The pathogenesis of systemic lupus erythematosus is believed to involve defects in regulatory T cell (Treg) activity and abnormal activation of B and T lymphocytes. The purpose of this study was to test the therapeutic potential of rabbit anti-mouse thymocyte globulin (ATG), a lymphocyte-depleting agent, in conjunction with transforming growth factor (TGF)-β1, a factor involved in the induction and expansion of Tregs. MRL/lpr mice with active disease were treated with ATG followed by a 12-day course of latent TGF-β1 during the period of lymphocyte repopulation. Treatment with ATG + latent TGF-β1 synergistically inhibited the progression of proteinuria and albuminuria and provided a significant improvement in long-term survival. This therapeutic benefit correlated histologically with reduced glomerular pathology and protein cast formation. The mechanism of action did not involve suppression of autoantibody formation but may involve the activity of CD4+CD25+FoxP3+ Tregs, which were found to be induced by ATG + TGF-β1 treatment in vitro.
1 Miyara M Amoura Z Parizot C . Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol2005; 175: 8392–8400.
2.
2 Liu MF Wang CR Fung LL Wu CR . Decreased CD4+CD25+ T cells in peripheral blood of patients with systemic lupus erythematosus. Scand J Immunol2004; 59: 198–202.
3.
3 Valencia X Yarboro C Illei G Lipsky PE . Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J Immunol2007; 178: 2579–2588.
5 Schlomchik MJ Craft JE Mamula MJ . From T to B and back again: positive feedback in systemic autoimmune disease. Nature Rev Immunol2001; 1: 147–153.
6.
6 Stohl W . Therapeutic targeting of B lymphocyte stimulator (BLyS) in the rheumatic disease. Endocr Metab Immune Disord Drug Targets2006; 6: 351–358.
7.
7 Gillis JZ Dall’era M Gross A Yazdany J Davis J . Six refractory lupus patients treated with rituximab: a case series. Arhtritis Rheum2007; 57: 538–542.
8.
8 Tanaka Y Yamamoto K Takeuchi T . A multicenter phase I/II trial of rituximab for refractory systemic lupus erythematosus. Mod Rheumatol2007; 17: 191–197.
9.
9 Brennan DC Flavin K Lowell JA . A randomized, double-blinded comparison for thymoglobulin versus ATGAM for induction immunosuppressive therapy in adult renal transplant recipients. Transplantation1999; 67: 1011–1018.
10.
10 Lopez M Clarkson MR Albin M . A novel mechanism of action for anti-thymocyte globulin: induction of CD4+CD25+Foxp3+ regulatory T cells. Am Soc Nephrol2006; 17: 2844–2853.
11.
11 Minamimura K Gao W Maki T . CD4+ regulatory T cells are spared from deletion by antilymphocyte serum, a polyclonal anti-T cell antibody. J Immunol2006; 176: 4125–4132.
12.
12 Yamagiwa S Gray JD Hashimoto S Horwitz DA . A role for TGF-β in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol2001; 166: 7282–7289.
13.
13 Chen W Jin W Hargeden N . Conversion of peripheral CD24+25− naïve T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J Exp Med2003; 198: 1875–1886.
14.
14 Huber S Schramm C Lehr HA . TGF-β signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol2004; 173: 6526–6531.
15.
15 Rao PE Petrone AL Ponath PD . Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF-β. J Immunol2005; 174: 1446–1455.
16.
16 Selvaraj RK Geiger TL . A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-β. J Immunol2007; 178: 7667–7677.
17.
17 Zheng SG Wang J Wang P Gray JD Horwitz DA . IL-2 is essential for TGF-β to convert naïve CD4+CD25− cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J Immunol2007; 178: 2018–2027.
18.
18 Calabresi PA Fields NS Maloni HW . Phase I trial of transforming growth factor β2 in chronic progressive MS. Neurology1998; 51: 289–292.
19.
19 Munger JS Harpel JG Gleizes PE . Latent transforming growth factor-β: structural features and mechanisms of activation. Kidney Int.1997; 51: 1376–1382.
20.
20 Wang J Zhu Z Nolfo R Elisa J . Dexamethasone regulation of lung epithelial cell and fibroblast interleukin-11 production. Am J Physiol1999; 276: L175–L185.
21.
21 Chan OTM Hannum LG Haberman AM . A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med1999; 189: 1639–1647.
22.
22 Clynes R Dumitru C Ravetch JV . Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science1998; 279: 1052–1054.
23.
23 Balomenos D Rumold R Theofilopoulos AN . Interferon-γ is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice. J Clin Invest1998; 101: 364–371.
24.
24 Kulkarni O Pawar RD Purschke W . Spiegelmer inhibition of CCL2/MCP-1 ameliorates lupus nephritis in MRL-(Fas)lpr mice. J Am Soc Nephrol2007; 18: 2350–2358.
25.
25 Rodriguez W Mold C Marnell LL . Prevention and reversal of nephritis in MRL/lpr mice with a single injection of C-reactive protein. Arthritis Rheum2006; 54: 325–335.
26.
26 Marie JC Letterio JJ Gavin M Rudensky AY . TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med2005; 7: 1061–1067.
27.
27 Harada M Makino S . Suppression of overt diabetes in NOD mice by anti-thymocyte serum or anti-Thy 1.2 antibody. Exp Anim1986; 35: 501–504.
28.
28 Maki T Ichikawa T Blanco R Porter J . Long-term abrogation of autoimmune diabetes in nonobese diabetic mice by immunotherapy with anti-lymphocyte serum. Proc Natl Acad Sci1992; 89: 3434–3438.
29.
29 Ogawa N List JF Habener JF Maki T . Cure of overt diabetes in NOD mice by transient treatment with anti-lymphocyte serum and exendin-4. Diabetes2004; 53: 1700–1705.
30.
30 Yang M-H Suen J-L Li S-L Chiang B-L . Identification of T-cell epitopes on U1A protein in MRL/lpr mice: double-negative T cells are the major responsive cells. Immunology2005; 115: 279–286.
31.
31 Ahuja A Shupe J Dunn R . Depletion of B cells in murine lupus: efficacy and resistance. J Immunol2007; 179: 3351–3361.
32.
32 Wahl SM Wen J Moutsopoulos N . TGF-β: a mobile purveyor of immune privilege. Immunol Rev2006; 213: 213–227.
