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Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulin-binding peptide

Nature Biotechnology volume 18, pages 735–739 (2000)Cite this article

Abstract

Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory disease of unknown etiology that affects many organs, including the kidney. The presence of multiple autoantibodies and other immunological abnormalities point to basic defects in immunoregulatory controls that normally maintain self-tolerance. The deposition on kidney tissue of autoantibodies as immune complexes (ICs) through the interaction with Fc-receptor γ-chains is thought to trigger an inflammatory response typical of SLE, leading to glomerulonephritis. Using combinatorial chemistry approaches, we have identified a peptide able to bind to immunoglobulins and to interfere with Fcγ-receptor recognition. Administration of this peptide to MRL/lpr mice, an animal model used to study SLE, resulted in a remarkable enhancement of the survival rate (80%) compared to placebo-treated animals (10%). Consistent with this was a significant reduction of proteinuria, a clinical sign of SLE. Kidney histological examination of treated animals confirmed the preservation of tissue integrity and a remarkable reduction in IC deposition. These results support the role of Fcγ receptors in SLE pathogenesis and open new avenues for the development of drugs to treat autoimmune disorders.

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Figure 1: In vitro biological activity of TG19320.
Figure 2: In vivo biological activity of TG19320.
Figure 3: Histopathological examination of kidneys from TG19320-treated and control MRL/lpr mice.
Figure 4: Immunohistochemical examination of kidneys from TG19320-treated and control MRL/lpr mice.

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References

  1. O'Dell, J.R. & Kotzin, B.L. Systemic lupus erythematosus. In Samter's immunologic diseases. (eds Frank, M.M., Austen, K.F., Claman, H.N., & Unanue, E. R.) 667–697 (Little, Brown, Boston; 1995).

    Google Scholar 

  2. Baccala, R., Quang, T.V., Gilbert, M., Ternyck, T. & Avrameas, S. Two murine natural polyreactive autoantibodies are encoded by non-mutated germ-line genes. Proc. Natl. Acad. Sci USA 86, 4624–4628 (1989).

    Article  CAS  Google Scholar 

  3. Marion, T.N., Bothwell, A.L.M., Briles, D.E. & Janeway, C.A. IgG anti-DNA autoantobodies within an individual autoimmune mouse are the products of clonal selection. J. Immunol. 142, 4269–4274 (1989).

    CAS  PubMed  Google Scholar 

  4. Schett, G. et al. The lupus erythematosus cell phenomenon: comparative analysis of antichromatin antibody specificity in lupus erythematosus cell-positive and -negative sera. Arthritis Rheum. 43, 420–428 (2000).

    Article  CAS  Google Scholar 

  5. Reichlin, M. Current perspectives on serological reactions in SLE patients. Clin. Exp. Immunol. 44, 1–10 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Franceschini, F. et al. Chilblain lupus erythematosus is associated with antibodies to SSA/Ro. Lupus 8, 215–219 (1999).

    Article  CAS  Google Scholar 

  7. Mattioli, M. & Rechlin, M. Heterogeneity of RNA protein antigens reactive with sera of patients with systemic lupus erythematosus. Arthritis Rheum. 17, 421–429 (1974).

    Article  CAS  Google Scholar 

  8. Reichlin, M. et al. Prevalence of autoantibodies to ribosomal P proteins in juvenile-onset systemic lupus erythematosus compared with the adult disease. Arthritis Rheum. 42, 69–75 (1999).

    Article  CAS  Google Scholar 

  9. Hasegawa, H. et al. High frequency of antibody activity against ribosomal protein S10 in anti-Sm sera from patients with systemic lupus erythematosus. Lupus 8, 439–443 (1999).

    Article  CAS  Google Scholar 

  10. Tsao, B.P. et al. Failed self-tolerance and autoimmunity in IgG anti-DNA transgenic mice. J. Immunol. 149, 350–358 (1992).

    CAS  PubMed  Google Scholar 

  11. Mannik, M. Pathophysiology of circulating immune complexes. Arthritis Rheum. 25, 783–787 (1982).

    Article  CAS  Google Scholar 

  12. Baumann, U. et al. A codominant role of Fc gamma RI/III and C5aR in the reverse Arthus reaction. J. Immunol. 164, 1065–1070 (2000).

    Article  CAS  Google Scholar 

  13. Szalai, A. J. et al. The Arthus reaction in rodents: species-specific requirement of complement. J. Immunol. 164, 463–468 (2000).

    Article  CAS  Google Scholar 

  14. Jazwinska, E.C., Banyer, J.L., Gatenby, P.A. & Serjeantson, S.W. Fc gamma RII alpha: sequencing of the ligand binding domain in systemic lupus erythematosus patients. Clin. Exp. Immunol. 86, 199–202 (1991).

    Article  CAS  Google Scholar 

  15. Clynes, R., Dumitru, C. & Ravetch, J.V. Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis. Science 279, 1052–1054 (1998).

    Article  CAS  Google Scholar 

  16. Ravetch, J.V. & Clynes, R.A. Divergent roles for Fc receptors and complement in vivo. Annu. Rev. Immunol. 16, 421–432 (1998).

    Article  CAS  Google Scholar 

  17. Sylvestre, D.L. & Ravetch, J.V. Fc receptors initiate the Arthus reaction: redefining the inflammatory cascade. Science 265, 1095–1098 (1994).

    Article  CAS  Google Scholar 

  18. Fassina, G., Verdoliva, A., Odierna, M.R., Ruvo, M. & Cassani, G. Protein A mimetic peptide ligand for affinity purification of antibodies. J. Mol. Recog. 9, 564–569 (1996).

    Article  CAS  Google Scholar 

  19. Fassina, G., Verdoliva, A., Palombo, G., Ruvo, M. & Cassani, G. Immunoglobulin specificity of TG19318: a novel synthetic ligand for antibody affinity purification. J. Mol. Recog. 11, 128–133 (1998).

    Article  CAS  Google Scholar 

  20. Burton, D.R., Jefferis, R., Partridge, L.J. & Woof, J.M., Molecular recognition of antibody (IgG) by cellular Fc receptor (FcRI). Molec. Immunol. 25, 1175–1181 (1988).

    Article  CAS  Google Scholar 

  21. Lund, J. et al. Oligosaccharide-protein interactions in IgG can modulate recognition by Fc gamma receptors. FASEB J. 9, 115–119 (1995).

    Article  CAS  Google Scholar 

  22. Theofilopoulos, A.N. Murine models of lupus. In Systemic lupus erythematosus. (ed. Lahita, R.G.) 121–194 (Churchill Livingstone, New York, NY; 1992).

    Google Scholar 

  23. Watanabe-Fukunaga, R., Brannan, C.I., Copeland, N.G., Jekins, N.A. & Nagata, S. Lymphoproliferation disorder in mice explained by effects in Fas antigen that mediates apoptosis. Nature 356, 314–317 (1992).

    Article  CAS  Google Scholar 

  24. Lemay, S., Mao, C. & Singh, A. Cytokine gene expression in the MRL/lpr model of lupus nephritis. Kidney Int. 50, 85–93 (1996).

    Article  CAS  Google Scholar 

  25. Mannik, M., Agodoa, L.Y. & David, K.A. Rearrangement of immune complexes in glomeruli leads to persistence and development of electron dense deposits. J. Exp. Med. 157, 1516–1528 (1983).

    Article  CAS  Google Scholar 

  26. Gauthier, V.J. & Mannik, M. Only the initial binding of cationic immune complexes to glomerular anionic sites is mediated by charge–charge interactions. J. Immunol. 136, 3266–3271 (1986).

    CAS  PubMed  Google Scholar 

  27. Wang, Y. et al. Amelioration of lupus-like autoimmune disease in NZB/W F1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc. Natl Acad. Sci. USA 93, 8563–8568 (1996).

    Article  CAS  Google Scholar 

  28. Baylink, D.J. Glucocorticoid-induced osteoporosis. N. Engl. J. Med. 309, 306–308 (1983).

    Article  CAS  Google Scholar 

  29. Piper, J.M., Ray, W.A., Daugherty, J.R. & Griffin, M.R. Corticosteroid use and peptic ulcer disease: role of non-steroidal anti-inflammatory drugs. Ann. Intern. Med. 114, 735–740 (1991).

    Article  CAS  Google Scholar 

  30. Pryor, B.D., Bologna, S.G. & Kahl, L.E. Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus. Arthritis Rheum. 39, 1475–1482 (1996).

    Article  CAS  Google Scholar 

  31. Hoover, R.G. et al. Autoregulatory circuits in myeloma. Tumor cell cytotoxicity mediated by soluble CD16. J. Clin. Invest 95, 241–247 (1995).

    Article  CAS  Google Scholar 

  32. Fearon, D.T. & Wong, W.W. Complement ligand–receptor interactions that mediate biological responses. Annu. Rev. Immunol. 1, 243–271 (1983).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. TECNOGEN S.C.p.A. Biopharmaceuticals, Piana di Monte Verna (CE), 81015, Italy

    Maria Marino, Menotti Ruvo, Sandro De Falco & Giorgio Fassina

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  1. Maria Marino
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  2. Menotti Ruvo
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  4. Giorgio Fassina
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Correspondence to Giorgio Fassina.

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Marino, M., Ruvo, M., De Falco, S. et al. Prevention of systemic lupus erythematosus in MRL/lpr mice by administration of an immunoglobulin-binding peptide. Nat Biotechnol 18, 735–739 (2000). https://doi.org/10.1038/77296

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