Hahn B H, Singh R R, Wong W K, Tsao B P, Bulpitt K, Ebling F M
University of California, Los Angeles, USA.
Arthritis Rheum. 2001 Feb;44(2):432-41. doi: 10.1002/1529-0131(200102)44:2<432::AID-ANR62>3.0.CO;2-S.
To test the hypothesis that an artificial peptide, based on an algorithm describing T cell stimulatory sequences from the VH regions of murine IgG antibodies to DNA, is an effective tolerogen in vivo in the (NZB/NZW)F1 (BWF1) mouse model of systemic lupus erythematosus.
Using proliferative T cell responses to 439 Ig peptides, an algorithm was constructed that describes the amino acid sequences likely to stimulate BWF1 T cells. Stimulatory (pConsensus [pCONS]) or nonstimulatory (pNegative [pNEG]) peptides were synthesized. Groups of 10-week-old (healthy) or 20-week-old (diseased) BWF1 mice received monthly intravenous injections of 1,000 microg of peptide or saline. Ex vivo splenic T cell responses and in vivo clinical effects were measured.
Tolerance was induced by pCONS, but not by pNEG, with respect to ex vivo T cell proliferation and T cell help for antibodies to DNA. T cell help for IgG anti-DNA was impaired not only after T cell stimulation by pCONS but also after stimulation by some peptides from nucleosomal and Ro antigens. Treatment with pCONS significantly delayed the onset of nephritis and inhibited increases in the plasma levels of total IgG, IgG antibodies to DNA, nucleosome, cardiolipin, interferon-gamma, and interleukin-4. In contrast, antibody responses to an exogenous antigen were not impaired. Survival was significantly prolonged in both healthy and diseased mice treated with pCONS.
Induction of immune tolerance in response to treatment with pCONS in autoreactive T cell helper populations is highly effective in delaying the appearance of multiple autoantibodies, cytokine increases, and nephritis 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 induced by multiple, structurally unrelated self antigens.
检验基于一种算法设计的人工肽在体内作为有效免疫耐受原的假设，该算法描述了小鼠IgG抗体针对DNA的VH区的T细胞刺激序列，采用（NZB/NZW）F1（BWF1）小鼠系统性红斑狼疮模型进行研究。
利用对439种Ig肽的增殖性T细胞反应构建一种算法，该算法描述了可能刺激BWF1 T细胞的氨基酸序列。合成了刺激性（pConsensus [pCONS]）或非刺激性（pNegative [pNEG]）肽。10周龄（健康）或20周龄（患病）的BWF1小鼠组每月静脉注射1000μg肽或生理盐水。检测体外脾T细胞反应和体内临床效果。
就体外T细胞增殖和针对DNA抗体的T细胞辅助而言，pCONS可诱导耐受，而pNEG则不能。不仅pCONS刺激T细胞后，而且核小体和Ro抗原的一些肽刺激后，针对IgG抗DNA的T细胞辅助均受损。用pCONS治疗显著延迟了肾炎的发作，并抑制了总IgG、抗DNA IgG抗体、核小体、心磷脂、干扰素-γ和白细胞介素-4血浆水平的升高。相比之下，对外源抗原的抗体反应未受损。用pCONS治疗的健康和患病小鼠的生存期均显著延长。
在自身反应性T细胞辅助群体中，pCONS治疗诱导的免疫耐受在延迟BWF1小鼠多种自身抗体出现、细胞因子增加和肾炎方面非常有效，并显著延长生存期。该肽的一个显著作用是能够使多种结构不相关的自身抗原诱导的针对抗DNA的T细胞辅助产生耐受。
