A Peptide Based on the Complementarity Determining Region 1 of a Human Monoclonal Autoantibody Ameliorates Spontaneous and Induced Lupus Manifestations in Correlation with Cytokine Immunomodulation
Tóm tắt
A peptide based on the sequence of the complementarity determining region (CDR) 1 of a human monoclonal anti-DNA autoantibody that bears the 16/6 idiotype (16/6Id) was synthesized as a potential candidate for the treatment of SLE patients. The peptide, designated hCDR1, did not induce experimental SLE upon active immunization of mice. The ability of the peptide to treat an already established lupus that was either induced in BALB/c mice or developed spontaneously in (NZB × NZW)F1 mice was tested. Ten weekly injections of hCDR1 (200, 50 μg/mouse) given subcutaneously mitigated disease manifestations (e.g., leukopenia, proteinuria and kidney damage) and resulted in a prominent reduction in the dsDNA specific antibody titers. Furthermore, treatment with hCDR1 resulted in reduced secretion and expression of the “pathogenic” cytokines [i.e., INFγ, IL-1β, TNFα (in the induced model) and IL-10], whereas the immunosuppressive cytokine TGFβ was up-regulated. Thus, the significant ameliorating effects of hCDR1 are manifested at least partially via the immunomodulation of the cytokine profile. These results suggest that hCDR1 is a potential candidate for a novel treatment of SLE patients.
Tài liệu tham khảo
Hahn BH: An overview of the pathogenesis of systemic lupus erithematosus. In Dubois’ Lupus Erithematosus. BH DJ Wallace (ed). Philadelphia, Williams and Wilkins, 1993, pp 69–76
Theofilopoulos A: Murine models of lupus. In Systemic Lupus Erithematosus. LR G (ed). New York, Charchill Livingston, 1992, pp 121–194
Morel L, Wakeland EK: Susceptibility to lupus nephritis in the NZB/W model system. Curr Opin Immunol10:718–725, 1998
Mendlovic S, Brocke S, Shoenfeld Y, Ben-Bassat M, Meshorer A, Bakimer R, Mozes E: Induction of a systemic lupus erythematosus-like disease in mice by a common human anti-DNA idiotype. Proc Natl Acad Sci U S A85:2260–2264, 1988
Waisman A, Mendlovic S, Ruiz PJ, Zinger H, Meshorer A, Mozes E: The role of the 16/6 idiotype network in the induction and manifestations of systemic lupus erythematosus. Int Immunol5:1293–1300, 1993
Mendlovic S, Brocke S, Fricke H, Shoenfeld Y, Bakimer R, Mozes E: The genetic regulation of the induction of experimental SLE. Immunology69:228–236, 1990
Horwitz DA, Jacob CO: The cytokine network in the pathogenesis of systemic lupus erythematosus and possible therapeutic implications. Springer Semin Immunopathol 16:181–200, 1994
Handwerger BS, Rus V, da Silva L, Via CS: The role of cytokines in the immunopathogenesis of lupus. Springer Semin Immunopathol16:153–180, 1994
Segal R, Bermas BL, Dayan M, Kalush F, Shearer GM, Mozes E: Kinetics of cytokine production in experimental systemic lupus erythematosus: Involvement of T helper cell 1/T helper cell 2-type cytokines in disease. J Immunol158:3009–3016, 1997
Akahoshi M, Nakashima H, Tanaka Y, Kohsaka T, Nagano S, Ohgami E, Arinobu Y, Yamaoka K, Niiro H, Shinozaki M, Hirakata H, Horiuchi T, Otsuka T, Niho Y: Th1/Th2 balance of peripheral T helper cells in systemic lupus erythematosus. Arthritis Rheum42:1644–1648, 1999
Waisman A, Ruiz PJ, Israeli E, Eilat E, Konen-Waisman S, Zinger H, Dayan M, Mozes E: Modulation of murine systemic lupus erythematosus with peptides based on complementarity determining regions of a pathogenic anti-DNA monoclonal antibody. Proc Natl Acad Sci USA94:4620–4625, 1997
Eilat E, Zinger H, Nyska A, Mozes E: Prevention of systemic lupus erythematosus-like disease in (NZB×NZW)F1 mice by treating with CDR1- and CDR3-based peptides of a pathogenic autoantibody. J Clin Immunol20:268–278, 2000
Eilat E, Dayan M, Zinger H, Mozes E: The mechanism by which a peptide based on complementarity-determining region-1 of a pathogenic anti-DNA auto-Ab ameliorates experimental systemic lupus erythematosus. Proc Natl Acad Sci USA98:1148–1153, 2001
Zinger H, Eilat E, Meshorer A, Mozes E: Peptides based on the complementarity-determining regions of a pathogenic autoantibody mitigate lupus manifestations of (NZB×NZW)F1 mice via active suppression. Int Immunol 15:205–214, 2003
Waisman A, Shoenfeld Y, Blank M, Ruiz PJ, Mozes E: The pathogenic human monoclonal anti-DNA that induces experimental systemic lupus erythematosus in mice is encoded by a VH4 gene segment. Int Immunol7:689–696, 1995
Sthoeger ZM, Dayan M, Tcherniack A, Green L, Toledo S, Segal R, Elkayam O, Mozes E: Modulation of autoreactive responses of peripheral blood lymphocytes of patients with systemic lupus erythematosus by peptides based on human and murine anti-DNA autoantibodies. Clin Exp Immunol131:385–392, 2003
Shoenfeld Y, Hsu-Lin SC, Gabriels JE, Silberstein LE, Furie BC, Furie B, Stollar BD, Schwartz RS: Production of autoantibodies by human-human hybridomas. J Clin Invest 70:205–208, 1982
Tillman DM, Jou NT, Hill RJ, Marion TN: Both IgM and IgG anti-DNA antibodies are the products of clonally selective B cell stimulation in (NZB×NZW)F1 mice. J Exp Med176:761–779, 1992
Wloch MK, Alexander AL, Pippen AM, Pisetsky DS, Gilkeson GS: Molecular properties of anti-DNA induced in preautoimmune NZB/W mice by immunization with bacterial DNA. J Immunol158:4500–4506, 1997
Waisman A, Mozes E: Variable region sequences of autoantibodies from mice with experimental systemic lupus erythematosus. Eur J Immunol23:1566–1573, 1993
Hahn BH, Singh RR, Wong WK, Tsao BP, Bulpitt K, Ebling FM: Treatment with a consensus peptide based on amino acid sequences in autoantibodies prevents T cell activation by autoantigens and delays disease onset in murine lupus. Arthritis Rheum44:432–441, 2001
Jouanne C, Avrameas S, Payelle-Brogard B: A peptide derived from a polyreactive monoclonal anti-DNA natural antibody can modulate lupus development in (NZB×NZW)F1 mice. Immunology96:333–339, 1999
Kaliyaperumal A, Michaels MA, Datta SK: Antigen-specific therapy of murine lupus nephritis using nucleosomal peptides: Tolerance spreading impairs pathogenic function of autoimmune T and B cells. J Immunol162:5775–5783, 1999
Gaynor B, Putterman C, Valadon P, Spatz L, Scharff MD, Diamond B: Peptide inhibition of glomerular deposition of an anti-DNA antibody. Proc Natl Acad Sci USA94:1955–1960, 1997
Dean GS, Tyrrell-Price J, Crawley E, Isenberg DA: Cytokines and systemic lupus erythematosus. Ann. Rheum. Dis.59:243–251, 2000
PruD’homme GJ, Kono DH, Theofilopoulos AN: Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1 beta, interleukin-1 and interferon-gamma mRNA in the lymph nodes of lupus-prone mice. Mol Immunol32:495–503, 1995
Kirou KA, Crow MK: New pieces to the SLE cytokine puzzle. Clin Immunol91:1–5, 1999
Jacob CO, McDevitt HO: Tumour necrosis factor-alpha in murine autoimmune ‘lupus’ nephritis. Nature331:356–358, 1988
Brosh N, Zinger H, Mozes E: Treatment of induced murine SLE with a peptide based on the CDR3 of an anti-DNA antibody reverses the pattern of pathogenic cytokines. Autoimmunity35:211–219, 2002
Yaswen L, Kulkarni AB, Fredrickson T, Mittleman B, Schiffman R, Payne S, Longenecker G, Mozes E, Karlsson S: Autoimmune manifestations in the transforming growth factor-beta 1 knockout mouse. Blood87:1439–1445, 1996
Raz E, Watanabe A, Baird SM, Eisenberg RA, Parr TB, Lotz M, Kipps TJ, Carson DA: Systemic immunological effects of cytokine genes injected into skeletal muscle. Proc Natl Acad Sci USA90:4523–4527, 1993
Ohtsuka K, Gray JD, Stimmler MM, Toro B, Horwitz DA: Decreased production of TGF-beta by lymphocytes from patients with systemic lupus erythematosus. J Immunol160:2539–2545, 1998