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Science 20 December 1996:
Vol. 274. no. 5295, pp. 2054 - 2057
DOI: 10.1126/science.274.5295.2054
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Reports

Late Complications of Immune Deviation Therapy in a Nonhuman Primate

Claude P. Genain, * Kristina Abel, Nicole Belmar, François Villinger, Daniel P. Rosenberg, Christopher Linington, Cedric S. Raine, Stephen L. Hauser

The administration of antigens in soluble form can induce antigen-specific immune tolerance and suppress experimental autoimmune diseases. In a marmoset model of multiple sclerosis induced by myelin oligodendrocyte glycoprotein (MOG), marmosets tolerized to MOG were protected against acute disease, but after tolerization treatment a lethal demyelinating disorder emerged. In these animals, MOG-specific T cell proliferative responses were transiently suppressed, cytokine production was shifted from a T helper type 1 (TH1) to a TH2 pattern, and titers of autoantibodies to MOG were enhanced. Thus, immune deviation can increase concentrations of pathogenic autoantibodies and in some circumstances exacerbate autoimmune disease.

C. P. Genain, K. Abel, N. Belmar, D. P. Rosenberg, S. L. Hauser, Department of Neurology, University of California, San Francisco, CA 94143, USA.
F. Villinger, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
C. Linington, Department of Neuroimmunology, Max Planck Institut für Psychiatrie, Martinsried, Germany.
C. S. Raine, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
*   To whom correspondence should be addressed.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system (CNS) that serves as a laboratory model for the human demyelinating disease multiple sclerosis (MS) (1, 2). In rodents, EAE is mediated by effector T cells that respond to myelin antigens and secrete proinflammatory (TH1) cytokines, primarily interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha ), and interferon-gamma (IFN-gamma ) (3). The therapeutic administration of myelin antigens in nonimmunogenic form can suppress disease-inducing T cells and protect against EAE (4). This protection may result from enhanced production of anti-inflammatory (TH2) cytokines, notably IL-4, IL-6, and IL-10 (5), an effect known as immune deviation (6). Protection can be conferred by adoptive transfer of antigen-specific TH2 cells or administration of TH2 cytokines, and is abrogated by antibodies to IL-4 (7).

We have developed a primary demyelinating form of EAE in the common marmoset Callithrix jacchus that has a clinical and pathological similarities to human MS (8, 9). In this species, synergistic T cell and B cell responses result in the MS-like lesion. Diverse populations of TH1-cells recognizing myelin basic protein (MBP) or myelin oligodendrocyte glycoprotein (MOG) mediate the inflammatory component of the lesion, whereas antibodies to MOG mediate demyelination (9). Thus, MOG, a minor constituent of myelin comprising less than 0.05% of myelin proteins by weight, is a major encephalitogenic antigen capable of inducing pathogenic T cell and B cell responses in C. jacchus. Here, we characterize the effects of immune deviation in this model.

Seven C. jacchus marmosets were immunized with a recombinant protein corresponding to the extracellular domain of rat MOG (rMOG) in adjuvant (10). From day 7 to day 18 after immunization, animals received either soluble rMOG (rMOG-tolerized) or placebo (control-tolerized). Consistent with previous observations in rMOG-immunized marmosets (9), clinical signs of EAE developed in four control-tolerized animals between 9 and 16 days after immunization. In contrast, in the three animals treated with soluble rMOG, signs of EAE were suppressed, indicating that tolerization was successful. However, after cessation of treatment a rapidly progressive, lethal form of hyperacute EAE developed that was clinically more severe than in controls (Fig. 1) or than in any of more than 40 previously studied marmosets with acute EAE.

Fig. 1. Clinical course of EAE in placebo-treated and rMOG-treated C. jacchus marmosets. Animals were treated from day 7 until day 18 (shaded area) after immunization and received either 300 µg of rMOG dissolved in 0.025M Naacetate buffer, pH 3.0 (left panel) or placebo [right panel: buffer alone, recombinant glutathione-S-transferase (rGST), or cytochrome c] by intraperitoneal injection every other day for a total of six injections. Clinical signs were graded by blinded observers according to a scale of 1 to 5 as described (19). [View Larger Version of this Image (24K GIF file)]

Neuropathologic findings confirmed the presence of widespread and histologically severe lesions. Lesions in the cerebral hemispheres and spinal cord of rMOG-tolerized animals were visible to the naked eye and were microscopically centered on blood vessels around which there was residual inflammation rich in plasma cells, demyelination, and macrophage activity. In the spinal cord and optic nerve (Fig. 2), lesions consisted of broad bands of subpial and perivascular white matter involvement. In contrast to control-tolerized animals in which lesion activity was limited to perivascular and subpial areas, in rMOG-tolerized animals there was a prominent zone of myelin pallor, sometimes up to 2 mm in width, surrounding a narrow band of demyelination and extending into the adjacent white matter. Within this zone of myelin pathology, cellular infiltration was absent and affected nerve fibers displayed dilated myelin sheaths with the axon either lying to one side of a large myelin vacuole or within a web of dissociated membranes. These changes, confirmed at the ultrastructural level, suggested that the CNS demyelination was humorally mediated (11). Within this zone of myelin vacuolation, except for a small number of oligodendrocytes that displayed evidence of cytolysis but not apoptosis, oligodendrocyte degeneration was not seen. The histopathologic and ultrastructural characteristics of these lesions were similar to those of typical acute MS (12).

Fig. 2. Neuropathologic findings. Representative control-tolerized (left) and rMOG-tolerized (right) animals. Low (A, B, E, F) and high (C, D) power views stained with luxol fast blue/periodic acid Schiff. Bars = 200 µm and 40 µm, respectively. (A) and (B) represent transverse sections of the optic nerves, showing a small perivascular infiltrate with concentric demyelination in the control (A, arrow), and a broad band of extensive subpial demyelination in the rMOG-tolerized marmoset (B). (C) and (D) illustrate lesion detail; the cellular infiltrate in the control animal is comprised of mononuclear cells and macrophages (arrows) with astrogliosis (C), whereas there is sparse mononuclear cell infiltration (arrows) but extensive demyelination in the rMOG-tolerized animal (D). (E) and (F) represent comparison of deep periventricular (v) white matter lesions in typical control (E) and hyperacute (F) EAE; in hyperacute EAE there is extensive confluence of infiltrates, and demyelination is widespread. [View Larger Version of this Image (144K GIF file)]

Consistent with previous experience (9), control-tolerized marmosets developed T cell proliferative responses to rMOG in circulating peripheral blood mononuclear cells (PBMCs) and in lymph node cells (LNCs). In contrast, no response could be detected in any rMOG-tolerized marmoset during the period of antigen administration (Fig. 3), but after treatment proliferative responses appeared concurrent with the development of lethal EAE. Circulating antibodies to rMOG were present in all animals in both groups; however, by day 21 after immunization, titers were higher in rMOG-tolerized animals despite the fact that they remained asymptomatic (Fig. 4, A and B). Epitope mapping studies indicated that rMOG-tolerized and control marmosets developed antibodies to rMOG with similar fine specificities (Fig. 4C). At the time of lethal EAE, rMOG-tolerized marmosets had identical proliferative responses to rMOG as did controls, but autoantibodies were detected in serum at dilutions that were four- to eightfold higher (Figs. 3 and 4). Prior studies indicated that polyclonal marmoset antibodies to MOG can transfer severe demyelination in marmosets, but only in the presence of disease-inducing T cells capable of disrupting the blood brain barrier (9). In hyperacute EAE, it is likely that antibody-mediated demyelination was similarly facilitated by disease-inducing T cells that were activated after cessation of tolerance treatment.

Fig. 3. T cell responses in PBMC of control-tolerized and rMOG-tolerized marmosets. T cell proliferative responses were measured by a standard proliferation assay (9). Briefly, 105 cells were plated in triplicate in 96 well plates at a cell density of 106 cells/ml in AIM-V medium (Gibco-BRL). The following antigens were added to the wells: none (control), rMOG (10 µg/ml), or phytohemagglutinin (2.5 µg/ml). After 48 hours, 0.5 µCi per well of [3H]thymidine was added and cells harvested 18 hours later. Stimulation indices (SI) were calculated as the ratio of cpm in stimulated/unstimulated (control) wells. Data are presented as mean ± SD. *, P < 0.05 when compared to days 0, 14, and 21 (ANOVA). Identical proliferative responses were observed from LNC obtained at biopsy. [View Larger Version of this Image (29K GIF file)]

Fig. 4. Antibody responses in control-tolerized and rMOG-tolerized marmosets. (A) Time course of the appearance of antibodies to rMOG in individual control (open symbols) and rMOG-tolerized (closed symbols) animals. Serum antibody titers were serially measured by ELISA. ELISA plates (Pierce) were coated overnight with rMOG (1 µg/ml) in 0.25 M carbonate buffer, pH 8.6, washed with phosphate- buffered saline containing 0.05% Tween 20 and blocked with 1% bovine serum albumin in the same buffer. After washing, 100 µl of a 1:800 dilution of immune sera were incubated in the wells for 2 hours at 37°C, and immunoperoxidase-conjugated anti-monkey IgG (Sigma, 1:6000) was applied for 1 hour at 37°C. Plates were developed with o-phenylenediamine dihydrochloride in 0.05 M phosphate-citrate buffer, pH 5.0 (Sigma) for 30 min and read at 490 nm in a Vmax ELISA reader (Molecular Devices). (B) Serum titers at day 21 after immunization (mean ± SD). Control-tolerized, open symbols; rMOG-tolerized, closed symbols. Titers were measured by ELISA using serial dilutions of immune sera (1:200 to 1:6400). (C) Fine specificity of anti-MOG antibodies was studied in five animals with the same ELISA system with 20 residue synthetic overlapping peptides corresponding to the published sequence of rat MOG (20) (1 µg/well), and 1:200 dilutions of immune sera. (Inset) The legend indicates individual animals with their respective treatments. Antibodies from placebo- and rMOG-tolerized marmosets recognized similar regions of the rMOG molecule, located between aa 1 to 42 and aa 50 to 80. [View Larger Version of this Image (39K GIF file)]

Cytokine gene expression was measured in LNC and PBMC by reverse transcriptase-polymerase chain reaction (RT-PCR) after stimulation in vitro with either rMOG or MBP. Compared to control-tolerized animals, rMOG-tolerized marmosets had increased synthesis of IL-10 and IL-6 mRNA, and decreased IFN-gamma and TNF-alpha mRNA, in response to stimulation with rMOG (Fig. 5). No significant stimulation of any cytokine mRNA was observed after stimulation with MBP. The shift from a TH1-like to a TH2-like pattern of cytokine production in response to rMOG was present by day 14 after immunization, and persisted until the end of the study. The inability to detect a proliferative response to rMOG in tolerized animals may have resulted from antiproliferative effects of TH2 cytokines (13), from reversible T cell anergy or apoptotic T cell death (14). The appearance of proliferative responses after cessation of treatment suggested that the state of unresponsiveness was reversible.

Fig. 5. Cytokine gene expression in control-tolerized and rMOG-tolerized marmosets. Sequential analysis of TNF-alpha , IFN-gamma , IL-10, and IL-6 mRNA in LNCs obtained at biopsy or autopsy in representative control-tolerized (A) and rMOG-tolerized (B) animals at day 14 and day 24 after immunization, respectively. For measurement of cytokine mRNA levels, 106 LNC were cultured in 1 ml AIM-V in the presence of: no antigen (control); rMOG (10 µg/ml) or MBP (50 µg/ml). After 4 hours, cells were harvested and total RNA extracted using TriZol (Gibco-BRL). A first strand cDNA was synthesized using 2.5 µg of total RNA in a 100 µl reaction containing PCR buffer (Promega), 1.5 mM MgCl2, 1 unit of Moloney murine leukemia virus reverse transcriptase (Gibco-BRL), 1 mM dNTP, 25 nM random hexamers and ribonuclease inhibitor (Pharmacia). Ten microliters of cDNA was used for PCR amplification in a 25-µl reaction in the presence of PCR buffer, 0.5 mM MgCl2, 1 unit of Taq polymerase (Gibco), and 0.5 µM of each of G3PDH upstream and downstream primers (as internal control for the RT-PCR reaction) and primers specific for TNF-alpha , IFN-gamma , IL-10, and IL-6 (22). [View Larger Version of this Image (32K GIF file)]

Our data show that induction of a TH2 response may exacerbate autoimmunity by enhancing production of pathogenic autoantibodies. This effect is likely mediated by the known functions of TH2 cytokines on induction of B cell differentiation, switch of immunoglobulin production from low-affinity immunoglobulin M (IgM) to high-affinity IgG, and synthesis of IgG1 (6, 15). In human MS, T cell mediation is one likely pathogenic mechanism (2, 16), but myelin-specific autoantibodies are also present (17) and antibody- and complement-mediated tissue damage may occur (18). This raises the possibility that in MS, as in C. jacchus EAE, induction of a TH2 response to myelin antigens might promote humoral autoimmunity. Strategies that induce long-term tolerance both for T cells and B cells may be required for successful immunotherapy of complex autoimmune disorders.

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  22. The sequences of the primers were as follows: 5'- CATGTGGGCCATGAGGTCCACCAC-3' (3'-G3PDH); 5'-TGAAGGTCGGAGTCAACGGATTTGGT-3' (5'-G3PDH); 5'-GCAATGATCCCAAAGTAGACCTGCCCAGACT-3' (3'-TNF-alpha ); 5'-GAGTGACAAGCCTGTAGCCCATGTTGTAGCA-3' (5'-TNF-alpha ); 5'-GCATCGTTTTGGGTTCTCTTGGCTGTTACTGC-3' (3'-IFN-gamma ); 5'-CTCCTTTTTCGCTTCCCTGTTTTAGCTGCTGG-3' (5'-IFN-gamma ); 5'-TCTCAAGGGGCTGGGTCAGCTATCCCA-3' (3'-IL-10); 5'-ATGCCCCAAGCTGAGAACCAAGACCCAGAC-3' (5'-IL-10); 5'-GAAGAGCCCTCAGGCTGGACTG-3' (3'-IL-6); and 5'-ATGAACTCCTTCTCCACAAGCGC-3' (5'-IL-6). PCR amplification was carried out for 25 cycles (TNF-alpha and IFN-gamma ) or 35 cycles (IL-10 and IL-6).
  23. Supported by the Nancy Davis Center Without Walls; the National Institutes of Health NS 30727 (S.L.H.) and NS 08952 and NS 11920 (C.S.R.); the National Multiple Sclerosis Society NMSS Reg 1001-I-9 (C.S.R.); the Deutsche Forschungsgemeinschaft SFB217 (C.L.); and the National Multiple Sclerosis Society (C.P.G.). rGST was supplied by R. H. Edwards and D. Krantz, and Bordetella pertussis from Wyeth Lederle Vaccine and Pediatrics, Pearl River, NY. We thank J. R. Oksenberg for helpful discussions and K. Lovett and L. Brovarney for their dedicated work with the animals.

18 July 1996; accepted 18 November 1996


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   Abstract »    Full Text »    PDF »
Revisiting Tolerance Induced by Autoantigen in Incomplete Freund's Adjuvant.
P. S. Heeger, T. Forsthuber, C. Shive, E. Biekert, C. Genain, H. H. Hofstetter, A. Karulin, and P. V. Lehmann (2000)
J. Immunol. 164, 5771-5781
   Abstract »    Full Text »    PDF »
Short-lived immunization site inflammation in self-limited active experimental allergic encephalomyelitis.
F. Di Rosa, B. Serafini, P. Scognamiglio, A. Di Virgilio, L. Finocchi, F. Aloisi, and V. Barnaba (2000)
Int. Immunol. 12, 711-719
   Abstract »    Full Text »    PDF »
Encephalomyelitis-associated antimyelin autoreactivity induced by streptococcal exotoxins.
P. G. Jorens, A. VanderBorght, B. Ceulemans, H. P. Van Bever, L. L. Bossaert, M. Ieven, H. Goossens, P. M. Parizel, H. Van Dijk, J. Raus, et al. (2000)
Neurology 54, 1433-1441
   Abstract »    Full Text »    PDF »
Prevention of Type 1 Diabetes: Is Now the Time?.
D. J. Becker, R. E. LaPorte, I. Libman, M. Pietropaolo, and H.-M. Dosch (2000)
J. Clin. Endocrinol. Metab. 85, 498-506
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Interleukin-10 . The Missing Link in Asthma Regulation?.
D. T. Umetsu and R. H. DeKruyff (1999)
Am. J. Respir. Cell Mol. Biol. 21, 562-563
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Multiple sclerosis: B- and T-cell responses to the extracellular domain of the myelin oligodendrocyte glycoprotein.
R.-B. Lindert, C. G. Haase, U. Brehm, C. Linington, H. Wekerle, and R. Hohlfeld (1999)
Brain 122, 2089-2100
   Abstract »    Full Text »    PDF »
Antigen-specific modulation of experimental myasthenia gravis: Nasal tolerization with recombinant fragments of the human acetylcholine receptor alpha -subunit.
D. Barchan, M. C. Souroujon, S.-H. Im, C. Antozzi, and S. Fuchs (1999)
PNAS 96, 8086-8091
   Abstract »    Full Text »    PDF »
Serial MR Imaging of Experimental Autoimmune Encephalomyelitis Induced by Human White Matter or by Chimeric Myelin-Basic and Proteolipid Protein in the Common Marmoset.
E. K. Jordan, H. I. McFarland, B. K. Lewis, N. Tresser, M. A. Gates, M. Johnson, M. Lenardo, L. A. Matis, H. F. McFarland, and J. A. Frank (1999)
AJNR Am. J. Neuroradiol. 20, 965-976
   Abstract »    Full Text »
Candidate autoantigens in multiple sclerosis.
S. Schmidt (1999)
Multiple Sclerosis 5, 147-160
   Abstract »    PDF »
Mechanisms of Nasal Tolerance Induction in Experimental Autoimmune Myasthenia Gravis: Identification of Regulatory Cells.
F.-D. Shi, H. Li, H. Wang, X. Bai, P. H. van der Meide, H. Link, and H.-G. Ljunggren (1999)
J. Immunol. 162, 5757-5763
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Microbial Epitopes Act as Altered Peptide Ligands to Prevent Experimental Autoimmune Encephalomyelitis.
P. J. Ruiz, H. Garren, D. L. Hirschberg, A. M. Langer-Gould, M. Levite, M. V. Karpuj, S. Southwood, A. Sette, P. Conlon, and L. Steinman (1999)
J. Exp. Med. 189, 1275-1284
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Elevated Levels of Antibody to Myelin Oligodendrocyte Glycoprotein Is Not Specific for Patients With Multiple Sclerosis.
A. Karni, R. Bakimer-Kleiner, O. Abramsky, and A. Ben-Nun (1999)
Arch Neurol 56, 311-315
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Determinant Spreading Associated with Demyelination in a Nonhuman Primate Model of Multiple Sclerosis.
H. I. McFarland, A. A. Lobito, M. M. Johnson, J. T. Nyswaner, J. A. Frank, G. R. Palardy, N. Tresser, C. P. Genain, J. P. Mueller, L. A. Matis, et al. (1999)
J. Immunol. 162, 2384-2390
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Induction or Protection from Experimental Autoimmune Encephalomyelitis Depends on the Cytokine Secretion Profile of TCR Peptide-Specific Regulatory CD4 T Cells.
V. Kumar and E. Sercarz (1998)
J. Immunol. 161, 6585-6591
   Abstract »    Full Text »    PDF »
Attenuation of Inducible Th2 Immunity with Autoimmune Disease Progression.
J. Tian and D. L. Kaufman (1998)
J. Immunol. 161, 5399-5403
   Abstract »    Full Text »    PDF »
A 29-Year-Old Man With Multiple Sclerosis.
R. A. Rudick (1998)
JAMA 280, 1432-1439
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Oligodendrocyte Apoptosis and Primary Demyelination Induced by Local TNF/p55TNF Receptor Signaling in the Central Nervous System of Transgenic Mice : Models for Multiple Sclerosis with Primary Oligodendrogliopathy.
K. Akassoglou, J. Bauer, G. Kassiotis, M. Pasparakis, H. Lassmann, G. Kollias, and L. Probert (1998)
Am. J. Pathol. 153, 801-813
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Widespread expression of an autoantigen-GAD65 transgene does not tolerize non-obese diabetic mice and can exacerbate disease.
L. Geng, M. Solimena, R. A. Flavell, R. S. Sherwin, and A. C. Hayday (1998)
PNAS 95, 10055-10060
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Experimental Autoimmune Encephalomyelitis Induced with a Combination of Myelin Basic Protein and Myelin Oligodendrocyte Glycoprotein Is Ameliorated by Administration of a Single Myelin Basic Protein Peptide.
E. A. Leadbetter, C. R. Bourque, B. Devaux, C. D. Olson, G. H. Sunshine, S. Hirani, B. P. Wallner, D. E. Smilek, and M. P. Happ (1998)
J. Immunol. 161, 504-512
   Abstract »    Full Text »    PDF »
Neuropathology in multiple sclerosis: new concepts.
H. Lassmann (1998)
Multiple Sclerosis 4, 93-98
   Abstract »    PDF »
Disease activity and the immune set in multiple sclerosis: blood markers for immunotherapy.
A J Coles, M G Wing, and D A. Compston (1998)
Multiple Sclerosis 4, 232-238
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Vaccination with DNA Encoding an Immunodominant Myelin Basic Protein Peptide Targeted to Fc of Immunoglobulin G Suppresses Experimental Autoimmune Encephalomyelitis.
A. Lobell, R. Weissert, M. K. Storch, C. Svanholm, K. L. de Graaf, H. Lassmann, R. Andersson, T. Olsson, and H. Wigzell (1998)
J. Exp. Med. 187, 1543-1548
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Management of Multiple Sclerosis.
R. A. Rudick, J. A. Cohen, B. Weinstock-Guttman, R. P. Kinkel, and R. M. Ransohoff (1997)
N. Engl. J. Med. 337, 1604-1611
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Thyrotropin-Receptor and Thyroid Peroxidase-Specific T Cell Clones and Their Cytokine Profile in Autoimmune Thyroid Disease.
M. E. Fisfalen, E. M. Palmer, G. A. van Seventer, K. Soltani, Y. Sawai, E. Kaplan, Y. Hidaka, C. Ober, and L. J. DeGroot (1997)
J. Clin. Endocrinol. Metab. 82, 3655-3663
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Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia.
K. J. Becker, R. M. McCarron, C. Ruetzler, O. Laban, E. Sternberg, K. C. Flanders, and J. M. Hallenbeck (1997)
PNAS 94, 10873-10878
   Abstract »    Full Text »    PDF »
T Helper 2 (Th2) T Cells Induce Acute Pancreatitis and Diabetes in Immune-compromised Nonobese Diabetic (NOD) Mice.
S. V. Pakala, M. O. Kurrer, and J. D. Katz (1997)
J. Exp. Med. 186, 299-306
   Abstract »    Full Text »    PDF »
Myelin Basic Protein-specific T Helper 2 (Th2) Cells Cause Experimental Autoimmune Encephalomyelitis in Immunodeficient Hosts Rather than Protect Them from the Disease.
J. J. Lafaille, F. V. d. Keere, A. L. Hsu, J. L. Baron, W. Haas, C. S. Raine, and S. Tonegawa (1997)
J. Exp. Med. 186, 307-312
   Abstract »    Full Text »    PDF »
Immune Cell Traffic in the Brain: Blundering and Migration of Autoreactive T Lymphocytes.
M. D. Carrithers (1997)
Neuroscientist 3, 207-210
   Abstract »    PDF »


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