Abstract
摘要:氣喘是兒童最常見的慢性疾病,氣喘的特徵包括氣道發炎,伴隨有氣道過度反應(airway hyper-responsiveness)以及重塑(remodeling)。據估氣喘病人有90%對塵螨過敏,塵螨過敏原第一組與第二組Dermatophagoides pteronyssinus (Dp1和Dp2)蛋白為主要過敏原。之前的研究發現,經由注射會引起免疫反應的抗原經由口服的方式反而會誘發抗原的不反應性,這樣的免疫反應稱為口服耐受性(oral tolerance),目前有關口服耐受性的機轉之一包括利用低劑量抗原誘發出調節性T細胞(regulatory T cells,簡稱Treg)來抑制抗原特異性免疫反應。目前口服耐受性的原理已成功應用於成人與孩童氣喘的減敏治療。 一般假定口服耐受性是針對口服的抗原蛋白產生的耐受性,然而有研究發現口服抗原A可引發對其他不相關的抗原B的耐受性,稱為交叉免疫耐受性(cross-immune tolerance)。雖然特異性T細胞的活化是具有抗原特異性,他們可產生非抗原特異性的抑制作用,藉由分泌抑制性的細胞激素(IL-10或TGF- β)或是細胞表面接受器的作用,此現象稱為旁觀性抑制(bystander suppression) 。交叉免疫耐受性的應用具有治療發炎疾病的潛力,由皮膚移植實驗中已證明。我們研究目的是欲驗證小鼠氣喘是否有交叉免疫耐受性存在,我們藉由兩個常見過敏原ovalbumin (簡稱OVA,屬雞蛋白過敏原)和β-lactoglobulin (簡稱BLG,屬牛奶蛋白過敏原)來證實,我們的前驅研究已證實小鼠先用OVA和BLG致敏,而之後使用口服OVA誘發OVA耐受性,發現能降低BLG-IgE和抑制淋巴球對BLG之增生反應,我們假設由OVA誘發之免疫耐受性可調控BLG之免疫反應,是藉由OVA專一性調節性T細胞之作用。本實驗的第二個目的是研究另一個假說,交叉免疫耐受性存在於合成塵螨蛋白(recombinant Dp1或rDp2)和原始塵螨蛋白(crude mite)兩抗原之間,若對口服合成塵螨蛋白可誘發原始塵螨蛋白耐受性,合成塵螨蛋白未來可取代原始塵螨蛋白成為目前氣喘減敏治療的抗原,這必然在氣喘治療是一項重大突破。
Abstract: Asthma is the most common chronic disease in children. It is characterized by airwayinflammation, airway hyper-reactivity and remodeling. About 90% of asthmatic children aresensitized to house dust mite Dermatophagoides pteronyssinus (Dp). Group 1 and 2 allergensderived from house dust mite (Dp1 and Dp2) are considered major allergens.Oral tolerance is defined by the specific suppression of humoral or cellular immuneresponses to an antigen that is induced by prior administration of the antigen through the oralroute. One of the mechanisms in oral tolerance is the induction of antigen-specific regulatoryT cells (Tregs) by low dose antigen administration. Administration of antigens to induceantigen-specific tolerance by a different route, namely subcutaneous immunotherapy (SCIT)and sublingual immunotherapy (SLIT), has been confirmed effective for asthma. It isgenerally assumed that oral tolerance is specific for the orally administered protein.However, the inclusion of an antigen for which oral tolerance has already been establishedleads to inhibition of responses to other, unrelated antigens that are included in theimmunization, the so-called “cross-immune tolerance”. Mechanistically, although Tregs canby activated in an antigen-specific manner, they can suppress immune responses in theimmediate surrounding area in an antigen-non-specific manner, using suppressive cytokines(IL-10 or TGF-β) and cell-surface ligands. This phenomenon is known as ‘bystandersuppression’. On the other hands, Tregs can modulate the immune-stimulatory capacity ofdendritic cells through surface-expressed molecules CTLA-4, PD-1. The application of‘cross immune tolerance’ is a potentially powerful therapeutic tool for controllinginflammatory conditions, which is demonstrated in skin graft transplantation experiments.The aim of our study is to test the hypothesis that cross-immune tolerance exists in amurine model asthma by using two antigens ovalbumin (OVA, an egg-white allergen) andβ-lactoglobulin (BLG, a cow’s milk allergen). In our preliminary results, mice previouslysensitized OVA mixed with bovine BLG and then orally delivered OVA showed asignificant decreased of BLG-specific IgE, BLG-induced splenic lymphoproliferation. Wepropose that induced tolerant response to OVA can regulate BLG-specific response byOVA-specific Treg cells.Moreover, the second aim of our study is to test the hypothesis that cross toleranceexists between recombinant mite allergen (rDp1 or rDp2) and crude mite protein. Iftolerance to crude mite could by induced by administration of recombinant mite allergen inasthmatic mice, recombinant mite allergen could be further used as antigen inimmunotherapy in asthmatic patients. Our study can provide a broader application byimproving current immunotherapy using crude mite protein in asthma. It will be abreakthrough in the treatment of asthma.
Keyword(s)
氣喘
口服耐受性
交叉耐受性
旁觀性抑制
asthma
oral tolerance
cross-immune tolerance
bystander suppression