Objective: To examine the efficacy of deoxyribonuclease I (DNAse) therapy in the (NZB6 NZW)F1 murine model of lupus.
Methods: Lupus-prone female (NZB6NZW)F1 mice were treated daily with 0–15 mg/gof recombinant DNAse for 1–6 months. Parameters including anti-DNA autoantibody production, activation of cytokine secreting cells, kidney function and longevity were monitored.
Results: DNAse treatment selectively reduced the number of B cells secreting anti-dsDNA antibodies for approximately one month. However, neither short-term nor long-term treatment altered cytokine production, delayed the onset or reduced the severity of glomerulonephritis, or prolonged survival.
Conclusion: DNAse treatment initiated before, during, or after the onset of murine lupus did not improve clinical outcome.
Klinman DM , Steinberg AD . Inquiry into Murine and Human Lupus . Immunol Rev1995; 144: 157–193 .
2.
Susuki N , Mihara S , Sakane T . Development of pathogenic anti-DNA antibodies in patients with systemic lupus erythematosus . FASEB J1997; 11: 1033–1038 .
3.
Raz E , Brezis M , Rosenmann E , Eilat D . Anti-DNA antibodies bind directly to renal antigens and induce kidney dysfunction in the isolated perfused rat kidney . J Immunol1989; 142: 3076–3082 .
4.
Hahn BH , Tsao BP.Antibodies to DNA. In: Wallace DJ , Hahn BH (eds). Dubois' Lupus Erythematosus. (5th edn) Williams and Wilkins pp. 407–422.
5.
Ehrenstein MR et al. Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice . Kidney Int1995; 48: 705–711 .
6.
Raz E , Ben-Bassat H , Davidi T , Shlomai Z , Eilat D . Cross-reactions of anti-DNAT autoantibodies with cell surface proteins . Eur J Immunol1993; 23: 383–390 .
Termaat RM et al. Anti-DNA antibodies can bind to the glomerulus via two distinct mechanisms . Kidney Int1992; 42: 1363–1371 .
9.
Naparstek Y , Madaio MP.Are DNA antobodies actually pathogenic?Lupus1997; 6: 307–309 .
10.
Isenberg DA , Ravirajan CT , Rahman A , Kalsi J . The role of antibodies to DNA in systemic lupus erythematosus—A review and introduction to an international workshop on DNA antibodies held in London, May 1996 . Lupus1997; 6: 294–304 .
11.
Klinman DM , Eisenberg RA , Steinberg AD . Development of the autoimmune B cell repertoire in MRL-lpr/lpr mice . J Immunol1990; 1440: 506–512 .
12.
Klinman DM , Steinberg AD . Systemic autoimmunue disease arises from polyclonal B cell activation . J Exp Med1987; 165: 1755–1760 .
13.
Chia D , Dorsch C , Barnett EV , Levy L.Metabolism of exogenous single stranded DNA in normal NZB/W mice . Immunology1977; 32: 351–358 .
14.
Raptis L , Menard H . Quantitation and characterization of plasma DNA in normals and patients with systemic lupus erythematosus . J Clin Invest1980; 66: 1391–1399 .
15.
Harbeck RJ , Hoffmann AA , Carr RI . Studies in the nature of circulating DNA in systemic lupus erythematosus . J Rheumatol1975; 2: 194–203 .
16.
McCoubrey-Hoyer A , Okarma TB , Holman HR . Partial purification and characterization of plasma DNA and its relation to disease activity in systemic lupus erythematosus . Am J Med1984; 77: 23–34 .
17.
Emlen W , Niebur J , Kadera R . Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus . J Immunol1994; 152: 3685–3692 .
18.
Mohan C , Adams S , Stanik V , Datta SK . Nucleosome: A major immunogen for pathogenic autoantibody-inducing T cells of lupus . J Exp Med1993; 177: 1367–1381 .
19.
Chitrabamrung S , Rubin RL , Tan EM . Serum deoxyribonuclease I and clinicalactivityofsystemiclupuserythematosus .RheumInt1981;1: 55–60 .
20.
Puccett A , Madaio MP , Bellese G , Migliorini P . Anti-DNA antibodies bind to DNAse I . J Exp Med1995; 181: 1797–1804 .
21.
Macanovic M , Lachmann PJ . Measurement of deoxyribonuclease I (DNase) in the serum and urine of systemic lupus erythematosus (SLE)-prone NZB/NZW mice by a new radial enzyme diffusion assay . Clin Exp Immunol1997; 108: 220–226 .
22.
Lachmann PJ . Allergic reactions, connective tissue, and disease . Sci Basis Med Annu Rev1967; 36–58 .
23.
Murai K et al. Purification and properties of deoxyribonuclease from human urine . Biochim Biophys Acta1978; 517: 186–194 .
24.
Shak S , Capon DJ , Hellmiss R , Marsters SA , Baker CL . Recombinant human DNase reduces the viscosity of cystic fibrosis sputum . Proc Natl Acad Sci USA1990; 87: 9188–9192 .
25.
Ranasinha C et al. Efficacy and safety of short-term administration of aerosolised recombinant human DNAse I in adults with stable stage cystic fibrosis . Lancet1993; 342: 624–625 .
26.
Macanovic M et al. The treatment of systemic lupus of erythematosus (SLE) in NZB/W F1 hybrid mice; studies with recombinant murine DNAse and with dexamethasone . Clin Exp Immunol1996; 106: 243–252 .
27.
Klinman DM , Shirai A , Ishigatsubo Y , Conover J , Steinberg AD . Quantitation of IgG and IgM secreting B cells in the peripheral blood of patients with systemic lupus erythematosus . Arthritis Rheum1991; 34: 1404–1410 .
28.
Hagiwara E , Gourley M , Lee S , Klinman DM . Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of IL-10 IFNgamma secreting cells in the peripheral blood . Artihritis Rheum1996; 39: 379–385 .
29.
Klinman DM , Nutman TB . ELIspot assay to detect cytokine-secreting murine and human cells. In: Coligan JE , Kruisbeek AM , Margulies DH , Shevach EM , Strober W (eds). Current Protocols in Immunology. (7th edn). Greene Publishing Associates: Brooklyn , 1994.
30.
Klinman DM , Yi A , Beaucage SL , Conover J , Krieg AM . CpG motifs expressed by bacterial DNA rapidly induce lymphocytes to secrete IL-6, IL-12 and IFNg . Proc Natl Acad Sci USA1996; 93: 2879–2883 .
31.
Mor G et al. Complexity of the cytokine and antibody response elicited by immunizing mice with Plasmodium yoelii circumsporozoite protein plasmid DNA . J Immunol1995; 155: 2039–2046 .
32.
Klinman DM , Yamshchikov G , Ishigatsubo Y . Contribution of CpG motifs of the immunogenicity of DNA vaccines . J Immunol1997; 158: 3635–3642 .
33.
Austin HA , Muenz LR , Joyce KM , Antonovych TT , Barlow JE . Diffuse proliferative lupus nephritis: identification of specific pathogenic features affecting renal outcome . Kidney Int1984; 25: 689–695 .
34.
Klinman DM . Polyclonal B cell activation in lupus-prone mice precedes and predicts the development of autoimmune disease . J Clin Invest1990; 86: 1249–1254 .
35.
Hardin JA . The lupus autoantigens and the pathogenesis of SLE . Arthritis Rheum1986; 29: 457–460 .
36.
Hahn BH , Ebling RM . Suppression of murine lupus nephritis by administration of an anti-idiotypic antibody to anti-DNA . J Immunol1984; 132: 187–190 .
37.
Tanphaichitr K , Hahn BH . Studies of tolerance to DNA in NZB/NZW F1 mice . J Immunol1977; 119: 330–336 .
38.
Horgan C , Emlen W . Complement fixation by small, DNase-resistant DNA-anti-DNA immune complexes . Mol Immunol1987; 24: 109–116 .
39.
Clark QP , Lazarus RA . Engineering hyperactive variants of human deoxyribonuclease I by altering its functional mechanism . Biochemistry1997; 36: 6624–6632 .
40.
Horowitz D.The role of T lymphocytes in SLE. In: Wallace DJ , Hahn BH (eds). Dubois' lupus erythematosus (5th edn). Williams & Wilkins: Baltimore , 1997, pp. 155–194.
41.
Steinberg AD , Gelfand MC , Hardin JA , Lowenthal DT . Therapeutic studies in NZB/W mice. III Relationship between renal status and efficacy of immunosuppressive drug therapy . Arthritis Rheum1975; 18: 9–14 .
42.
Gladman DD , Urowitz MB . Prognostic subsets and mortality in systemic lupus erythematosus. In: Wallace DJ , Hahn BH (eds). Dubois' Lupus Erythematosus (5th edn). Williams & Wilkins: Baltimore , 1997, pp. 1213–1229.
43.
Institute of Laboratory Animal Resources . Guide for the Care and Use of Laboratory Animals. National Research Council, 1985. DHHS Publ. (NIH)86–23.
