The mainstay of the current treatment for systemic lupus erythematosus consists of steroids and immunosuppressants. However, these non-specific immunosuppressive therapies can cause infection and other serious adverse events. The regulation of the autoantigen-specific immune response is a promising therapeutic approach with maximal efficacy and minimal adverse effects. T cells are essential components of antigen-specificity in the immune system. At present, we do not have a sufficient strategy for manipulating the responses of antigen-specific T cells. In this review, we describe the efficacy of two therapeutic approaches involving the modulation of autoantigen recognition by T cells in lupus model mice: (1) therapy involving engineered autoantigen-specific regulatory T cells generated by the gene transfer of autoantigen-specific TCR genes and appropriate regulatory genes into self lymphocytes; (2) therapy involving selective depletion of autoantigen presenting phagocytes. These selective immunosuppressive approaches could be useful strategies for the treatment of systemic lupus erythematosus.
Cervera R., Khamashta MA, Font J., et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore ) 2003; 82: 299-308.
2.
Blanco P., Palucka AK, Gill M., Pascual V., Banchereau J.Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science2001; 294: 1540-1543.
3.
Stewart TANeutralizing interferon alpha as a therapeutic approach to autoimmune diseases . Cytokine Growth Factor Rev2003; 14: 139-154.
4.
Baechler EC, Gregersen PK, Behrens TWThe emerging role of interferon in human systemic lupus erythematosus. Curr Opin Immunol2004; 16: 801-807.
5.
Sanz I.Connective tissue diseases: The conundrum of B cell depletion in SLE. Nat Rev Rheumatol2009; 5: 304-305.
6.
Vanderlugt CL , Miller SDEpitope spreading in immune-mediated diseases: implications for immunotherapy. Nat Rev Immunol2002; 2: 85-95.
7.
Yamamoto K., Masuko-Hongo K., Tanaka A., et al. Establishment and application of a novel T cell clonality analysis using single-strand conformation polymorphism of T cell receptor messenger signals. Hum Immunol1996; 48: 23-31.
8.
Fujio K., Okamoto A., Tahara H., et al. Nucleosome-specific regulatory T cells engineered by triple gene transfer suppress a systemic autoimmune disease. J Immunol2004; 173: 2118-2125.
9.
Okamoto A., Fujio K., van Rooijen N., et al. Splenic phagocytes promote responses to nucleosomes in (NZB x NZW) F1 mice. J Immunol2008; 181: 5264-5271.
10.
Yamamoto K. , Sakoda H., Nakajima T., et al. Accumulation of multiple T cell clonotypes in the synovial lesions of patients with rheumatoid arthritis revealed by a novel clonality analysis. Int Immunol1992 ; 4: 1219-1223.
11.
Iwakura Y., Tosu M., Yoshida E., et al. Induction of inflammatory arthropathy resembling rheumatoid arthritis in mice transgenic for HTLV-I. Science1991; 253: 1026-1028.
12.
Kobari Y., Misaki Y., Setoguchi K., et al. T cells accumulating in the inflamed joints of a spontaneous murine model of rheumatoid arthritis become restricted to common clonotypes during disease progression. Int Immunol2004 ; 16: 131-138.
13.
Zhou G., Fujio K., Sadakata A., et al. Identification of systemically expanded activated T cell clones in MRL/lpr and NZB/W F1 lupus model mice. Clin Exp Immunol2004; 136: 448-455.
14.
Van den Elzen P., Menezes JS, Ametani A., et al. Limited clonality in autoimmunity: drivers and regulators. Autoimmun Rev2004; 3: 524-529.
15.
Huang JC, Ober RJ, Ward ESThe central residues of a T cell receptor sequence motif are key determinants of autoantigen recognition in murine experimental autoimmune encephalomyelitis . Eur J Immunol2005; 35: 299-304.
16.
Hofbauer M. , Wiesener S., Babbe H., et al. Clonal tracking of auto-aggressive T cells in polymyositis by combining laser microdissection, single-cell PCR, and CDR3-spectratype analysis. Proc Natl Acad Sci USA2003; 100: 4090-4095.
17.
Kent SC, Chen Y., Bregoli L., et al. Expanded T cells from pancreatic lymph nodes of type 1 diabetic subjects recognize an insulin epitope. Nature2005; 435: 224-228.
18.
Amrani A., Verdaguer J., Serra P., et al. Progression of autoimmune diabetes driven by avidity maturation of a T-cell population. Nature2000; 406: 739-742.
19.
Kedzierska K., Turner SJ, Doherty PCConserved T cell receptor usage in primary and recall responses to an immunodominant influenza virus nucleoprotein epitope . Proc Natl Acad Sci USA2004; 101: 4942-4947.
20.
Malherbe L. , Hausl C., Teyton L., McHeyzer-Williams MGClonal selection of helper T cells is determined by an affinity threshold with no further skewing of TCR binding properties. Immunity2004; 21: 669-679.
21.
Facchinetti A. , Dalla Santa S., Mezzalira S., Rosato A., Biasi G.A large number of T lymphocytes recognize Moloney-murine leukemia virus-induced antigens, but a few mediate long-lasting tumor immunosurveillance. J Immunol2005; 174: 5398-5406.
22.
Mohan C., Adams S., Stanik V., Datta SKNucleosome - a major immunogen for pathogenic autoantibody-inducing T-cells of lupus. J Exp Med1993; 177: 1367-1381.
23.
Kaliyaperumal A., Mohan C., Wu W., Datta SKNucleosomal peptide epitopes for nephritis-inducing T helper cells of murine lupus. J Exp Med1996; 183: 2459-2469.
24.
Lu L., Kaliyaperumal A., Boumpas DT, Datta SKMajor peptide autoepitopes for nucleosome-specific T cells of human lupus . J Clin Invest1999; 104: 345-355.
25.
Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M.Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol1995; 155: 1151-1164.
26.
Sakaguchi S.Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol2005; 6: 345-352.
27.
Miyara M., Amoura Z., Parizot C., et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol2005; 175: 8392-8400.
28.
Valencia X. , Yarboro C., Illei G., Lipsky PEDeficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol2007; 178: 2579-2588.
29.
Bluestone JA , Tang Q.Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells. Proc Natl Acad Sci USA2004; 101: 14622-14626.
30.
Tang Q., Henriksen KJ, Bi M., et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med2004; 199: 1455-1465.
31.
Tarbell KV, Yamazaki S., Olson K., Toy P., Steinman RMCD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med2004; 199: 1467-1477.
32.
Fujio K., Okamoto A., Araki Y., et al. Gene therapy of arthritis with TCR isolated from the inflamed paw. J Immunol2006; 177: 8140-8147.
33.
Van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LSCD4(+)CD25(+) regulatory T cells in rheumatoid arthritis: differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum2004; 50: 2775-2785.
34.
Morgan RA, Dudley ME, Wunderlich JR, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science2006; 314: 126-129.
35.
Hanayama R. , Tanaka M., Miyasaka K., et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science2004; 304: 1147-1150.
36.
Scott RS, McMahon EJ, Pop SM, et al. Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature2001; 411: 207-211.
37.
Devitt A., Parker KG, Ogden CA, et al. Persistence of apoptotic cells without autoimmune disease or inflammation in CD14-/mice. J Cell Biol2004 ; 167: 1161-1170.
38.
Ding D., Mehta H., McCune WJ, Kaplan MJAberrant phenotype and function of myeloid dendritic cells in systemic lupus erythematosus. J Immunol2006; 177: 5878-5889.
39.
Van Rooijen N., Sanders A.Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Methods1994; 174: 83-93.
40.
Aichele P., Zinke J., Grode L., et al. Macrophages of the splenic marginal zone are essential for trapping of blood-borne particulate antigen but dispensable for induction of specific T cell responses. J Immunol2003; 171: 1148-1155.
41.
Mebius RE, Kraal G.Structure and function of the spleen. Nat Rev Immunol2005; 5: 606-616.
42.
Kuwana M., Okazaki Y., Ikeda Y.Splenic macrophages maintain the anti-platelet autoimmune response via uptake of opsonized platelets in patients with immune thrombocytopenic purpura. J Thromb Haemost2009; 7: 322-329.
43.
Koh JS, Wang Z., Levine JSCytokine dysregulation induced by apoptotic cells is a shared characteristic of murine lupus. J Immunol2000; 165: 4190-4201.
44.
Fan H., Patel VA, Longacre A., Levine JSAbnormal regulation of the cytoskeletal regulator Rho typifies macrophages of the major murine models of spontaneous autoimmunity. J Leukoc Biol2006; 79: 155-165.
45.
Sze DM, Toellner KM, Garcia de Vinuesa C., Taylor DR, MacLennan ICIntrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J Exp Med2000; 192: 813-821.
