重组核小体通用性Th表位诱导SLE口服免疫耐受的实验研究
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摘要
研究背景及研究目的
系统性红斑狼疮(SLE)是一种慢性、累及多系统的自身免疫性疾病,临床表现复杂,好发于青年女性,其确切病因和发病机制尚未阐明,发病率有逐渐增高趋势。目前临床上主要以糖皮质激素联合环磷酰胺等非特异性免疫抑制剂治疗为主,虽然可以在一定程度上控制病情进展,但由于疾病的进展和长期治疗带来的毒副作用使SLE患者的平均寿命明显短于正常人。这种以免疫系统的普遍抑制为代价的疗法,在发挥治疗作用的同时,往往也造成患者多器官或系统的损伤。因此有必要探索一种可控性的免疫治疗措施,这种措施只抑制特定的自身反应性淋巴细胞克隆,这是SLE等自身免疫性疾病防治研究的方向,其中治疗或预防性肽耐受疫苗被认为最具发展前景。
应用特异性抗原诱导免疫耐受治疗自身免疫病已有很长历史。该方法可高度选择性地抑制针对特定抗原的淋巴细胞克隆,而对机体正常免疫功能基本没有影响,克服了传统化学类药物的毒副作用。早期多应用完整抗原来进行免疫耐受的研究取得较好效果,但应用结构复杂抗原作为耐受原存在易激发自身免疫的缺陷,且来源也比较困难。目前已明确不论是内源性或外源性抗原必须经过APC内部的蛋白酶降解以后,以短肽表位-MHC复合物的形式提呈在APC表面,才能被T细胞受体识别,进而诱导T细胞及B细胞的活化。由于器官特异性和非器官特异性AID一般由T细胞直接介导或T细胞调节,因此诱导T细胞的免疫耐受在理论上便可以预防或治疗AID。且相对于B细胞,诱导T细胞的免疫耐受相对容易,需要的抗原量较少,维持时间较长。与完整或大分子抗原相比,肽疫苗更容易诱导机体免疫耐受,而且可大规模化学合成,易于纯化,使用也相对安全。基于上述理论,用自身抗原的Th细胞表位代替完整抗原进行AID的免疫耐受,即制备治疗性肽耐受疫苗逐渐成为AID防治研究的热点。
自身抗原表位的筛选和鉴定是AID耐受性肽疫苗研究的关键。诱导SLE发病的自身抗原来自于凋亡的外周血单一核细胞,种类繁多,目前已明确核小体是诱导SLE发病及介导组织损伤的重要或关键致病性抗原,阻断核小体的免疫病理反应具有潜在
Background and objectives
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect virtually every organ system. Female is often related. The accurate etiology and pathogenesis are still unknown. Epidemiological evidence shows that the incidence of SLE has increased gradually. Though glucocorticoid and cyclophosphamide combination therapy can prevent the disease from advancing, it causes nonspecific immune suppression which leads to multiple organ damages and shortened lifespan. It is necessary to pursuit a controllable immunotherapy that selectively inhibits certain autoreactive lymphcyte clone, among which, therapeutic or prophylactic peptide vaccine is believed to be most prospective.
It has been a long time to use specific antigens to induce immune tolerance. The method can highly selectively inhibit lymphcyte clones reactive to certain antigen, but has no influence on normal immune function. In early stages, progresses had been made in using complete antigens to induce immuno tolerance. The problems are it can irritate immune system and the antigens are difficult to obtain. Recent researches reveal that whether endogenous or exogenous antigens must be presented on the surface of APC as the pattern of peptide epitope-MHC complex by protease degradation of APC before they are recognized by T cell receptors and induce T and B cell activation. T cell immune tolerance may be easier to be induced because organ-specific and nonorgan-specific AID are mediated by T cells and low dose antigens are enough. Compared with complete or large molecular antigens, peptide vaccines are easier to induce immune tolerance, easy to synthesis, purification and more safe. So it has been the hot spot to use Th cell epitope of autoantigen instead of complete antigen to prepare therapeutic peptide-based vaccines.
The screening and identification of the autoantigen epitope are important to peptide
系统性红斑狼疮(SLE)是一种慢性、累及多系统的自身免疫性疾病,临床表现复杂,好发于青年女性,其确切病因和发病机制尚未阐明,发病率有逐渐增高趋势。目前临床上主要以糖皮质激素联合环磷酰胺等非特异性免疫抑制剂治疗为主,虽然可以在一定程度上控制病情进展,但由于疾病的进展和长期治疗带来的毒副作用使SLE患者的平均寿命明显短于正常人。这种以免疫系统的普遍抑制为代价的疗法,在发挥治疗作用的同时,往往也造成患者多器官或系统的损伤。因此有必要探索一种可控性的免疫治疗措施,这种措施只抑制特定的自身反应性淋巴细胞克隆,这是SLE等自身免疫性疾病防治研究的方向,其中治疗或预防性肽耐受疫苗被认为最具发展前景。
应用特异性抗原诱导免疫耐受治疗自身免疫病已有很长历史。该方法可高度选择性地抑制针对特定抗原的淋巴细胞克隆,而对机体正常免疫功能基本没有影响,克服了传统化学类药物的毒副作用。早期多应用完整抗原来进行免疫耐受的研究取得较好效果,但应用结构复杂抗原作为耐受原存在易激发自身免疫的缺陷,且来源也比较困难。目前已明确不论是内源性或外源性抗原必须经过APC内部的蛋白酶降解以后,以短肽表位-MHC复合物的形式提呈在APC表面,才能被T细胞受体识别,进而诱导T细胞及B细胞的活化。由于器官特异性和非器官特异性AID一般由T细胞直接介导或T细胞调节,因此诱导T细胞的免疫耐受在理论上便可以预防或治疗AID。且相对于B细胞,诱导T细胞的免疫耐受相对容易,需要的抗原量较少,维持时间较长。与完整或大分子抗原相比,肽疫苗更容易诱导机体免疫耐受,而且可大规模化学合成,易于纯化,使用也相对安全。基于上述理论,用自身抗原的Th细胞表位代替完整抗原进行AID的免疫耐受,即制备治疗性肽耐受疫苗逐渐成为AID防治研究的热点。
自身抗原表位的筛选和鉴定是AID耐受性肽疫苗研究的关键。诱导SLE发病的自身抗原来自于凋亡的外周血单一核细胞,种类繁多,目前已明确核小体是诱导SLE发病及介导组织损伤的重要或关键致病性抗原,阻断核小体的免疫病理反应具有潜在
Background and objectives
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect virtually every organ system. Female is often related. The accurate etiology and pathogenesis are still unknown. Epidemiological evidence shows that the incidence of SLE has increased gradually. Though glucocorticoid and cyclophosphamide combination therapy can prevent the disease from advancing, it causes nonspecific immune suppression which leads to multiple organ damages and shortened lifespan. It is necessary to pursuit a controllable immunotherapy that selectively inhibits certain autoreactive lymphcyte clone, among which, therapeutic or prophylactic peptide vaccine is believed to be most prospective.
It has been a long time to use specific antigens to induce immune tolerance. The method can highly selectively inhibit lymphcyte clones reactive to certain antigen, but has no influence on normal immune function. In early stages, progresses had been made in using complete antigens to induce immuno tolerance. The problems are it can irritate immune system and the antigens are difficult to obtain. Recent researches reveal that whether endogenous or exogenous antigens must be presented on the surface of APC as the pattern of peptide epitope-MHC complex by protease degradation of APC before they are recognized by T cell receptors and induce T and B cell activation. T cell immune tolerance may be easier to be induced because organ-specific and nonorgan-specific AID are mediated by T cells and low dose antigens are enough. Compared with complete or large molecular antigens, peptide vaccines are easier to induce immune tolerance, easy to synthesis, purification and more safe. So it has been the hot spot to use Th cell epitope of autoantigen instead of complete antigen to prepare therapeutic peptide-based vaccines.
The screening and identification of the autoantigen epitope are important to peptide
引文
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23. Zonana-Nacach A, Barr SG, Magder LS, et al. Damage in systemic lupus erythematosus and its association with corticosteroids. Arthritis Rheum, 2000,43(8):1801-1808
24. Butani L. Corticosteroid-induced hypersensitivity reactions. Ann Allergy Asthma Immunol, 2002,89(5):439-445
25. Zimmerman R, Radhakrishnan J, Valeri A, et al. Advances in the treatment of lupus nephritis. Ann Rev Med, 2001, 52:63-78
26. Hejaili FF, Moist LM, Clark WF. Treatment of lupus nephritis. Drugs, 2003, 63(3):257-274
27. Isenberg D, Leckie MJ. Biological treatments for systemic lupus erythematosus. Scand J Rheumatol, 2002, 31(4):187-192
28. Bagchi D, Misner B, Bagchi M. Effects of orally administered undernatured type Ⅱ collagen against arthritic inflammatory disease: a mechanistic exploration. Int J Clin Pharmacal Res, 2002, 22(3-4):101-110
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