Protection from autoimmune brain inflammation in mice lacking IFN-regulatory factor-1 is associated with Th2-type cytokines

Thorsten Buch1, Claudia Uthoff-Hachenberg1 and Ari Waisman1

1 Laboratory of Molecular Immunology, Institute for Genetics, University of Cologne, Weyertal 121, 50931 Cologne, Germany

Correspondence to: A. Waisman; E-mail: ari{at}uni-koeln.de
Transmitting editor: L. Steinman


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
IFN-regulatory factor-1 (IRF-1) is a transcription factor that regulates the expression of IFN-induced genes and type I IFN. It has previously been demonstrated that IRF-1-deficient mice show reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) induced by a peptide from myelin basic protein. To further study the role of IRF-1 in brain inflammation, we analyzed EAE induced by immunization with a myelin oligodendrocyte glycoprotein-derived peptide in 129/Sv mice lacking IRF-1. We found that these mice were almost completely resistant to EAE induction and that this unresponsiveness was intrinsically related to the IRF-1 deficiency of the T cells, but not with any other cell type. Furthermore, we show that the amelioration of EAE was associated with increased production of Th2-type and decreased production of Th1-type cytokines. These results demonstrate that absence of IRF-1 in myelin-specific T cells results in protection from severe EAE and is associated with a skewing of the T cell response towards Th2.

Keywords: autoimmunity, experimental autoimmune encephalomyelitis, IFN-regulatory factor-1, Th1, Th2


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) characterized by plaques of infiltrating CD4 and CD8 T cells (1,2). The mechanism underlying the development of MS is unknown; however, experimental autoimmune encephalomyelitis (EAE), an animal model for MS (3), has established a prominent role of CD4+ T cells and, to a minor extent, also CD8+ T cells in the development of the disease. EAE is induced in mice by immunization with myelin antigens or transfer of myelin-specific T cells (3). Specifically, in C57Bl/6 mice immunization with a myelin oligodendrocyte glycoprotein (MOG)-derived peptide (4) induces a strong, but transient disease that can be assessed by a clinical score ranging from 1 to 5 (3,4). Development of EAE is associated with the production of Th1 and inflammatory cytokines such as IFN-{gamma} and tumor necrosis factor (TNF)-{alpha}. These cytokines are detected in brain tissue of MS patients as well as brains from mice suffering from EAE (2,5,6). Additional data suggest that these cytokines are mainly secreted by disease-inducing T cells (5,6). In contrast, Th2-type cytokines, such as IL-4 and IL-10, have not been detected in the brain tissue of MS patients. Furthermore, the latter cytokines are associated with protection from disease in the EAE model (59).

IFN-regulatory factor-1 (IRF-1) was originally identified as a transcriptional activator of type I IFN (10,11). Studies with mice deficient in IRF-1 have revealed a role of IRF-1 in the induction of IFN-{gamma} and IL-12, which are typically expressed in Th1-type responses (12,13). Moreover, IRF-1 plays a significant role in many other aspects of inflammatory responses, including the regulation of expression of inducible nitric oxidase (14), cyclooxygenase (15) and caspase-mediated apoptosis (16). Previous experiments indicated that upon immunization with myelin basic protein (MBP), IRF-1–/– mice developed an attenuated form of disease as compared to wild-type mice (17). However, as IRF-1–/– mice were generated in the 129/Sv background and backcrossed to the PL/J strain only 2–3 times to introduce the H-2u MHC locus, the genetic background of the experimental and control animals was in all cases a mixture of the 129/Sv and PL/J strains, a possible cause for the observed diminished incidence of EAE in the IRF-1–/– group (17). To further study the role of IRF-1 in EAE, we investigated the induction of EAE in mice lacking IRF-1 in a pure 129/Sv background.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
EAE induction
EAE was induced in 10- to 12-week-old female 129/Sv mice (IRF-1+/+, IRF-1+/– and IRF-1–/–) using 50 µg MOG p35–55 in complete Freund’s adjuvant containing 8 mg/ml H37Ra (Difco, Detroit, MI). MOG p35–55 was described previously (14) and synthesized by Neosystem (Strasburg, France). Mice were injected in the base of the tail. Bordetella pertussis toxin (200 ng; List Biologicals, Campbell, CA) was administered i.v. on days 0 and 2. Mice were scored as follows: 0, clinically normal; 1, flaccid tail; 2, partial hind limb paralysis; 3, full hind limb paralysis; 4, front and hind limb paralysis.

T cell line (TCL) establishment and proliferation assays
Inguinal and popliteal lymph nodes were isolated from MOG p35–55 injected IRF-1–/– or wild-type mice 10 days after immunization. The lymph node cells were used to establish short-term TCL as previously described (9). T cell cultures were grown in RPMI 1640 complete medium (RPMI 1640 medium with 10% FBS; Life Technologies, Rockville, MD). For proliferation, 2.5 x 104 lymphocytes from MOG peptide-primed mice per well were cultured in the presence of MOG peptide or C-reactive protein (CRP) peptide and 2 x 105 splenocytes/well in triplicate for 72 h. After incubation with 0.5 µCi/well [3H]thymidine (DuPont, Boston, MA) for the last 18 h the cultures were harvested using a Harvester96 (Tomtec, Orange, CT). The radioisotope incorporation as index of T cell proliferation was determined using a ß-plate gas scintillation counter.

Cytokine measurements
CD4+ T cells were isolated from lymph nodes following immunization with the MOG p35–55. Freshly isolated T cells, as well as TCL, were activated with either plate-bound anti-CD3 mAb (clone 145-2C11; Becton Dickinson, Franklin Lakes, NJ) or with 5 µg/ml MOG p35–55 and antigen-presenting cells (APC). Supernatants were collected after 24 h (for TNF-{alpha}) or 48 h (all other cytokines). The cytokine concentrations were measured by ELISA as described previously (9) using recombinant standard cytokines (Becton Dickinson).

RNase protection assay (RPA)
Total RNA was extracted from TCL using the TRIzol reagent (Life Technologies, Grand Island, NY). The RNA was subjected to an RPA using probe kits mck-1 and mck-3b as described by the manufacturer (Becton Dickinson). Results were normalized to the expression levels of the housekeeping genes GAPDH and L32.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
To study the role of IRF-1 in EAE we analyzed IRF-1–/– mice which were generated and kept on a pure 129/Sv background [(18) mice were kindly provided by C. Weissmann, Zürich]. These mice were bred to wild-type 129/Sv mice to generate animals heterozygous for the mutation. IRF-1+/– and IRF-1–/– mice as well as 129/Sv wild-type controls were immunized with MOG p35–55, a peptide shown to induce EAE in mice carrying the H-2b locus (4). After immunization with the MOG peptide, IRF-1–/– mice developed an attenuated disease compared to wild-type mice. The clinical symptoms were reduced from an average score of 2.5 in IRF-1+/– and wild-type mice to a score of 1 in IRF-1–/– mice (Fig. 1). Furthermore, the onset of the disease was delayed for 4 days in IRF-1–/– mice as compared to wild-type and IRF-1+/– controls (Fig. 1). The majority (nine of 12) of IRF-1–/– animals showed signs of disease, which was comparable to the fraction of diseased animals found in the control groups (10 of 12 of wild-type and 11 of 12 of IRF-1+/–). Since the role of IRF-1 is not restricted to the regulation of activation and of cytokine production by T cells, other cell types that may be involved in brain inflammation, such as macrophages and astrocytes, could participate in an inflammatory response via IRF-1-induced gene expression (1921). In addition, CD8 T cell and NK cell development are disturbed in IRF-1–/– mice (22,23), which could also result in changes in the immune response. We therefore designed experiments to distinguish the part played by IRF-1 in T cells as compared with other cell types in the course of a myelin-specific immune response. TCL from IRF-1–/– and wild-type mice were generated after immunization with MOG p35–55. To determine the reactivity of the lines towards the antigenic peptide we performed a T cell proliferation assay testing specificities of the TCL (Fig. 2A). The IRF-1–/– TCL showed a markedly higher rate of background proliferation as compared to wild-type cells (Fig. 2A) when cultured with a control peptide from human CRP (24,25). A similarly high background proliferation against MOG peptide was observed in an IRF-1–/– TCL specific for CRP (data not shown), indicating a hyperproliferative phenotype of T cells lacking IRF-1. Upon peptide stimulation specific proliferation was found in both lines, albeit that a higher peptide concentration was required to induce specific proliferation in the IRF-1–/– TCL than in the wild-type TCL (Fig. 2A). We further addressed the ability of both cell lines to induce EAE upon adoptive transfer of 1 x 107 cells of the IRF-1–/– or control TCL into 129/Sv hosts. In contrast to wild-type TCL, an IRF-1–/– TCL was not able to induce EAE in the host animals, (Fig. 2B). Thus, absence of IRF-1 expression in the myelin-specific T cells is sufficient to protect against induction of EAE.



View larger version (13K):
[in this window]
[in a new window]
 
Fig. 1. IRF-1–/– mice are partially resistant to EAE induction. EAE was induced in 10- to 12-week-old female 129/Sv mice (IRF-1+/+, IRF-1+/– and IRF-1–/–). The mice were scored every second day. SD < 10%.

 


View larger version (27K):
[in this window]
[in a new window]
 
Fig. 2. Auto-reactive T cells isolated from IRF-1–/– mice do not induce EAE in wild-type mice. Lymph nodes were isolated from MOG p35–55 injected IRF-1–/– or wild-type mice. The lymph node cells were used to establish short-term TCL. (A) MOG peptide-primed lymphocytes (2.5 x 104/well) were cultured in the presence of MOG peptide or CRP peptide and 2 x 105 splenocytes/well in triplicate for 72 h. The cultures were harvested after incubation with [3H]thymidine for the last 18 h of the culture. SD < 10%. (B) MOG-specific TCL from IRF-1–/– and IRF-1+/+ mice were activated for 3 days with APC pulsed with MOG p35–55 and subsequently transferred to 8-week-old wild-type 129/Sv mice. Mice were monitored and scored daily. SD < 10%.

 
It has previously been shown that development of EAE was associated with a Th1 response, whereas Th2-polarized T cells protected from disease, even if myelin-reactive T cells of both types were mixed and adoptively transferred to induce disease (26). Thus, different polarization of T cells in IRF-1–/– mice could explain the observed results. To study whether the T cells or TCL of wild-type and IRF-1–/– mice had polarized into Th1- or Th2-type cells respectively, the cells were activated with either plate-bound anti-CD3 antibody or with MOG p35–55-pulsed APC. The supernatants of these cultures were analyzed for cytokine content by ELISA. The Th1-type cytokines IFN-{gamma} and TNF-{alpha} were present in all cultures (Fig. 3), but supernatants from cultures of IRF-1–/– cells contained lower amounts of these cytokines. On the other hand, the Th2-associated cytokines IL-4 and IL-10 were only found in cultures of IRF-1–/–, and were undetectable in cultures of wild-type cells.



View larger version (41K):
[in this window]
[in a new window]
 
Fig. 3. T cells isolated from IRF-1–/– mice secrete primarily Th2-type cytokines. Ten days after immunization with the MOG p35–55 CD4+ T cells were isolated from lymph nodes. The T cells, as well as the TCL described in Fig. 2 and CRP-specific TCL isolated from IRF-1–/– mice were activated with either plate-bound anti-CD3 mAb or peptide and APC. Supernatants were collected and analyzed for the presence of cytokines as described in Methods. Similar results were obtained from three different experiments.

 
To extend the analysis to other cytokines we assessed the mRNA levels of various cytokines produced by a variety of different TCL by RPA (Fig. 4). The increased expression levels of the Th2 cytokines IL-4 and IL-10 were confirmed in this assay. In addition, the mRNA levels of three other Th2 cytokines, i.e. IL-5, IL-6 and IL-13, were higher in the IRF-1–/– TCL as compared to the wild-type TCL. The decreased expression of the Th1 cytokine IFN-{gamma} in IRF-1–/–TCL was also confirmed by RPA. In addition, we found that the proinflammatory cytokines TNF-{alpha}, lymphotoxin-{alpha} and lymphotoxin-ß showed higher expression in wild-type TCL as compared to IRF-1–/– TCL (Fig. 4). Thus, the Th2 cytokines IL-4, IL-5, IL-10 and IL-13 are expressed specifically in MOG peptide-reactive IRF-1–/–, but not wild-type T cells. Expression of inflammatory cytokines is reduced, but not absent, in IRF-1–/– TCL. To test whether polarization towards a Th2 phenotype was specific to a T cell response against the MOG peptide in IRF-1-deficient mice or whether Th2 polarization could be found in any peptide-induced T cell response, we also analyzed the cytokine production in the CRP-reactive TCL from IRF-1–/– and wild-type mice. Like MOG-reactive TCL, the CRP-specific TCL from IRF-1–/– mice secreted primarily Th2-type cytokines (similar to the MOG-reactive TCL) (Fig. 3). Thus it seems that due to the lack of IRF-1 the T cell response is shifted to Th2- rather than to Th1-type independent of the antigen specificity of the T cells tested.



View larger version (35K):
[in this window]
[in a new window]
 
Fig. 4. Relative levels of cytokine mRNA in IRF-1 and wild-type TCL after activation. T cell lines specific for the MOG p35–55 from IRF-1–/– and wild-type mice were activated for 24 h with the MOG peptide; thereafter RNA was extracted and subjected to an RPA.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The mouse model of MS, EAE, can be induced in a variety of mouse strains (30). The type of mouse strain used to perform EAE experiments determines the reactivity and strength of disease with respect to a particular antigen (30). It was previously reported that EAE was ameliorated in IRF-1–/– mice of mixed background, but the incidence of disease was comparably low in this experimental set-up. Tada et al. reported that only four of 13 IRF-1-deficient mice developed symptoms of EAE after immunization with MBP (17). In our model involving IRF-1-deficient mice on the 129/Sv background EAE was also ameliorated upon induction with the MOG peptide. However, we observed a higher incidence of EAE (nine of 12 IRF-1–/– mice) than in the report by Tada et al. The frequency in our experimental group was similar to the one observed in the control groups (10 of 12 of wild-type and 11 of 12 of IRF-1+/–). Thus, in contrast to the data by Tada et al., which imply that IRF-1 deficiency reduces not only severity but also incidence of EAE induced by MBP, we found that after immunization of 129/Sv mice with MOG the incidence of EAE is independent of the presence or absence of IRF-1 expression. Tada et al. also suggested that IRF-1 induced inducible nitric oxidase synthase production by glial cells and that infiltrating macrophages may participate in the EAE development (17). We showed that adoptively transferred IRF-1–/– T cells were not able to induce disease in a wild-type environment. Thus, the contribution of IRF-1-controlled inflammatory responses by non-T cells in EAE is either not essential for disease development or dependent on a Th1-type myelin-specific T cell response.

As IRF-1 deficiency in T cells is already sufficient to decrease the severity of EAE, we further assessed the changes intrinsic to the IRF-1–/– myelin-specific T cells. In an analysis of cytokine production and secretion, the T cells showed a skewing towards increased production of Th2 cytokines. Polarization of Th cells towards a Th2 phenotype was reported to protect against development of severe EAE in a variety of models (31). Whether it is merely the Th2 phenotype that protects from disease or whether other functional changes in IRF-1-deficient T cells also contribute to this protection remains unclear. We also observed a hyperproliferative phenotype of the IRF-1–/– TCL, the cause of which is presently unclear. The changes in T cell physiology could include altered expression levels of Fas ligand (FasL), since its expression is dependent on IRF-1 as a transcription factor (27). The Fas–FasL pathway was also shown to be involved in the development of EAE, as a mutation in the death receptor Fas, the ligand of FasL on target cells, results in amelioration of EAE (28). We plan to investigate this mechanism in more detail in the future.


    Acknowledgements
 
We thank Dr Klaus Rajewsky for support. This work was funded by the EC grant TAGAPO, no. QLG1-1999.00200. T. B. is fellow of the International Graduate School of Functional Genomics and Genetics at the Institute for Genetics, Cologne. We thank Dr Ulrich Kalinke, Iana Parvanova and Andrew Croxford for critically reading the manuscript.


    Abbreviations
 
APC—antigen-presenting cell

CRP—C-reactive protein

EAE—experimental autoimmune encephalomyelitis

FasL—Fas ligand

IRF-1—IFN-regulatory factor-1

MBP—myelin basic protein

MOG—myelin oligodendrocyte glycoprotein

MS—multiple sclerosis

RPA—RNase protection assay

TCL—T cell line

TNF—tumor necrosis factor


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Babbe, H., Roers, A., Waisman, A., Lassmann, H., Goebels, N., Hohlfeld, R., Friese, M., Schroder, R., Deckert, M., Schmidt, S., Ravid, R. and Rajewsky, K. 2000. Clonal expansions of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J. Exp. Med. 192:393.[Abstract/Free Full Text]
  2. Hohlfeld, R. and Wekerle, H. 2001. Immunological update on multiple sclerosis. Curr. Opin. Neurol. 14:299.[CrossRef][ISI][Medline]
  3. Zamvil, S. S. and Steinman, L. 1990. The T lymphocyte in experimental allergic encephalomyelitis. Annu. Rev. Immunol. 8:579.[CrossRef][ISI][Medline]
  4. Mendel, I., Kerlero de Rosbo, N. and Ben-Nun, A. 1995. A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expression of encephalitogenic T cells. Eur. J. Immunol. 25:1951.[ISI][Medline]
  5. Olsson, T. 1992. Cytokines in neuroinflammatory disease: role of myelin autoreactive T cell production of interferon-gamma. J. Neuroimmunol. 40:211.[CrossRef][ISI][Medline]
  6. Okuda, Y., Sakoda, S. and Yanagihara, T. 1998. The pattern of cytokine gene expression in lymphoid organs and peripheral blood mononuclear cells of mice with experimental allergic encephalomyelitis. J. Neuroimmunol. 87:147.[CrossRef][ISI][Medline]
  7. Saoudi, A., Simmonds, S., Huitinga, I. and Mason, D. 1995. Prevention of experimental allergic encephalomyelitis in rats by targeting autoantigen to B cells: evidence that the protective mechanism depends on changes in the cytokine response and migratory properties of the autoantigen-specific T cells. J. Exp. Med. 182:335.[Abstract]
  8. Mars, L. T., Laloux, V., Goude, K., Desbois, S., Saoudi, A., Van Kaer, L., Lassmann, H., Herbelin, A., Lehuen, A. and Liblau, R. S. 2002. Cutting edge: V alpha 14–J alpha 281 NKT cells naturally regulate experimental autoimmune encephalomyelitis in nonobese diabetic mice. J. Immunol. 168:6007.[Abstract/Free Full Text]
  9. Waisman, A., Ruiz, P. J., Hirschberg, D. L., Gelman, A., Oksenberg, J. R., Brocke, S., Mor, F., Cohen, I. R. and Steinman, L. 1996. Suppressive vaccination with DNA encoding a variable region gene of the T-cell receptor prevents autoimmune encephalomyelitis and activates Th2 immunity. Nat. Med. 2:899.[ISI][Medline]
  10. Harada, H., Fujita, T., Miyamoto, M., Kimura, Y., Maruyama, M., Furia, A., Miyata, T. and Taniguchi, T. 1989. Structurally similar but functionally distinct factors, IRF-1 and IRF- 2, bind to the same regulatory elements of IFN and IFN-inducible genes. Cell 58:729.[ISI][Medline]
  11. Miyamoto, M., Fujita, T., Kimura, Y., Maruyama, M., Harada, H., Sudo, Y., Miyata, T. and Taniguchi, T. 1988. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell 54:903.[ISI][Medline]
  12. Taki, S., Sato, T., Ogasawara, K., Fukuda, T., Sato, M., Hida, S., Suzuki, G., Mitsuyama, M., Shin, E. H., Kojima, S., Taniguchi, T. and Asano, Y. 1997. Multistage regulation of Th1-type immune responses by the transcription factor IRF. Immunity 6:673.[ISI][Medline]
  13. Lohoff, M., Ferrick, D., Mittrucker, H. W., Duncan, G. S., Bischof, S., Rollinghoff, M. and Mak, T. W. 1997. Interferon regulatory factor-1 is required for a T helper 1 immune response in vivo. Immunity 6:681.[ISI][Medline]
  14. Kamijo, R., Harada, H., Matsuyama, T., Bosland, M., Gerecitano, J., Shapiro, D., Le, J., Koh, S. I., Kimura, T., Green, S. J., et al. 1994. Requirement for transcription factor IRF-1 in NO synthase induction in macrophages. Science. 263:1612.[ISI][Medline]
  15. Blanco, J. C., Contursi, C., Salkowski, C. A., DeWitt, D. L., Ozato, K. and Vogel, S. N. 2000. Interferon regulatory factor (IRF)-1 and IRF-2 regulate interferon gamma-dependent cyclooxygenase 2 expression. J. Exp. Med. 191:2131.[Abstract/Free Full Text]
  16. Tamura, T., Ishihara, M., Lamphier, M. S., Tanaka, N., Oishi, I., Aizawa, S., Matsuyama, T., Mak, T. W., Taki, S. and Taniguchi, T. 1995. An IRF-1-dependent pathway of DNA damage-induced apoptosis in mitogen- activated T lymphocytes. Nature 376:596.[CrossRef][ISI][Medline]
  17. Tada, Y., Ho, A., Matsuyama, T. and Mak, T. W. 1997. Reduced incidence and severity of antigen-induced autoimmune diseases in mice lacking interferon regulatory factor. J. Exp. Med. 185:231.[Abstract/Free Full Text]
  18. Reis, L. F., Ruffner, H., Stark, G., Aguet, M. and Weissmann, C. 1994. Mice devoid of interferon regulatory factor 1 (IRF-1) show normal expression of type I interferon genes. EMBO J. 13:4798.[Abstract]
  19. Matsuyama, T., Kimura, T., Kitagawa, M., Pfeffer, K., Kawakami, T., Watanabe, N., Kundig, T. M., Amakawa, R., Kishihara, K., Wakeham, A., et al. 1993. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell 75:83.[ISI][Medline]
  20. Manzella, L., Conte, E., Cocchiaro, G., Guarniera, E., Sciacca, B., Bonaiuto, C., Stagno, F. and Messina, A. 1999. Role of interferon regulatory factor 1 in monocyte/macrophage differentiation. Eur. J. Immunol. 29:3009.[CrossRef][ISI][Medline]
  21. Nikcevich, K. M., Piskurich, J. F., Hellendall, R. P., Wang, Y. and Ting, J. P. 1999. Differential selectivity of CIITA promoter activation by IFN-gamma and IRF-1 in astrocytes and macrophages: CIITA promoter activation is not affected by TNF-alpha. J. Neuroimmunol. 99:195.[CrossRef][ISI][Medline]
  22. Ogasawara, K., Hida, S., Azimi, N., Tagaya, Y., Sato, T., Yokochi-Fukuda, T., Waldmann, T. A., Taniguchi, T. and Taki, S. 1998. Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature 391:700.[CrossRef][ISI][Medline]
  23. Penninger, J. M., Sirard, C., Mittrucker, H. W., Chidgey, A., Kozieradzki, I., Nghiem, M., Hakem, A., Kimura, T., Timms, E., Boyd, R., Taniguchi, T., Matsuyama, T. and Mak, T. W. 1997. The interferon regulatory transcription factor IRF-1 controls positive and negative selection of CD8+ thymocytes. Immunity 7:243.[ISI][Medline]
  24. Doffinger, R., Klein, T. C., Pepys, M. B., Casanova, J. L. and Kyewski, B. A. 1997. The MHC class II-restricted T cell response of C57BL/6 mice to human C-reactive protein: homology to self and the selection of T cell epitopes and T cell receptors. Mol. Immunol. 34:115.[CrossRef][ISI][Medline]
  25. Ferber, I., Schonrich, G., Schenkel, J., Mellor, A. L., Hammerling, G. J. and Arnold, B. 1994. Levels of peripheral T cell tolerance induced by different doses of tolerogen. Science 263:674.[ISI][Medline]
  26. Steinman, L. 2001. Immunotherapy of multiple sclerosis: the end of the beginning. Curr. Opin. Immunol. 13:597.[CrossRef][ISI][Medline]
  27. Chow, W. A., Fang, J. J. and Yee, J. K. 2000. The IFN regulatory factor family participates in regulation of Fas ligand gene expression in T cells. J. Immunol. 164:3512.[Abstract/Free Full Text]
  28. Okuda, Y., Bernard, C. C., Fujimura, H., Yanagihara, T. and Sakoda, S. 1998. Fas has a crucial role in the progression of experimental autoimmune encephalomyelitis. Mol. Immunol. 35:317.[CrossRef][ISI][Medline]
  29. Sabelko-Downes, K. A., Russell, J. H. and Cross, A. H. 1999. Role of Fas–FasL interactions in the pathogenesis and regulation of autoimmune demyelinating disease. J. Neuroimmunol. 100:42.[CrossRef][ISI][Medline]
  30. Gold, R., Hartung, H. P. and Toyka, K. V. 2000. Animal models for autoimmune demyelinating disorders of the nervous system. Mol. Med. Today 6:88.[CrossRef][ISI][Medline]
  31. Falcone, M. and Bloom, B. R. 1997. A T helper cell 2 (Th2) immune response against non-self antigens modifies the cytokine profile of autoimmune T cells and protects against experimental allergic encephalomyelitis. J. Exp. Med. 185:901.[Abstract/Free Full Text]




This Article
Abstract
FREE Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Request Permissions
Google Scholar
Articles by Buch, T.
Articles by Waisman, A.
PubMed
PubMed Citation
Articles by Buch, T.
Articles by Waisman, A.