Interleukin 6 promotes murine lupus in NZB/NZW F1 mice.
To investigate the role of IL-6 in systemic lupus erythematosus (SLE), we selectively inhibited IL-6 in lupus-prone NZB/NZW F1(B/W) mice by chronic administration of a rat mAb to mouse IL-6. Anti-IL-6 alone elicited an anti-rat response that blocked its biologic effects. To circumvent this problem, we rendered B/W mice tolerant to the rat mAb by administration of anti-CD4 concurrent with the first dose of anti-IL-6. Thereafter, the mice received weekly injections of anti-IL-6 alone. There were two control groups: one group received the tolerizing regimen of anti-CD4 along with a control rat IgG1 mAb (GL113) instead of anti-IL-6; the other control group received PBS. Mice that received anti-CD4 were tolerant to the rat mAb for 6 mo. Throughout this period, treatment with anti-IL-6 prevented production of anti-dsDNA, significantly reduced proteinuria, and prolonged life. Mice that received anti-IL-6 without anti-CD4 developed an immune response to the rat mAb and then developed anti-dsDNA antibodies, proteinuria, and mortality comparable with control mice. These findings establish that IL-6 promotes autoimmunity in B/W mice. They further indicate that, although mAb to IL-6 can suppress murine lupus, the development of host immunity to the mAb abrogates its beneficial effects. Finally, this is the first study to demonstrate that a brief course of anti-CD4 can induce tolerance to another therapeutic mAb, in this case an anti-cytokine mAb.
Finck
B K
BK
Arthritis/Immunology Section, Veterans Administration Medical Center, San Francisco, California 94121.
Chan
B
B
Wofsy
D
D
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015704:CD4 Antigens / Q000502:physiology; D005260:Female; D007136:Immunoglobulins / Q000097:blood; D015850:Interleukin-6 / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D051381:Rats
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007136:Immunoglobulins; D015850:Interleukin-6