Treatment with a consensus peptide based on amino acid sequences in autoantibodies prevents T cell activation by autoantigens and delays disease onset in murine lupus

Objective. To test the hypothesis that an artificial peptide, based on an a lgorithm describing T cell stimulatory sequences from the V-H regions of mu rine IgG antibodies to DNA, is an effective tolerogen in vivo in the (NZB/N ZW)F-1 (BWF1) mouse model of systemic lupus erythematosus. Methods. Using proliferative T cell responses to 439 Ig peptides, an algori thm was constructed that describes the amino acid sequences likely to stimu late BWF1 T cells. Stimulatory (pConsensus [pCONS]) or nonstimulatory (pNeg ative [pNEG]) peptides were synthesized. Groups of 10-week-old (healthy) or 20-week-old (diseased) BWF1 mice received monthly intravenous injections o f 1,000 mug of peptide or saline. Ex vivo splenic T cell responses and in v ivo clinical effects were measured. Results. Tolerance was induced by pCONS, but not by pNEG, with respect to e x vivo T cell proliferation and T cell help for antibodies to DNA. T cell h elp for IgG anti-DNA was impaired not only after T cell stimulation by pCON S but also after stimulation by some peptides from nucleosomal and Ro antig ens. Treatment with pCONS significantly delayed the onset of nephritis and inhibited increases in the plasma levels of total IgG, IgG antibodies to DN A, nucleosome, cardiolipin, interferon-gamma, and interleukin-4. In contras t, antibody responses to an exogenous antigen were not impaired. Survival w as significantly prolonged in both healthy and diseased mice treated with p CONS. Conclusion. Induction of immune tolerance in response to treatment with pCO NS in autoreactive T cell helper populations is highly effective in delayin g the appearance of multiple autoantibodies, cytokine increases, and nephri tis in BWF1 mice, and dramatically prolongs survival. A striking effect is the ability of the peptide to tolerize T cell help for anti-DNA that is ind uced by multiple, structurally unrelated self antigens.