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IL-10, a key effector regulatory cytokine in experimental autoimmune encephalomyelitis
Journal of Autoimmunity 20 (2003) 265–267 www.elsevier.com/locate/issn/08968411
Forum on interleukin-10
IL-10, a key effector regulatory cytokine in experimental autoimmune encephalomyelitis Estelle Bettelli, Lindsay B. Nicholson, Vijay K. Kuchroo * Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, HIM Room 706, 77 Ave Louis Pasteur, Boston, MA 02115, USA
Experimental autoimmune encephalomyelitis (EAE) is a Th1 mediated inflammatory autoimmune disease of the central nervous system (CNS), which is used as a model of multiple sclerosis [1,2]. Experiments by many investigators have demonstrated that, at least in some circumstances, CNS autoantigen specific Th2 and Th3 cells, and treatments that induce these cell types can regulate EAE [3–6]. These cells secrete many different and important anti-inflammatory effector cytokines including IL-4, IL-10 and TGF-, however, the relative role of each of these cytokines is not understood in complete detail. There is a growing consensus that IL-10 plays an important role in regulating autoimmune reactions, acting in a number of different ways. Also, a number of experimental strategies suggest that IL-10 may be a more significant therapeutic target than IL-4 [7,8]. IL-10 was originally identified as a counter-regulatory cytokine that inhibited Th1 responses [9]. IL-10 inhibits Th1 cell proliferation and cytokine production and, importantly, acts on macrophages to inhibit the secretion of proinflammatory cytokines such as TNF- and IL-12, the expression of MHC class II molecules and the expression of costimulatory molecules, all of which diminish effective antigen presentation. IL-10 binds to a receptor composed of two subunits, the ligand-binding IL-10R1 and the signaling IL-10R2. IL-10R1 and IL-10R2 are expressed on most hematopoietic cells. Interestingly, IL-10R1 expression is actively regulated and is decreased on T cells but increased on monocytes after activation [10]. In experiments in vivo, administration of IL-10 by repeated injection of recombinant cytokine diminished the severity of actively induced EAE when mice were treated at the time of the immunization or during the * Corresponding author. Present address: Center for Neurologic Diseases, HIM 706, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Tel.: +1-617-525-5350; fax: +1-617-525-5333. E-mail address: [email protected] (V.K. Kuchroo).
initial phase of the disease [8,11], but not when IL-10 was given intravenously 12 days after the immunization [12]. These data are consistent with the data obtained from IL-10 producing T cell transgenic mice, which are resistant to the development of EAE [7]. The effects of intracranial delivery of recombinant IL-10 remain controversial with a decrease in disease severity observed in one report [13], but no effect on progression of EAE in another [12]. In contrast to the effects on actively induced EAE, the intravenous injection of IL-10 exacerbated adoptively transferred EAE which may reflect the importance of kinetics of IL-10 expression [14]. IL-10 has also been administered in several novel ways, including plasmid containing IL-10 cDNAcationic complexes, cells transfected or infected with constructs containing IL-10 and IL-10 containing adenovirus. The transfer of fibroblasts infected with IL-10 encoding retrovirus, or of a PLP139–151 specific T cell clone over-expressing IL-10 [15], to mice after the induction phase of disease, decreased the severity of EAE. However, the transfer of a T cell hybridoma which over-expressed IL-10 did not prevent the development of EAE [16]. In addition, opposite results have also been obtained with adenoviral delivery of IL-10 in mice. Intracranial injection of 5106 PFU of type 5 human adenovirus coding for mouse IL-10 (AdRIL10) failed to protect the mice from EAE progression [13]. However, other investigators reported that injection of 3108 PFU of replication deficient adenovirus expressing human IL-10 (hIL10r-Ad) could prevent the development of the disease [12]. The reason for the discrepancy between these results is not clear yet may lie in the amount of adenovirus used. On balance these studies point to an important role of IL-10 in the regulation of EAE progression, but variability in effectiveness due to factors which have not yet been well defined. Experiments in which IL-10 is removed also support a critical role for this cytokine in EAE. We and others have reported that IL-10 deficient (IL-10-/-) mice are
0896-8411/03/$ - see front matter 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0896-8411(03)00048-9
266
E. Bettelli et al. / Journal of Autoimmunity 20 (2003) 265–267
highly susceptible to EAE [7,17,18]. T cells from myelin oligodendrocyte protein (MOG) 35–55 immunized IL-10/ mice hyperproliferate and produce more IFN- in response to the antigen. Also, transfer of MOG reactive IL-10/ T cells induces more severe disease in wild type (WT) C57Bl/6 than equivalent numbers of control WT T cells. On the other hand, transgenic mice over-expressing IL-10 under the control of the CD2 promoter were protected from the development of EAE [7]. Similarly, MHCII IL-10 transgenic mice in which IL-10 is under the control of the MHC class II promoter are resistant to EAE [19]. T cells from these mice also produce lower levels of IFN-. Therefore, experiments manipulating the levels of IL-10 support the assertion that it is a key regulatory cytokine. What is less clear is where, when and how its actions are manifested. Is it a commonly used effector mechanism important in several different modes of immunoregulation, or is there a common mechanism involving specific cell types that has yet to be defined? Certainly, experiments in several different systems have emphasized the importance of distinct populations of cells. These include various regulatory T cells, Tr1 cells and CD4+CD25+ T cells, and autoantigen specific B cells. IL-10 also appears to have a role of great importance in establishing neonatal tolerance [20]. In addition, it may contribute to the control of autoreactive T cell repertoire size. Regulatory T cells that predominantly produce IL-10 have been identified. Some of these T cells are induced in the presence of IL-10, show low proliferative response and inhibit autoimmunity upon adoptive transfer [21]. Treatment of mice with immunosuppressive drugs also generates some IL-10 producing regulatory cells capable of suppressing EAE upon adoptive transfer [22]. The activation of T cells in the presence of IL-10 can induce anergy or non-responsiveness in the treated cells [23]. In addition, non-responsiveness of T cells is often itself associated with increased production of IL-10. Anergic influenza hemagglutinin (HA) specific CD4+ T cells produce high levels of IL-10 and failed to transfer diabetes in an HA-islet expressing transgenic model [24]. Also, oral administration of ovalbumin to DO11.10 TCR transgenic mice induced regulatory CD4+CD25+ T cells capable of suppressing proliferation of CD4+CD25 T cells. This suppression was partially reversible by provision of IL-10 soluble receptor [25]. Finally, intranasal administration of MBP to MBP specific TCR transgenic mice protected the mice from EAE and was associated with increased IL-10 production by the T cells [26]. Whether they represent a distinct population [22] or belong to a Th0/Th2 subtype [27], IL-10 producing cells are critical for limiting EAE development. Overall, therefore, there seems to be a good case that IL-10 production by T cells can fulfill a critical immunoregulatory role.
On the other hand, T cells are not the only cell type relevant to these questions, as is shown in a recent paper which demonstrates that mice recovering from EAE induced with MOG 35–55 have MOG specific B cells secreting IL-10 [28]. Using bone marrow chimeric mice in which the B cell compartment was deficient in IL-10, the authors showed that recovery was dependant on IL-10 in the B cell compartment, although there were significant amounts of IL-10 available from other sources. Thus, IL-10 in the right place and delivered by specific cells may be necessary for maximum therapeutic effect, which will be an important consideration in the therapeutic application of this cytokine. In trying to understand the importance of the kinetics of IL-10 expression, it is clear that the systemic injection of recombinant IL-10, or its inoculation into animals by other means, show that increased levels of IL-10 during the effector phase of the disease have to be achieved in order for the cytokine to mediate its therapeutic effects. In addition, systemic IL-10 seems most effective when present during or just after the induction of EAE. This leads to the possibility that besides controlling IFN- production and the proliferation of pathogenic T cells, IL-10 may also inhibit their migration to the CNS by inhibiting chemokine receptor and adhesion molecule expression. Another intriguing possibility is that IL-10 may influence the repertoire size as well as the expansion of autoreactive T cells. Comparison of autoantigen specific T cell populations in WT and IL-10/ mice would address this question. We have reported that naive SJL mice have a high frequency of autoreactive PLP139–151 specific T cells. Thus, if IL-10 does control the expansion of the naive autoantigen reactive T cell repertoire, there may be a change in the frequency or composition of PLP139–151 reactive T cells in the SJL IL-10/ mice. Our preliminary data using myelin PLP139–151/I-As tetramers suggest that there is indeed an increase in the size of endogenous PLP139–151 reactive repertoire in IL-10/ SJL mice (Reddy, Anderson, Nicholson and Kuchroo, unpublished data). In conclusion, it is clear that IL-10 is a critical regulatory cytokine in organ specific autoimmune disease. It inhibits Th1 cells, but it is also a key effector cytokine produced by regulatory T cells. It inhibits macrophage activation and may also play a key role in controlling the size of the autoreactive repertoire in normal individuals. It is an effector cytokine whose importance has been demonstrated both in T cell and B cell compartments, as well as during the development of neonatal tolerance. Much has been learned about the biology of this cytokine, but because it is widely distributed and multifunctional, much remains to be learned about the subtleties of its place in the immune response in organ specific autoimmune diseases such as EAE and multiple sclerosis. The cytokine and its receptor remain
E. Bettelli et al. / Journal of Autoimmunity 20 (2003) 265–267
tantalizing therapeutic targets for the treatment of autoimmune diseases. References [1] Zamvil SS, Steinman L. The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 1990;8:579–621. [2] Wekerle H. Experimental autoimmune encephalomyelitis as a model of immune-mediated CNS disease. Curr Opin Neurobiol 1993;3:779–84. [3] Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS, Sobel RA et al. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 1995;80:707–18. [4] Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 1995;3:397–405. [5] Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994;265:1237–40. [6] Saoudi A, Simmonds S, Huitinga I, Mason D. 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 1995; 182:335–44. [7] Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol 1998; 161:3299–306. [8] Nagelkerken L, Blauw B, Tielemans M. IL-4 abrogates the inhibitory effect of IL-10 on the development of experimental allergic encephalomyelitis in SJL mice. Int Immunol 1997; 9:1243–51. [9] Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell IV Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989;170:2081–95. [10] Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683–765. [11] Rott O, Fleischer B, Cash E. Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 1994; 24:1434–40. [12] Cua DJ, Hutchins B, LaFace DM, Stohlman SA, Coffman RL. Central nervous system expression of IL-10 inhibits autoimmune encephalomyelitis. J Immunol 2001;166:602–8. [13] Croxford JL, Feldmann M, Chernajovsky Y, Baker D. Different therapeutic outcomes in experimental allergic encephalomyelitis dependent upon the mode of delivery of IL-10: a comparison of the effects of protein, adenoviral or retroviral IL-10 delivery into the central nervous system. J Immunol 2001;166:4124–30.
267
[14] Cannella B, Gao YL, Brosnan C, Raine CS. IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J Neurosci Res 1996;45:735–46. [15] Mathisen PM, Yu M, Johnson JM, Drazba JA, Tuohy VK. Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells. J Exp Med 1997;186:159–64. [16] Shaw MK, Lorens JB, Dhawan A, DalCanto R, Tse HY, Tran AB et al. Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. J Exp Med 1997;185:1711–4. [17] Segal BM, Dwyer BK, Shevach EM. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 1998;187:537–46. [18] Samoilova EB, Horton JL, Chen Y. Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery. Cell Immunol 1998;188:118–24. [19] Cua DJ, Groux H, Hinton DR, Stohlman SA, Coffman RL. Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis. J Exp Med 1999;189:1005–10. [20] Pack CD, Cestra AE, Min B, Legge KL, Li L, Caprio-Young JC et al. Neonatal exposure to antigen primes the immune system to develop responses in various lymphoid organs and promotes bystander regulation of diverse T cell specificities. J Immunol 2001;167:4187–95. [21] Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–42. [22] Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002;195:603–16. [23] Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996;184:19–29. [24] Buer J, Lanoue A, Franzke A, Garcia C, von Boehmer H, Sarukhan A. Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J Exp Med 1998;187:177–83. [25] Zhang X, Izikson L, Liu L, Weiner HL. Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration. J Immunol 2001;167:4245–53. [26] Burkhart C, Liu GY, Anderton SM, Metzler B, Wraith DC. Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. Int Immunol 1999; 11:1625–34. [27] Stohlman SA, Pei L, Cua DJ, Li Z, Hinton DR. Activation of regulatory cells suppresses experimental allergic encephalomyelitis via secretion of IL-10. J Immunol 1999;163:6338–44. [28] Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002;3:944–50.
Forum on interleukin-10
IL-10, a key effector regulatory cytokine in experimental autoimmune encephalomyelitis Estelle Bettelli, Lindsay B. Nicholson, Vijay K. Kuchroo * Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, HIM Room 706, 77 Ave Louis Pasteur, Boston, MA 02115, USA
Experimental autoimmune encephalomyelitis (EAE) is a Th1 mediated inflammatory autoimmune disease of the central nervous system (CNS), which is used as a model of multiple sclerosis [1,2]. Experiments by many investigators have demonstrated that, at least in some circumstances, CNS autoantigen specific Th2 and Th3 cells, and treatments that induce these cell types can regulate EAE [3–6]. These cells secrete many different and important anti-inflammatory effector cytokines including IL-4, IL-10 and TGF-, however, the relative role of each of these cytokines is not understood in complete detail. There is a growing consensus that IL-10 plays an important role in regulating autoimmune reactions, acting in a number of different ways. Also, a number of experimental strategies suggest that IL-10 may be a more significant therapeutic target than IL-4 [7,8]. IL-10 was originally identified as a counter-regulatory cytokine that inhibited Th1 responses [9]. IL-10 inhibits Th1 cell proliferation and cytokine production and, importantly, acts on macrophages to inhibit the secretion of proinflammatory cytokines such as TNF- and IL-12, the expression of MHC class II molecules and the expression of costimulatory molecules, all of which diminish effective antigen presentation. IL-10 binds to a receptor composed of two subunits, the ligand-binding IL-10R1 and the signaling IL-10R2. IL-10R1 and IL-10R2 are expressed on most hematopoietic cells. Interestingly, IL-10R1 expression is actively regulated and is decreased on T cells but increased on monocytes after activation [10]. In experiments in vivo, administration of IL-10 by repeated injection of recombinant cytokine diminished the severity of actively induced EAE when mice were treated at the time of the immunization or during the * Corresponding author. Present address: Center for Neurologic Diseases, HIM 706, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. Tel.: +1-617-525-5350; fax: +1-617-525-5333. E-mail address: [email protected] (V.K. Kuchroo).
initial phase of the disease [8,11], but not when IL-10 was given intravenously 12 days after the immunization [12]. These data are consistent with the data obtained from IL-10 producing T cell transgenic mice, which are resistant to the development of EAE [7]. The effects of intracranial delivery of recombinant IL-10 remain controversial with a decrease in disease severity observed in one report [13], but no effect on progression of EAE in another [12]. In contrast to the effects on actively induced EAE, the intravenous injection of IL-10 exacerbated adoptively transferred EAE which may reflect the importance of kinetics of IL-10 expression [14]. IL-10 has also been administered in several novel ways, including plasmid containing IL-10 cDNAcationic complexes, cells transfected or infected with constructs containing IL-10 and IL-10 containing adenovirus. The transfer of fibroblasts infected with IL-10 encoding retrovirus, or of a PLP139–151 specific T cell clone over-expressing IL-10 [15], to mice after the induction phase of disease, decreased the severity of EAE. However, the transfer of a T cell hybridoma which over-expressed IL-10 did not prevent the development of EAE [16]. In addition, opposite results have also been obtained with adenoviral delivery of IL-10 in mice. Intracranial injection of 5106 PFU of type 5 human adenovirus coding for mouse IL-10 (AdRIL10) failed to protect the mice from EAE progression [13]. However, other investigators reported that injection of 3108 PFU of replication deficient adenovirus expressing human IL-10 (hIL10r-Ad) could prevent the development of the disease [12]. The reason for the discrepancy between these results is not clear yet may lie in the amount of adenovirus used. On balance these studies point to an important role of IL-10 in the regulation of EAE progression, but variability in effectiveness due to factors which have not yet been well defined. Experiments in which IL-10 is removed also support a critical role for this cytokine in EAE. We and others have reported that IL-10 deficient (IL-10-/-) mice are
0896-8411/03/$ - see front matter 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0896-8411(03)00048-9
266
E. Bettelli et al. / Journal of Autoimmunity 20 (2003) 265–267
highly susceptible to EAE [7,17,18]. T cells from myelin oligodendrocyte protein (MOG) 35–55 immunized IL-10/ mice hyperproliferate and produce more IFN- in response to the antigen. Also, transfer of MOG reactive IL-10/ T cells induces more severe disease in wild type (WT) C57Bl/6 than equivalent numbers of control WT T cells. On the other hand, transgenic mice over-expressing IL-10 under the control of the CD2 promoter were protected from the development of EAE [7]. Similarly, MHCII IL-10 transgenic mice in which IL-10 is under the control of the MHC class II promoter are resistant to EAE [19]. T cells from these mice also produce lower levels of IFN-. Therefore, experiments manipulating the levels of IL-10 support the assertion that it is a key regulatory cytokine. What is less clear is where, when and how its actions are manifested. Is it a commonly used effector mechanism important in several different modes of immunoregulation, or is there a common mechanism involving specific cell types that has yet to be defined? Certainly, experiments in several different systems have emphasized the importance of distinct populations of cells. These include various regulatory T cells, Tr1 cells and CD4+CD25+ T cells, and autoantigen specific B cells. IL-10 also appears to have a role of great importance in establishing neonatal tolerance [20]. In addition, it may contribute to the control of autoreactive T cell repertoire size. Regulatory T cells that predominantly produce IL-10 have been identified. Some of these T cells are induced in the presence of IL-10, show low proliferative response and inhibit autoimmunity upon adoptive transfer [21]. Treatment of mice with immunosuppressive drugs also generates some IL-10 producing regulatory cells capable of suppressing EAE upon adoptive transfer [22]. The activation of T cells in the presence of IL-10 can induce anergy or non-responsiveness in the treated cells [23]. In addition, non-responsiveness of T cells is often itself associated with increased production of IL-10. Anergic influenza hemagglutinin (HA) specific CD4+ T cells produce high levels of IL-10 and failed to transfer diabetes in an HA-islet expressing transgenic model [24]. Also, oral administration of ovalbumin to DO11.10 TCR transgenic mice induced regulatory CD4+CD25+ T cells capable of suppressing proliferation of CD4+CD25 T cells. This suppression was partially reversible by provision of IL-10 soluble receptor [25]. Finally, intranasal administration of MBP to MBP specific TCR transgenic mice protected the mice from EAE and was associated with increased IL-10 production by the T cells [26]. Whether they represent a distinct population [22] or belong to a Th0/Th2 subtype [27], IL-10 producing cells are critical for limiting EAE development. Overall, therefore, there seems to be a good case that IL-10 production by T cells can fulfill a critical immunoregulatory role.
On the other hand, T cells are not the only cell type relevant to these questions, as is shown in a recent paper which demonstrates that mice recovering from EAE induced with MOG 35–55 have MOG specific B cells secreting IL-10 [28]. Using bone marrow chimeric mice in which the B cell compartment was deficient in IL-10, the authors showed that recovery was dependant on IL-10 in the B cell compartment, although there were significant amounts of IL-10 available from other sources. Thus, IL-10 in the right place and delivered by specific cells may be necessary for maximum therapeutic effect, which will be an important consideration in the therapeutic application of this cytokine. In trying to understand the importance of the kinetics of IL-10 expression, it is clear that the systemic injection of recombinant IL-10, or its inoculation into animals by other means, show that increased levels of IL-10 during the effector phase of the disease have to be achieved in order for the cytokine to mediate its therapeutic effects. In addition, systemic IL-10 seems most effective when present during or just after the induction of EAE. This leads to the possibility that besides controlling IFN- production and the proliferation of pathogenic T cells, IL-10 may also inhibit their migration to the CNS by inhibiting chemokine receptor and adhesion molecule expression. Another intriguing possibility is that IL-10 may influence the repertoire size as well as the expansion of autoreactive T cells. Comparison of autoantigen specific T cell populations in WT and IL-10/ mice would address this question. We have reported that naive SJL mice have a high frequency of autoreactive PLP139–151 specific T cells. Thus, if IL-10 does control the expansion of the naive autoantigen reactive T cell repertoire, there may be a change in the frequency or composition of PLP139–151 reactive T cells in the SJL IL-10/ mice. Our preliminary data using myelin PLP139–151/I-As tetramers suggest that there is indeed an increase in the size of endogenous PLP139–151 reactive repertoire in IL-10/ SJL mice (Reddy, Anderson, Nicholson and Kuchroo, unpublished data). In conclusion, it is clear that IL-10 is a critical regulatory cytokine in organ specific autoimmune disease. It inhibits Th1 cells, but it is also a key effector cytokine produced by regulatory T cells. It inhibits macrophage activation and may also play a key role in controlling the size of the autoreactive repertoire in normal individuals. It is an effector cytokine whose importance has been demonstrated both in T cell and B cell compartments, as well as during the development of neonatal tolerance. Much has been learned about the biology of this cytokine, but because it is widely distributed and multifunctional, much remains to be learned about the subtleties of its place in the immune response in organ specific autoimmune diseases such as EAE and multiple sclerosis. The cytokine and its receptor remain
E. Bettelli et al. / Journal of Autoimmunity 20 (2003) 265–267
tantalizing therapeutic targets for the treatment of autoimmune diseases. References [1] Zamvil SS, Steinman L. The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol 1990;8:579–621. [2] Wekerle H. Experimental autoimmune encephalomyelitis as a model of immune-mediated CNS disease. Curr Opin Neurobiol 1993;3:779–84. [3] Kuchroo VK, Das MP, Brown JA, Ranger AM, Zamvil SS, Sobel RA et al. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell 1995;80:707–18. [4] Nicholson LB, Greer JM, Sobel RA, Lees MB, Kuchroo VK. An altered peptide ligand mediates immune deviation and prevents autoimmune encephalomyelitis. Immunity 1995;3:397–405. [5] Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994;265:1237–40. [6] Saoudi A, Simmonds S, Huitinga I, Mason D. 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 1995; 182:335–44. [7] Bettelli E, Das MP, Howard ED, Weiner HL, Sobel RA, Kuchroo VK. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J Immunol 1998; 161:3299–306. [8] Nagelkerken L, Blauw B, Tielemans M. IL-4 abrogates the inhibitory effect of IL-10 on the development of experimental allergic encephalomyelitis in SJL mice. Int Immunol 1997; 9:1243–51. [9] Fiorentino DF, Bond MW, Mosmann TR. Two types of mouse T helper cell IV Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 1989;170:2081–95. [10] Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683–765. [11] Rott O, Fleischer B, Cash E. Interleukin-10 prevents experimental allergic encephalomyelitis in rats. Eur J Immunol 1994; 24:1434–40. [12] Cua DJ, Hutchins B, LaFace DM, Stohlman SA, Coffman RL. Central nervous system expression of IL-10 inhibits autoimmune encephalomyelitis. J Immunol 2001;166:602–8. [13] Croxford JL, Feldmann M, Chernajovsky Y, Baker D. Different therapeutic outcomes in experimental allergic encephalomyelitis dependent upon the mode of delivery of IL-10: a comparison of the effects of protein, adenoviral or retroviral IL-10 delivery into the central nervous system. J Immunol 2001;166:4124–30.
267
[14] Cannella B, Gao YL, Brosnan C, Raine CS. IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J Neurosci Res 1996;45:735–46. [15] Mathisen PM, Yu M, Johnson JM, Drazba JA, Tuohy VK. Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells. J Exp Med 1997;186:159–64. [16] Shaw MK, Lorens JB, Dhawan A, DalCanto R, Tse HY, Tran AB et al. Local delivery of interleukin 4 by retrovirus-transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. J Exp Med 1997;185:1711–4. [17] Segal BM, Dwyer BK, Shevach EM. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med 1998;187:537–46. [18] Samoilova EB, Horton JL, Chen Y. Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery. Cell Immunol 1998;188:118–24. [19] Cua DJ, Groux H, Hinton DR, Stohlman SA, Coffman RL. Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis. J Exp Med 1999;189:1005–10. [20] Pack CD, Cestra AE, Min B, Legge KL, Li L, Caprio-Young JC et al. Neonatal exposure to antigen primes the immune system to develop responses in various lymphoid organs and promotes bystander regulation of diverse T cell specificities. J Immunol 2001;167:4187–95. [21] Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–42. [22] Barrat FJ, Cua DJ, Boonstra A, Richards DF, Crain C, Savelkoul HF et al. In vitro generation of interleukin 10-producing regulatory CD4(+) T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002;195:603–16. [23] Groux H, Bigler M, de Vries JE, Roncarolo MG. Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996;184:19–29. [24] Buer J, Lanoue A, Franzke A, Garcia C, von Boehmer H, Sarukhan A. Interleukin 10 secretion and impaired effector function of major histocompatibility complex class II-restricted T cells anergized in vivo. J Exp Med 1998;187:177–83. [25] Zhang X, Izikson L, Liu L, Weiner HL. Activation of CD25(+)CD4(+) regulatory T cells by oral antigen administration. J Immunol 2001;167:4245–53. [26] Burkhart C, Liu GY, Anderton SM, Metzler B, Wraith DC. Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. Int Immunol 1999; 11:1625–34. [27] Stohlman SA, Pei L, Cua DJ, Li Z, Hinton DR. Activation of regulatory cells suppresses experimental allergic encephalomyelitis via secretion of IL-10. J Immunol 1999;163:6338–44. [28] Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 2002;3:944–50.