonal rabbit anti-bovine myelin basic protein (MBP; kindly provided by Dr. J. Bajramoviç, Netherlands Organization for Applied Scientific Research (TNO), Prevention and Health, Leiden, The Netherlands), rabbit anti-CD3 (DAKO) and mAbs directed against the encephalitogenic epitope of proteolipid protein (PLP) in SJL/J mice, i.e., PLP139–151 (J1/03; Ref. 31), MHC class II (L243; BD Biosciences, San Diego, CA), and the APC markers CD40 (5D12; Tanox Pharma, Amsterdam, The Netherlands), CD68 (KP-1; DAKO), CD83 (HB15A; Immunotech, Westbrook, ME), CD86 (1G10; kindly provided by Innogenetics, Gent, Belgium), DC-SIGN (AZN-D1; kindly provided by Dr. Y. van Kooyk, University Medical Center St. Radboud, Nijmegen, The Netherlands), and CCR7 (2H4; BD PharMingen, San Diego, CA). Secondary biotinylated Abs were rabbit-anti-mouse Ig (DAKO), donkey-anti-rabbit Ig (Amersham, Buckinghamshire, U.K.), horse-anti-mouse Ig (Vector Laboratories, Burlingame, CA), alkaline-phosphatase conjugated rabbit-anti-mouse Ig, goat-anti-rabbit Ig (both from DAKO), and rabbit-anti-goat Ig (Southern Biotechnology Associates, Birmingham, AL).
Quantitation of stained cells
To calculate the number of ORO-, anti-MBP-, or anti-PLP-stained cells per square millimeter in cervical LN sections, the cells were counted and the area of the sections was determined using a VIDAS-RT image analysis system (Kontron Elektronik/Carl Zeiss, Weesp, The Netherlands). Area measurements were performed using a 2.5-fold magnification objective.
T cell proliferation assays
Proliferation assays with cervical LN cells were performed essentially as previously described (21, 32). Briefly, LN cell suspensions were prepared from aseptically removed cervical LN from sacrificed marmoset and rhesus monkeys with EAE. LN cells were cultured with 10 µg/ml rhMOG or phMOG in HEPES-buffered RPMI 1640 (Life Technologies, Glasgow, U.K.) supplemented with 10% FCS (Flow Laboratories, McLean, VA), 10 mM MEM with nonessential amino acids, 2 mM L-glutamine, 100 U/ml penicillin G, 100 µg/ml streptomycin, and 2 x 10-4 M 2-ME (all from Life Technologies). Marmoset cervical LN cells were restimulated with EBV-transformed autologous B cells and 10 µg/ml rhMOG. Proliferation of marmoset cervical LN cells was tested after one or two rounds of restimulation, whereas proliferation of rhesus cervical LN cells was tested directly after the first round of stimulation. Marmoset and rhesus LN cells (2 x 104 cells/well) were seeded with or without relevant Ag in the presence of EBV-transformed autologous B cells (2 x 104 cells/well) or irradiated spleen cells (2 x 105cells/well), respectively, in 96-well flat-bottom plates (Greiner, Solingen, Germany) for 48 h and subsequently pulsed with 0.5 µCi [3H]thymidine for 18 h. [3H]thymidine incorporation was measured in a matrix 9600 beta-counter (Packard, Meriden, CT).
Statistics
Differences in the number of myelin Ag-containing cells in cervical LN between treatment groups were determined by a two-tailed Mann-Whitney test. The number of stained cells in the axillary and inguinal LN and spleen per visual field was scored using a 10-fold objective in a semiquantitative manner as: -, no positive cells; +/-, 1–5 positive cells; +, 6–20 positive cells; ++, 21–50 positive cells; or +++, >50 positive cells.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To investigate the drainage of myelin degradation products to
secondary lymphoid organs during active inflammation of the CNS, as
well as under normal physiological conditions, brain tissue, different
LN, and spleens were isolated from nonimmunized marmoset and cynomolgus
monkeys, from marmoset and rhesus monkeys immunized to develop EAE, and
from adjuvant control marmoset and rhesus monkeys. According to
clinical, radiological, and (immuno-)histochemical examination, all
myelin Ag-immunized monkeys possessed cellular infiltrates in the CNS
at the time of sacrifice (data not shown). (Immuno-)histochemical
analysis of inflammatory foci in EAE brains showed the presence of
ORO-positive cells (Fig. 1
A),
i.e., cells containing neutral lipids as a result of myelin
degradation, and PLP-containing cells (Fig. 1B), similar to
previous findings in marmoset EAE (17). In this respect,
the neuropathology of marmoset EAE closely mimics the situation in MS,
where abundant ORO-positive cells are also found in active brain
lesions (33, 34). In the EAE lesions, both ORO and PLP
staining were found mainly in the cytoplasm of large cells with a
morphology closely resembling macrophages. Furthermore, EAE lesions
contained numerous cells expressing MHC class II, acid phosphatase,
CD40 (26), and CD83 (data not shown), indicative of the
presence of APC.
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, C and D, respectively). Thus, in marmosets with EAE, myelin Ags are observed not only in the brain, as expected, but also in brain-draining cervical LN.
Myelin Ag load in cervical LN of marmosets and rhesus monkeys
To investigate whether the presence of myelin APC correlates with
the presence of demyelinating CNS disease, the number of ORO-positive
cells in cervical LN of marmosets with EAE induced by human whole
myelin or rhMOG immunization was compared with those found in healthy
control monkeys. A striking difference was found in the number of
ORO-positive cells, which were detected in nine of 10 marmosets with
EAE, but in none of the untreated marmosets (p
< 0.05) (Fig. 2A). Moreover,
a significantly higher number of MBP- and PLP-containing cells was
observed in the cervical LN of marmosets with EAE as compared with
those of the control group (p < 0.05) (Fig. 2, B and C).
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, A and B).
However, ORO-positive cells were not detected in cervical LN of rhesus
EAE and control monkeys. Furthermore, a paucity of myelin Ag-containing
cells was found in cervical LN (n = 10) of normal
cynomolgus monkeys, a species related to rhesus monkeys (data not
shown).
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Myelin-containing cells in cervical LN express APC markers and colocalize with T cells
Most myelin Ag-containing cells in the cervical LN of marmoset and
rhesus monkeys with EAE were detected in the medulla. However, some
myelin Ag-containing cells were found in the subcapsular sinus, the
site where leukocytes enter the LN with the afferent lymph, and in
extrafollicular areas of the cortex, the site where interaction of APC
with T cells occurs (data not shown). Myelin Ags were found mostly in
the cytoplasm of large cells with a morphology resembling macrophages,
similar to the findings in the brain. Indeed, most MBP- and
PLP-positive cells expressed macrophage markers, including the
lysosomal enzyme acid phosphatase (AP, Fig. 4A) and CD68 (Fig. 4B). To determine whether myelin Ag-containing cells in the
cervical LN of monkeys with EAE represented cells with the potential to
present Ags to CD4+ T cells, double-labeling
studies were performed with Abs cross-reactive with marmoset (MHC class
II, CD40, CD83) and rhesus (CD40, CD86, DC-SIGN, CCR7) surface
molecules. Myelin-containing cells displayed features of professional
APC, including expression of the DC markers CD83 (Fig. 4C)
and DC-SIGN (Fig. 4D), that are essential in DC-induced T
cell proliferation (35, 36). Staining for both acid
phosphatase activity and CD83 revealed many double-positive cells in
the cervical LN (data not shown), indicating that macrophage and DC
markers are coexpressed by cells loaded with myelin Ags. The majority
of MBP- and PLP-containing cells in the cervical LN also showed cell
surface expression of MHC class II (Fig. 4E) and of the
costimulatory molecules CD40 (Fig. 4F) and CD86 (not shown).
In addition, myelin Ag-containing cells expressed the chemokine
receptor CCR7 (Fig. 4G) and the receptor for the LN-derived
chemokines CCL19 (MIP-3
or ELC) and CCL21 (6-C-kine or SLC)
driving DC migration (37).
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H). PLP-containing cells were also found in the subcapsular
sinus at the border of the T cell area and occasionally within the T
cell areas of the cervical LN. These results demonstrate that myelin
Ags are present in the cervical LN in cells that have the
characteristics of mature professional APC and that are in direct
contact with T cells. Myelin-specific T cells in cervical LN of marmosets and rhesus monkeys with EAE
To determine whether cervical LN contain myelin-specific T cells
besides myelin Ag-containing APC, cervical LN cells of marmoset and
rhesus monkeys with EAE were tested for MOG-specific proliferative
responses. Because primary cervical LN cells showed low proliferative
responses as expected, proliferation was determined after a primary
stimulation or after one or two rounds of restimulation. Positive
responses (stimulation index >2) were found with cervical LN cells
from three of four marmosets and all rhesus monkeys (Fig. 5), indicating that myelin-specific T
cells are present in these brain-draining LN.
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In addition to the cervical LN, the spleen and the axillary and
inguinal LN of marmoset monkeys were analyzed for the presence of
myelin components to determine whether myelin Ags gain access to other
secondary lymphoid organs (Table I).
ORO-positive cells were detected in none of the spleens of myelin- or
rhMOG-immunized marmosets, nor in those of OVA-immunized marmosets or
untreated monkeys. However, a significant number of PLP-containing
cells and a few MBP-containing cells were detected in the red pulp and
around vessels within the spleens of marmosets with EAE. In contrast,
the spleens of adjuvant controls and untreated monkeys were almost
completely devoid of cells containing MBP and PLP. These results
provide further evidence that myelin Ags gain access to brain-draining
lymphoid organs as a direct result of CNS inflammation.
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), similar to the findings in the spleen. Comparable
small-to-moderate numbers of cells containing MBP and PLP were detected
in the LN of marmosets with EAE as well as adjuvant control marmosets.
These results indicate that myelin Ags in these LN, which drain the
immunization sites, may result from a response to the adjuvant
administration rather than from the inflammatory process in the
CNS. Myelin-containing cells in cervical LN of MS patients
To determine whether the findings in two nonhuman primate EAE
models appropriately reflect events in MS, we examined cervical LN of
two MS patients with active disease and those of two control patients
for the presence of myelin Ags. Cervical LN from both MS patients
contained cells loaded with MBP and PLP (Fig. 6, A and B,
respectively). As in rhesus EAE, ORO staining revealed a paucity of
cells containing neutral lipids from degraded myelin. Myelin
Ag-containing cells expressed APC markers such as CD40 and acid
phosphatase (Fig. 6, C and D, respectively).
Importantly, significantly more PLP-containing cells were observed in
the cervical LN of both MS patients compared with those of both control
patients (Table II)
(p < 0.005). The same pattern was observed for
MBP. However, although more MBP-containing cells were observed in MS
patients, this was not significantly more than control patient S01/216.
Interestingly, control patient S01/218, who suffered from peripheral
neuropathy, did have significantly fewer MBP-containing cells compared
with both MS patients (p < 0.05). These
results imply that, during MS, the presence of intracellular myelin Ags
in APC is not restricted to the brain but is also found in APC in
cervical LN, similar to what was observed with marmoset and rhesus
EAE.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Recently, we have provided evidence that MOG-induced EAE in marmosets is associated with intramolecular epitope spreading of the T cell response (21). MOG-induced EAE is initiated by the presentation of an encephalitogenic peptide of the extracellular domain of MOG (MOG14–36) in the context of a monomorphic Mhc-DR molecule, Caja-DRB*W1201 (21). This disease-initiating step is followed by spreading to other MOG epitopes. The present finding that cervical LN of MOG-immunized marmoset and rhesus monkeys contain cells loaded with MBP and PLP strongly suggests that the priming of lymphocytes specific for (intramolecular and intermolecular) spreading epitopes takes place in this brain-draining LN. The observed difference in myelin content of cells in the cervical LN of marmoset vs rhesus monkeys may be related to the different pathogenesis of EAE in these species; although the exact mechanisms underlying myelin breakdown in rhesus and marmoset EAE are unknown, rhesus EAE is characterized by acute inflammatory necrosis of the white matter with profound influx of granulocytes, rather than chronic demyelination (40). Local release of granulocyte enzymes and reactive oxygen species may affect myelin degradation. Alternatively, the differential persistence of myelin lipids within cells may result from species differences in the intracellular degradation process.
Active demyelinating lesions in both MS patients and marmosets with EAE
are characterized by activated macrophages loaded with neutral lipids
from degraded myelin, MBP, and PLP (17, 33, 34, 41), of
which the eventual fate is unclear. Furthermore, MBP levels in CSF are
elevated during relapsing-remitting MS (42). Studies
tracing the outflow pathways of the brain in healthy animals revealed
that both injected cells (macrophages and lymphocytes) and injected
proteins and other substances drain preferentially to the cervical LN
(14, 15, 43, 44). These findings imply that the
myelin Ags found in the cervical LN within cells with DC- and
macrophage-like characteristics (Figs. 1 and 4) have been ingested in
the LN or have been transported from the brain to the LN by phagocytic
cells, such as brain "resident" microglia, perivascular cells, DC
from the meninges or choroid plexus (16, 38), or
brain-infiltrated DC and macrophages. The latter notion is supported by
studies on inflammatory responses in the kidney (45) and
peritoneal cavity (46), which demonstrated that, during
inflammatory conditions, macrophages migrate from these sites to the
draining LN. Interestingly, Randolph et al. (4) showed, in
an elegant in vivo study, that phagocytes at inflammatory sites were
not merely macrophages but a substantial number of these cells
differentiated into DC upon migration to the T cell area of the
draining LN. This may explain the mixed phenotype (CD83 and acid
phosphatase-positive) of DC-macrophage-like cells containing myelin Ags
in the cervical LN observed in our study. The observation that myelin
Ag-containing cells express CCR7 suggests that these cells have
migrated to the LN in a regulated manner (47). Further
studies are required to determine the identity of the cells containing
myelin Ags in the cervical LN. In addition to transfer in phagocytotic
cells, myelin Ags in LN DC may also result from Ag transfer, i.e.,
uptake of Ags released by migratory cells, as shown in other systems
(48, 49). Alternatively, myelin Ags may have drained to
other locations, including LN, and been carried subsequently to the
cervical LN. However, our data from spleens and other LN of marmoset
monkeys (Table I) suggests that this would apply only for myelin
proteins. Although MBP and PLP can be transiently expressed in various
types of leukocytes during immune-stimulatory conditions
(50, 51, 52), the additional presence of neutral lipids from
degraded myelin within APC in the cervical LN makes this an unlikely
explanation for our findings. The presence of myelin proteins within
cells in the inguinal, axillary, and cervical LN of OVA- and
collagen-immunized animals may result from normal myelin turnover
(53) or be explained by such de novo expression of MBP and
PLP in response to the injection of CFA, which exerts strong effects on
phagocytic cells (54). Collectively, the findings of the
present study imply that, during EAE in marmoset and rhesus monkeys,
phagocytic cells take up myelin in brain lesions, migrate to the
cervical LN and the spleen, and present myelin Ags at these sites to T
cells.
Ample evidence is now available that there is functional specialization of individual LN from distinct anatomical sites. The cervical LN are instrumental in the induction of nasal tolerance (55), i.e., removal of cervical LN abrogated tolerance induction, which could be restored only by transplantation of cervical LN, but not of other LN. Cervical LN also play an important role in the induction of immune responses to brain-derived Ags (14, 56, 57, 58). Interestingly, Ags injected into the CNS evoke a deviant systemic immune response that is deficient in Ag-specific delayed-type hypersensitivity (59, 60). Recently, it was shown that this deviated immune response could be transferred to naive animals by cervical LN cells from donors that received an injection of Ag in the brain 8 days earlier (60). We hypothesize that, during EAE, inflammatory signals from the CNS environment prevent the induction of a deviant immune response (2, 3). The significance of cervical LN in the development of EAE is demonstrated by the finding that complete removal of the cervical LN markedly reduced the severity of cryolesion-enhanced EAE in Lewis rats (61). Moreover, there are indications that encephalitogenic T cells primed in the cervical LN may preferentially target the brain (62). The results of our study support the importance of the cervical LN in EAE in the modulation of autoreactivity.
Strategies to treat MS with therapeutic Abs directed against costimulatory molecules and cytokines are currently under development (19, 63). To interfere with effector functions of T cells and macrophages, it is generally assumed that such immunotherapeutics should necessarily reach the lesions in the CNS by crossing the blood-brain barrier. However, the results of the present study indicate that the cervical LN, which may be accessible via nasal drainage and the circulation, may also serve as a local target for immunotherapy of demyelinating diseases. In this respect, it is interesting that nasal application of low doses of cytokines such as IL-10 ameliorated relapsing EAE in DA rats (64).
In conclusion, the findings of the present study imply that, during MS and EAE in marmosets and rhesus monkeys, myelin Ags are transferred to the cervical LN. Subsequently, they can be presented to T cells by APC, resulting in modulation of T cell reactivity and proliferation. Future studies are warranted to elucidate the mechanisms involved. The monkey EAE models will be a valuable tool to study these mechanisms of Ag transfer and the role of cervical LN in the modulation of T cell responses during MS and may lead to the development of novel therapeutic strategies.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Jon D. Laman, Department of Immunology, Erasmus University Rotterdam, P. O. Box 1738, 3000 DR Rotterdam, The Netherlands. E-mail address: laman{at}immu.fgg.eur.nl
3 Abbreviations used in this paper: DC, dendritic cell; EAE, experimental autoimmune encephalomyelitis; LN, lymph node; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; ORO, oil-red O; PLP, proteolipid protein; phMOG, human MOG peptide; rhMOG, recombinant human MOG.
Received for publication June 17, 2002. Accepted for publication September 9, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, ELC)-dependent mobilization of dendritic cells to lymph nodes. Cell 103:757.[Medline]
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L. Walter and M. L. Albert Cutting Edge: Cross-Presented Intracranial Antigen Primes CD8+ T Cells J. Immunol., May 15, 2007; 178(10): 6038 - 6042. [Abstract] [Full Text] [PDF]
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 K. A. Whartenby, P. A. Calabresi, E. McCadden, B. Nguyen, D. Kardian, T. Wang, C. Mosse, D. M. Pardoll, and D. Small Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease PNAS, November 15, 2005; 102(46): 16741 - 16746. [Abstract] [Full Text] [PDF]
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N. Kuwashima, F. Nishimura, J. Eguchi, H. Sato, M. Hatano, T. Tsugawa, T. Sakaida, J. E. Dusak, W. K. Fellows-Mayle, G. D. Papworth, et al. Delivery of Dendritic Cells Engineered to Secrete IFN-{alpha} into Central Nervous System Tumors Enhances the Efficacy of Peripheral Tumor Cell Vaccines: Dependence on Apoptotic Pathways J. Immunol., August 15, 2005; 175(4): 2730 - 2740. [Abstract] [Full Text] [PDF]
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N. Grois, D. Prayer, H. Prosch, H. Lassmann, and the CNS LCH Co-operative Group Neuropathology of CNS disease in Langerhans cell histiocytosis Brain, April 1, 2005; 128(4): 829 - 838. [Abstract] [Full Text] [PDF]
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 Y. V. Mendez-Fernandez, M. J. Hansen, M. Rodriguez, and L. R. Pease Anatomical and Cellular Requirements for the Activation and Migration of Virus-Specific CD8+ T Cells to the Brain during Theiler's Virus Infection J. Virol., March 1, 2005; 79(5): 3063 - 3070. [Abstract] [Full Text] [PDF]
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 H. Kimura, M. Kimura, S.-C. Tzou, Y.-C. Chen, K. Suzuki, N. R. Rose, and P. Caturegli Expression of Class II Major Histocompatibility Complex Molecules on Thyrocytes Does Not Cause Spontaneous Thyroiditis but Mildly Increases Its Severity after Immunization Endocrinology, March 1, 2005; 146(3): 1154 - 1162. [Abstract] [Full Text] [PDF]
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M. Koller, B. Zwolfer, G. Steiner, J. S. Smolen, and C. Scheinecker Phenotypic and functional deficiencies of monocyte-derived dendritic cells in systemic lupus erythematosus (SLE) patients Int. Immunol., November 1, 2004; 16(11): 1595 - 1604. [Abstract] [Full Text] [PDF]
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J. Karman, C. Ling, M. Sandor, and Z. Fabry Initiation of Immune Responses in Brain Is Promoted by Local Dendritic Cells J. Immunol., August 15, 2004; 173(4): 2353 - 2361. [Abstract] [Full Text] [PDF]
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B. Ludewig and J. D. Laman The in and out of monocytes in atherosclerotic plaques: Balancing inflammation through migration PNAS, August 10, 2004; 101(32): 11529 - 11530. [Full Text] [PDF]
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P. A. Dullforce, K. L. Garman, G. W. Seitz, R. J. Fleischmann, S. M. Crespo, S. R. Planck, D. C. Parker, and J. T. Rosenbaum APCs in the Anterior Uveal Tract Do Not Migrate to Draining Lymph Nodes J. Immunol., June 1, 2004; 172(11): 6701 - 6708. [Abstract] [Full Text] [PDF]
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S. Camelo, A. Shanley, A. S. P. Voon, and P. G. McMenamin The Distribution of Antigen in Lymphoid Tissues following Its Injection into the Anterior Chamber of the Rat Eye J. Immunol., May 1, 2004; 172(9): 5388 - 5395. [Abstract] [Full Text] [PDF]
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L. Fan, B. W. Busser, T. Q. Lifsted, D. Lo, and T. M. Laufer Antigen presentation by keratinocytes directs autoimmune skin disease PNAS, March 18, 2003; 100(6): 3386 - 3391. [Abstract] [Full Text] [PDF]
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) or
rhMOG (
), was compared with that of healthy marmoset monkeys.
Significantly more ORO-, MBP-, and PLP-containing cells were observed
in cervical LN of marmosets with EAE as compared with those of control
marmosets (p < 0.05). The number of cells per
surface area was determined by counting stained cells and measuring the
area of the sections at 2.5-fold magnification using the VIDAS-RT image
analysis system.
),
were compared with those of adjuvant controls with collagen-induced
arthritis (CIA). Significantly more MBP- and PLP-positive cells were
observed in cervical LN of rhesus monkeys with EAE as compared with
those of OVA-immunized control monkeys. The number of MBP-containing
cells (A) and PLP-containing cells (B)
per surface area was determined as described in the legend for Fig. 2
