Publications

The gene product of the nef gene of HIV-1 acts both to increase the infectivity of viral particles and to reduce the expression of the CD4 receptor molecule on the cell surface. These two functions of Nef may be related, in that downregulation of CD4 may promote the production of HIV that has greater infectivity.

Monoclonal antibodies (mAb) to lymphocyte function-associated antigen-1 (LFA-1) have been used successfully in vivo to inhibit immune responses and to block inflammatory reactions. To determine whether these effects of anti-LFA-1 could retard autoimmune disease, we treated lupus-prone NZB/NZW F1 (B/W) mice with a rat mAb to LFA-1 (anti-CD11a). Mice received high-dose therapy (500 micrograms twice weekly), low-dose therapy (40 micrograms thrice weekly), or phosphate-buffered saline from age 5 months to age 10 months. Treatment with high doses of anti-CD11a suppressed both the immune response to the rat mAb and the production of autoantibodies to double-stranded DNA. In contrast, treatment with low doses of anti-CD11a elicited an immune response to the rat mAb and did not suppress autoantibody production. The immunosuppressive effects of high doses of anti-CD11a were not due to target cell depletion. In fact, treatment induced a marked lymphocytosis which involved all lymphocyte subsets equally. Despite inhibiting autoantibody production, high-dose therapy had only modest effects on longevity.

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.