Tumor necrosis factor alpha in murine systemic lupus erythematosus disease models: implications for genetic predisposition and immune regulation.
Recombinant tumor necrosis factor alpha (TNF-alpha) administration significantly delayed the development of lupuslike nephritis in the New Zealand black x New Zealand white (NZB x NZW)F1 and to a lesser extent in the MRL-lpr/lpr model systems. TNF-alpha treatment was effective when treatment was initiated at 2, 3, or 4 months of age but was ineffective if initiated as late as 6.5 months of age. Treatment of (NZB x NZW)F1 mice for 3 months was more effective than treatment continued for 6 months. Anti-TNF-alpha antibodies did not develop in these mice. Flow microfluorometry analysis showed no major effects on B, T, or monocyte cell population in cells from the peritoneum, spleen, lymph node, and thymus. A decrease in class II Ia expression on macrophages in the peritoneum of TNF-alpha-treated mice was noticed. A correlation between the level of TNF-alpha inducibility in vitro and the effect of TNF-alpha administration in vivo could be shown. Although a limited polymorphism could be shown by restriction fragment length polymorphism, using an amplified (AC)n microsatellite located in the 5' regulatory region of TNF-alpha, a much more extensive interallelic polymorphism was found. The AC microsatellite allele found in NZW mice was unique and different from other lupus strains and nonautoimmune strains. These results have possible implications to the pathogenesis of systemic lupus erythematosus.
Jacob
C O
CO
Department of Inflammation Biology and Immunology, Syntex Research, Palo Alto, CA 94303.
Hwang
F
F
Lewis
G D
GD
Stall
A M
AM
D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D001483:Base Sequence; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D012150:Polymorphism, Restriction Fragment Length; D011994:Recombinant Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000627:therapeutic use*
D000974:Antibodies, Antinuclear; D000949:Histocompatibility Antigens Class II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha