身體對(duì)替換蛋白(replacement protein)產(chǎn)生排斥作用的自然反應(yīng)代表著成功利用基因療法治療一系列危及生命的疾病時(shí)所面臨的一個(gè)主要障礙,。然而,，根據(jù)一篇發(fā)表在Human Gene Therapy期刊上的論文,，研究人員開發(fā)出一種新方法：利用身體自己的免疫細(xì)胞誘導(dǎo)身體對(duì)特異性蛋白產(chǎn)生耐受性,，并且證實(shí)該方法能夠抑制這種排斥反應(yīng),。
美國(guó)賓夕法尼亞大學(xué)佩雷爾曼醫(yī)學(xué)院教授James M. Wilson說,，“蛋白和基因治療方法的一個(gè)主要限制就是與之相關(guān)聯(lián)的免疫反應(yīng),，這種反應(yīng)能夠產(chǎn)生毒性和降低療效,。巧妙地利用免疫調(diào)節(jié)物可能阻止免疫反應(yīng)發(fā)生。”
在被稱作細(xì)胞因子的免疫刺激化合物存在下,，讓一類被稱作樹突細(xì)胞的免疫細(xì)胞接觸一種特異性的治療性蛋白能夠?qū)е旅庖吣褪苄缘臉渫患?xì)胞產(chǎn)生,。當(dāng)耐受性樹突細(xì)胞被導(dǎo)入小鼠體內(nèi)時(shí)，接著再給小鼠進(jìn)行經(jīng)設(shè)計(jì)能夠運(yùn)送治療性蛋白的基因療法治療,，這樣這些細(xì)胞就允許小鼠對(duì)治療性蛋白產(chǎn)生耐受性,，而不是排斥它。
當(dāng)前誘導(dǎo)對(duì)通過基因療法而產(chǎn)生的替換蛋白產(chǎn)生部分或完全耐受性的方法是比較昂貴,，而且失敗率高達(dá)40%,。在這項(xiàng)研究中，研究人員開發(fā)出的這種方法在這方面具有優(yōu)勢(shì),，能夠促進(jìn)基因療法的長(zhǎng)期成功。(生物谷：Bioon.com)
本文編譯自Method to Prevent Rejection of Disease-fighting Proteins Described in Human Gene Therapy Journal
doi: 10.1089/hum.2011.225
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Cytokine-Conditioned Dendritic Cells Induce Humoral Tolerance to Protein Therapy in Mice
Gautam Sule, Masataka Suzuki, Kilian Guse, Racel Cela, John R. Rodgers, and Brendan Lee
A major obstacle in the genetic therapy of inherited metabolic disease is host immune responses to the therapeutic protein. This is best exemplified by inhibitor formation in the protein therapy for hemophilia A. An approach to overcoming this is induction of immunological tolerance to the therapeutic protein. Tolerogenic dendritic cells (DCtols) have been reported to induce tolerance. In addition, cytokines such as interleukin (IL)-10 and transforming growth factor (TGF)-β1 are known to induce tolerance. To model protein therapy, we used ovalbumin (OVA) as antigen in BALB/c mice and their transgenic derivative, DO11.10 mice. In this study we show that adoptive transfer of antigen-pulsed dendritic cells (DCs) treated with a combination of IL-10 and TGF-β1 can suppress the antibody response in mice. Adoptive transfer of cytokine-conditioned DCs in preimmunized mice results in reduction of antibody response in the mice. Furthermore, the effect is antigen specific, as the recipient mice were able to mount a potent antibody response to the control antigen. Last, we show that TGF-β1 and IL-10-conditioned DCs are able to inhibit anti-FVIII antibody responses in FVIII knockout (KO) mice. Analysis of the contribution of IL-10 and TGF-β1 to the DCtol phenotype shows that IL-10 treatment of DCs is sufficient for inducing OVA-specific tolerance in BALB/c mice, but we observed a requirement for treatment with both human TGF-β1 and human IL-10 to significantly inhibit anti-FVIII antibody responses in FVIII KO mice. This paper demonstrates that autologous cell therapy for antigen-targeted immune suppression may be developed to facilitate long-term therapy.
