臺灣博碩士論文加值系統

氣喘（asthma）屬於呼吸道發炎疾病，其主要免疫機制為個體之CD4+ T 細胞偏向於第二型輔助型T細胞（type 2 T helper cells, TH2）免疫反應。目前治療氣喘大多使用類固醇藥物抑制發炎反應以控制病情，雖可有效抑制氣喘發生，但常伴隨著副作用或增加伺機性感染的危險性。實驗室在過去的研究中，嘗試以蜂膠（propolis）緩解呼吸道發炎小鼠之病情，復以蜂膠中特有成分咖啡酸苯乙酯（caffeic acid phenethyl ester, CAPE），使呼吸道發炎小鼠連續口服五天（劑量為每公斤體重投予5、10或20毫克CAPE），結果發現CAPE顯著抑制肺部支氣管沖出液中嗜酸性白血球之總數，並且抑制多種促發炎細胞激素。本研究以體外培養試驗進行CAPE調節機制之探討。
將CAPE與氣喘孩童（平均年齡5.5 ± 3.3歲, n=28）或健康受試者（平均年齡5.6 ± 2.8歲, n=23）之週邊血液淋巴球（peripheral blood mononuclear cells, PBMC）進行體外培養後，結果發現氣喘孩童PBMC中IL-10之自發性分泌量較健康受試者高。當PBMC以PMA（phorbol-12-myristate-13-acetate）-ionomycin活化時，健康受試者PBMC之IL-4（interleukin-4）與IFN-（interferon-gamma）分泌量皆較氣喘受試者高。在PBMC活化之情形下，額外添加2.5 g/mL CAPE，可顯著抑制健康受試者之IL-10與IFN-分泌，而對於氣喘孩童無顯著差異，但氣喘孩童之TGF-1（transforming growth factor-beta 1）分泌量則是顯著增加。研究中取得之氣喘孩童PBMC為處於急性發作期收集而得，因此體內傾向分泌IL-10，以平衡氣喘發作時所引起的發炎反應，故額外給予PMA-ionomycin刺激時，CAPE抑制細胞激素分泌之效果不若健康受試者明顯。另以細胞內細胞激素螢光染色法（intracellular cytokines staining）分析，發現兩組受試者PBMC與CAPE共同培養6小時後，均顯著增加CD4+IL-10+、CD4+IL-4+及CD4+CD25+細胞百分比，但不影響CD4+ T細胞之CD69表現量。
由於CAPE可促進以PMA-ionomycin刺激之PBMC分泌TGF-1，抑制細胞激素分泌，同時也顯著增加CD4+CD25+ T細胞之百分比，但不影響CD4+CD69+ T細胞之表現，因此CAPE可能活化某一群類似調節型T細胞（regulatory T –like cells, Treg-like cells）的細胞。為進一步探討CAPE對PBMC中Treg轉錄層次之影響，自成年健康受試者之PBMC純化出CD4+ T細胞，與2.5 g/mL CAPE共同培養6小時後萃取mRNA，由反轉錄酶-聚合酶連鎖反應（reverse transcription - polymerase chain reaction）結果發現，CAPE可顯著促進CD4+ T細胞表現TGF-1，抑制CTLA-4（cytotoxic T lymphocyte antigen-4）mRNA表現，對於FOXP3（forkhead box p3）之mRNA表現量則與控制組無差別。
由於CAPE抑制PBMC之細胞激素分泌，為探討CAPE對於TH細胞趨化（polarization）為TH1或TH2過程之影響，因此建立臍帶血TH細胞株。自臍帶血分離之naïve CD4+CD45RA+ T細胞，與基因重組之人類IL-4（recombinant human IL-4, rmhIL-4）、抗人類IL-12單株抗體（anti-human IL-12, anti-hIL-12）或rmhIL-12、anti-hIL-4共同培養以分別趨化為TH2與TH1細胞後，在細胞受到IL-2（10 ng/mL）與PMA-ionomycin之活化狀態下，額外添加CAPE於培養系統，結果發現0.5 g/mL CAPE分別抑制TH1與TH2細胞之IFN-與IL-5分泌，而2.5 g/mL CAPE可促進TH0細胞分泌TGF-1。
綜上所述，CAPE對PBMC免疫調節之可能機制為，在PBMC受活化之情況下，引發氣喘孩童或健康受試者PBMC中Treg-like cells的表現，進而促進T細胞分泌TGF-1，並抑制TH1/TH2細胞激素之分泌。由臍帶血TH細胞株之研究，發現CAPE可抑制T細胞趨化為TH1或TH2。由於最近許多研究顯示支持Treg對氣喘之調控具有正面意義，因此蜂膠中特有物質CAPE，將有很大的潛力發展為治療氣喘之藥物。

Asthma is characterized as chronic airway inflammation disease. TH2 cells (type 2 T helper cells) are crucial for the initiation and progression of asthma. Current treatments for asthma are mainly based on pharmacological interventions, such as treatment with glucocorticoids. Although these treatments are effective for controlling disease, many patients must take these drugs for life and concerns about side-effects. Previous study revealed that eosinophilia in bronchoalveolar lavage fluid and secretion of the pro-inflammatory cytokines, such as IL-6 (interleukin-6) and TNF- (tumor necrosis factor-alpha) were suppressed in airway inflammation murine model administered with 5, 10 or 20 mg CAPE (caffeic acid phenethyl ester)/ kg body weight/ day. The aim of this study is to investigate the mechanism of immunoregulatory effect of CAPE in vitro. Peripheral blood mononuclear cells (PBMC) from asthmatic children (5.5 ± 3.3 yr, n = 28) or healthy donors (5.6 ± 2.8 yr, n = 23) were cultured with CAPE in the presence of PMA (phorbol-12-myristate-13-acetate)-ionomycin in vitro. The spontaneous production of IL-10 by cultured PBMC was higher in asthmatic patients. Predominant IL-4 and IFN-(interferon-gamma) secretion of cultured supernatant were detected in healthy donors compared to asthmatics. However, CAPE treated could significantly inhibit IL-10 and IFN- secretion in healthy donors, and enhanced TGF-1 (transforming growth factor-beta 1) secretion in asthmatics. The lack of enhancement of IL-10 secretion in their frequency by PMA-ionomycin in asthmatics suggests that PBMC of asthmatic subjects are maximally stimulated with regards to IL-10 production to inhibit the inflammatory responses. The asthmatic patients suffer acute attacks were included in this study not the same as healthy donors. The data of intracellular cytokines staining shown that the percentage of CD4+IL-4+, CD4+IL-10+ and CD4+CD25+ cells were increased when PBMC co-cultured with CAPE for 6 h, but didn’t affect the percentage of CD4+CD69+ expression in both asthmatic and healthy children.
Our data shown that CAPE can significantly enhanced both TGF-1 secretion and the percentage of CD4+CD25+ cell, but it suppressed IL-4 and IFN- production in PBMC. These results suggested that the immunoregulatory effect of CAPE on modulate cytokines production where regulatory T-like cells may play a role. To further study the effect of CAPE on Treg-associated gene expression, CD4+ T cells purified from healthy adult volunteers were cultured with 2.5 g/mL CAPE for 6 h, and followed with RNA extraction. RT-PCR (reverse transcription-polymerase chain reaction) analysis showed that under the stimulation of CAPE, TGF-1 mRNA expression was increased, but CTLA-4 (cytotoxic T lymphocyte antigen-4) expression was reduced in CD4+ T cells and didn’t affect FOXP3 (forkhead box p3) expression.
To clarify the inhibition of CAPE on cytokine secretion in PBMC, we established the cord blood TH cell line to elucidate the polarization of TH cell in this study. Naïve CD4+CD45RA+ T cells separated from cord blood were stimulated to TH1 or TH2 cell phenotype in the presence of recombinant human IL-4 (rmhIL-4) and anti-human IL-12 (anti-hIL-12) or rmhIL-12 and anti-hIL-4, respectively. Both the IFN- and IL-5 produced from TH1 and TH2 subset were significantly suppressed by 0.5 g/mL CAPE, and promoted TGF-1 secretion from TH0 cell line by 2.5 g/mL CAPE.
In summary, these findings demonstrate that the possible immunoregulatory mechanism of CAPE is to induce the expression of Treg-like cells in activated PBMC from asthmatic and healthy subjects, which can promote TGF-1 secretion from T cells and further inhibit TH1/TH2 cytokines secretion. Recently Treg cells have emerged as a master regulator of immunity and a new target for asthmatic intervention. Our findings will be helpful for developing CAPE as a novel therapeutic medicine of asthma therapy.

中文摘要………………………………………………………….......................... I
英文摘要………………………………………………………………………….. IV
縮寫表………………………………………………………….............................. VII


第一章 緒言………………………………………………………….................. 1

第二章 文獻回顧………………………………………………………….......... 3
第一節 氣喘………………………………………………………….............. 3
2.1.1 氣喘的簡介與定義………………………………………………….. 3
2.1.2 致病機轉…………………………………………………………...... 3
2.1.2.1 T細胞所扮演的角色………………………………………… 3
2.1.2.2 IgE抗體對於調節肥大細胞所扮演的角色……………….... 4
2.1.2.3 氣喘發炎過程中重要的細胞激素與化學趨化物質………... 4
（1）發炎細胞激素………………………………………………. 5
（2）化學趨化物質……………………………………………... 5
（3）調節型細胞激素…………………………………………... 6
2.1.3 調節型T細胞（regulatory T cells, Treg）………………………….. 8
2.1.3.1 Treg簡介………………………………………………….…. 8
2.1.3.2 Treg在過敏疾病所扮演的角色……………………….……. 9
2.1.4 治療氣喘的方式………………………………………………….…. 9
第二節 蜂膠中的活性物質………………………………………….………. 10
2.2.1 CAPE之來源………………………………………………….…….. 10
2.2.2 CAPE之生物活性…………………………………………………... 11
2.2.2.1 抗氧化作用…………………………………….…………… 11
2.2.2.2 抗腫瘤作用……………………………………..………..… 11
2.2.2.3 抗發炎作用………………………………………………… 11
2.2.3 CAPE之免疫調節功能……………………………………………... 12

第三章 實驗材料與方法…………………………………………………….…. 14
第一節 實驗設計………………………………………………………….…. 14
第二節 實驗材料…………………………………………………………….. 17
4.2.1 檢體之收集………………………………………………………….. 17
4.2.1.1 週邊血液淋巴球……………………………………………. 17
4.2.1.2 臍帶血………………………………………………………. 17
4.2.2 試驗物質………………………………………………………….…. 17
第三節 測試項目與方法……………………………………………………….. 17
4.3.1 CAPE對氣喘或健康孩童PBMC細胞激素分泌之影響………..… 17
4.3.1.1 自週邊血液中分離PBMC………………………………..... 17
4.3.1.2 細胞培養上清液之收集與分析細胞激素分泌情形…….… 18
（1）酵素連結免疫分析法（ELISA）………………………... 18
4.3.1.3 細胞表面抗原與細胞內細胞激素之免疫螢光染色分析…. 19
（1）細胞表面抗原分析……………………………………….. 20
（2）CD4+淋巴細胞內細胞激素分泌情形……………………. 20
4.3.2 CAPE對CD4+ T細胞FOXP3表現之影響………………………... 21
4.3.2.1 分離CD4+ T細胞與鑑定純度……………………….….…. 21
（1）純化CD4+ T之操作步驟………………………………… 21
（2）CD4+ T純度之鑑定………………………………………. 22
4.3.2.2 將CD4+ T細胞與CAPE進行培養………………….….… 22
4.3.2.3 萃取RNA…………………………………………………… 22
4.3.2.4 反轉錄-聚合酶連鎖反應（RT-PCR）………………………. 23
（1）反轉錄反應……………………………………………….. 23
（2）聚合酶連鎖反應…………………………………………... 23
（3）DNA電泳………………………………………………… 24
4.3.3 CAPE對CBMC趨化反應之影響…………………………………. 24
4.3.3.1 自臍帶血分離CBMC……………………………………… 25
4.3.3.2 分離CD4+ T與naïve CD4+CD45RA+ T細胞純度之鑑定… 25
4.3.3.3 填覆抗人類CD3抗體之細胞培養盤……………………... 25
4.3.3.4 naïve CD4+CD45RA+ T之TH0/ TH1/ TH2趨化反應………. 25
4.3.3.5 CAPE對CB TH0/ TH1/ TH2細胞增生能力之影響………… 26
4.3.3.6 CAPE對CB TH0/ TH1/ TH2細胞株細胞激素分泌之影響… 26
4.3.3.7 CAPE對CB TH0細胞TGF-1表現之影響…………..….. 27
第四節 統計方法…………………………………………………………….. 27

第四章 結果與討論…………………………………………………………….. 28
第一節 CAPE對氣喘或健康孩童PBMC細胞激素分泌之影響………….. 29
5.1.1 CAPE抑制健康孩童PBMC之細胞激素分泌…………………….. 29
5.1.2 以細胞內細胞激素螢光染色評估氣喘與健康受試者體內的
TH1/TH2狀態…………………………………………………….....
34
5.1.2.1 培養系統中monensin之添加方式對細胞內細胞激素
螢光染色結果之影響………………………………………
34
5.1.2.2 不同培養時間對細胞內細胞激素螢光染色結果之影響…. 35
5.1.3 ELISA與細胞內細胞激素螢光染色之分析結果呈現不同的意義.. 39
5.1.3.1 細胞內細胞激素螢光染色為短時間內培養CAPE對
PBMC之影響結果…………………………………………
39
5.1.3.2 較長培養時間下CAPE對PBMC中所有細胞族群
之影響結果……………………………..…………………..
39
5.1.4 CAPE同時抑制TH1/TH2細胞激素分泌的可能原因……………… 40
第二節 CAPE是否具有活化PBMC中Treg之功能………………………… 41
5.2.1 CAPE促進PBMC中CD4+CD25+細胞百分比……………………. 41
5.2.2 以RT-PCR分析CAPE對Treg轉錄層次之影響…………………… 45
第三節 CAPE對naïve CD4+ T細胞趨化之影響…………………………… 49
5.3.1 CB TH1/TH2細胞株之建立………………………………………..... 50
5.3.2 CAPE抑制CB TH細胞之增生能力……………………….……….. 52
5.3.3 CAPE抑制CB TH1/TH2細胞株細胞激素之分泌…………………. 54
5.3.4 CAPE對CB TH0細胞株之影響…………………………………… 56

第五章 總結與未來展望……………………………………………………….. 61

第六章 參考文獻……………………………………………………………….. 62

附錄－常用試劑與配製方法…………………………………………………….. 74

吳玉琳（2003）蜂膠對氣喘模式實驗小鼠之免疫調節功效。輔仁大學食品營養學系碩士論文。
侯欣妙（2004）探討咖啡酸苯乙酯對卵白蛋白致敏呼吸道發炎小鼠之調節機制。輔仁大學食品營養學系碩士論文。
傅麒玲（1997）減敏治療前後家塵蟎過敏原Der pI專一性T細胞的細胞激素與抗原決定位之分析。台灣大學醫學院免疫學研究所碩士論文。
Adachi M, Oda N, Kokubu F and Minoguchi K (1999) IL-10 induces a Th2 cell tolerance in allergic asthma. Int Arch Allergy Immunol 118: 391-4.
Agea E, Forenza N, Piattoni S, Russano A, Monaco A, Flenghi L, Bistoni O, Gillies DA, Azuma M, Bertotto A and Spinozzi F (1998) Expression of B7 co-stimulatory molecules and CD1a antigen by alveolar macrophages in allergic bronchial asthma. Clin Exp Allergy 28: 1359-67.
Agertoft L and Pedersen S (2000) Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 343: 1064-9.
Akbari O, DeKruyff RH and Umetsu DT (2001) Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat Immunol 2: 725-31.
Akbari O, Stock P, Meyer E, Kronenberg M, Sidobre S and Nakayama T (2003) Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity. Nat Med 9: 582-8.
Akbari O, Freeman GJ, Meyer EH, Greenfield EA, Chang TT, Sharpe AH and Umetsu DT (2002) Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat Med 8: 1024-32.
Akira S, Taga T and Kishimoto T (1993) Interleukin-6 in biology and medicine. Adv Immunol 54: 1-78.
Alam R, Forsythe P, Stafford S, Heinrich J, Bravo R, Proost P and Van Damme J (1994) Monocyte chemotactic protein-2, monocyte chemotactic protein-3, and fibroblast-induced cytokine. Three new chemokines induce chemotaxis and activation of basophils. J Immunol 153: 3155-9.
Alevizopoulos A and Mermod N (1997) Transforming growth factor-beta: the breaking open of a black box. Bioessays 19: 581-91.
Andersson U, Andersson J, Lindfors A, Wagner K, Moller G and Heusser CH (1990) Simultaneous production of interleukin 2, interleukin 4 and interferon-gamma by activated human blood lymphocytes. Eur J Immunol 20: 1591-6.
Ansorge S, Reinhold D and Lendeckel U (2003) Propolis and some of its constituents down-regulate DNA synthesis and inflammatory cytokine production but induce TGF-beta1 production of human immune cells. Z Naturforsch [C] 58: 580-9.
Asai K, Hachimura S, Kimura M, Toraya T, Yamashita M, Nakayama T and Kaminogawa S (2002) T cell hyporesponsiveness induced by oral administration of ovalbumin is associated with impaired NFAT nuclear translocation and p27kip1 degradation. J Immunol 169: 4723-31.
Aubert JD, Dalal BI, Bai TR, Roberts CR, Hayashi S and Hogg JC (1994) Transforming growth factor beta 1 gene expression in human airways. Thorax 49: 225-32.
Azuma H, Yamada Y, Shibuya-Fujiwara N, Yamaguchi M, Murahashi H, Fujihara M, Sato N, Fukazawa K, Ikebuchi K and Ikeda H (2002) Functional evaluation of ex vivo expanded cord blood lymphocytes: possible use for adoptive cellular immunotherapy. Exp Hematol 30: 346-51.
Bankova VS, Popov SS and Marekov NI (1983) A study on flavonoids of propolis. J Nat Pro 46: 471-4.
Schmidt-Weber CB and Blaser K (2004) Regulation and role of transforming growth factor-beta in immune tolerance induction and inflammation. Curr Opin Immunol 16: 709-16.
Baumgartner RA, Deramo VA and Beaven MA (1996) Constitutive and inducible mechanisms for synthesis and release of cytokines in immune cell lines. J Immunol 157: 4087-93.
Beutler B and Cerami A (1989) The biology of cachectin/TNF: a primary mediator of the host response. Annu Rev Immunol 7: 625-55.
Bonfield TL, Konstan MW, Burfeind P, Panuska JR, Hilliard JB and Berger M (1995) Normal bronchial epithelial cells constitutively produce the anti-inflammatory cytokine interleukin-10, which is downregulated in cystic fibrosis. Am J Respir Cell Mol Biol 13: 257-61.
Borish L, Aarons A, Rumbyrt J, Cvietusa P, Negri J and Wenzel S (1996) Interleukin-10 regulation in normal subjects and patients with asthma. J Allergy Clin Immunol 97: 1288-96.
Borish LC and Steinke JW (2003) 2. Cytokines and chemokines. J Allergy Clin Immunol 111: S460-75.
Bousquet J, Jeffery PK, Busse WW, Johnson M and Vignola AM (2000) Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 161: 1720-45.
Brewster CE, Howarth PH, Djukanovic R, Wilson J, Holgate ST and Roche WR (1990) Myofibroblasts and subepithelial fibrosis in bronchial asthma. Am J Respir Cell Mol Bio 3: 507-11.
Brown PH, Crompton GK and Greening AP (1997) Proinflammatory cytokines in acute asthma. Lancet 338: 590-3.
Bruder D, Probst-Kepper M, Westendorf AM, Geffers R, Beissert S, Loser K, von Boehmer H, Buer J and Hansen W (2004) Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol 34: 623-30.
Busse WW, Coffman RL, Gelfand EW, Kay AB and Rosenwasser LJ (1995) Mechanisms of persistent airway inflammation in asthma. A role for T cells and T-cell products. Am J Respir Crit Care Med 152: 388-93.
Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, van As A and Gupta N (2001) Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol 108: 184-90.
D'Arena G, Musto P, Cascavilla N, Di Giorgio G, Fusilli S, Zendoli F and Carotenuto M (1998) Flow cytometric characterization of human umbilical cord blood lymphocytes: immunophenotypic features. Haematologica 83: 197-203.
Chen L, Grabowski KA, Xin JP, Coleman J, Huang Z, Espiritu B, Alkan S, Xie HB, Zhu Y, White FA, Clancy J Jr and Huang H (2004) IL-4 induces differentiation and expansion of Th2 cytokine-producing eosinophils. J Immunol 172: 2059-66.
Chen W, Frank ME, Jin W and Wahl SM (2001) TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14: 715-25.
Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G and Wahl SM (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198: 1875-86.
Chiao C, Carothers AM, Grunberger D, Solomon G, Preston GA and Barrett JC (1995) Apoptosis and altered redox state induced by caffeic acid phenethyl ester (CAPE) in transformed rat fibroblast cells. Cancer Res 55: 3576-83.
Chiang BL, Ding HJ, Chou CC and Hsieh KH (1996) Isolation of type 1 and type 2 cloned mite allergen-specific T cells from an asthmatic child. Pediatr Allergy Immunol 7: 193-8.
Coffer PJ and Burgering BM (2004) Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4: 889-99.
Constant SL (1999) B lymphocytes as antigen-presenting cells for CD4+ T cell priming in vivo. J Immunol 162: 5695-703.
Corrigan CJ (2002) Asthma refractory to glucocorticoids: the role of newer immunosuppressants. Am J Respir Med 1: 47-54.
Cottrez F, Hurst SD, Coffman RL and Groux H (2000) T regulatory cells 1 inhibit a Th2-specific response in vivo. J Immunol 165: 4848-53.
Curti A, Ratta M, Corinti S, Girolomoni G, Ricci F, Tazzari P, Siena M, Grande A, Fogli M, Tura S and Lemoli RM (2001) Interleukin-11 induces Th2 polarization of human CD4+ T cells. Blood 97: 2758-63.
D'Arena G, Musto P, Cascavilla N, Di Giorgio G, Fusilli S, Zendoli F and Carotenuto M (1998) Flow cytometric characterization of human umbilical cord blood lymphocytes: immunophenotypic features. Haematologica 83: 197-203.
DeLisi C and Siraganian RP (1979) Receptor cross-linking and histamine release. I. The quantitative dependence of basophil degranulation on the number of receptor doublets. J Immunol 122: 2286-92.
Dhodapkar MV, Steinman RM, Krasovsky J, Munz C and Bhardwaj N (2001) Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193: 233-8.
Dieckmann D, Bruett CH, Ploettner H, Lutz MB and Schuler G (2002) Human CD4+CD25+ regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med 196: 247-53.
Druilhe A, Letuve S and Pretolani M (2003) Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action. Apoptosis 8: 481-95.
Ellis TJ and Wagner GF (1995) Post-transcriptional regulation of the stanniocalcin gene by calcium. J Biol Chem 270: 1960-5.
Esnault S and Malter JS (2002) Extracellular signal-regulated kinase mediates granulocyte-macrophage colony-stimulating factor messenger RNA stabilization in tumor necrosis factor-alpha plus fibronectin-activated peripheral blood eosinophils. Blood 99: 4048-52.
Fitzpatrick LR, Wang J and Le T (2001) Caffeic acid phenethyl ester, an inhibitor of nuclear factor-kappaB, attenuates bacterial peptidoglycan polysaccharide-induced colitis in rats. J Pharmacol Exp Ther 299: 915-20.
Fiorentino DF, Bond MW and Mosmann TR (1989) Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170: 2081-95.
Fontana A, Constam DB, Frei K, Malipiero U and Pfister HW (1992) Modulation of the immune response by transforming growth factor beta. Int Arch Allergy Immunol 99: 1-7.
Fontenot JD and Rudensky AY (2005) A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat Immunol 6: 331-7.
Fontenot JD, Gavin MA, and Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330-6.
Frenkel K, Wei H, Bhimani R, Ye J, Zadunaisky JA, Huang MT, Ferraro T, Conney AH and Grunberger D (1993) Inhibition of tumor promoter-mediated processes in mouse skin and bovine lens by caffeic acid phenethyl ester. Cancer Res 53: 1255-61.
Fu S, Zhang N, Yopp AC, Chen D, Mao M, Chen D, Zhang H, Ding Y and Bromberg JS (2004) TGF-beta induces Foxp3+ T-regulatory cells from CD4+ CD25- precursors. Am J Transplant 4: 1614-27.
Gangur V and Oppenheim JJ (2000) Are chemokines essential or secondary particioants in allergic responses? Ann Allergy Asthma Immunol 84: 569-81.
Gleizes PE, Munger JS, Nunes I, Harpel JG, Mazzieri R, Noguera I and Rifkin DB (1997) TGF-beta latency: biological significance and mechanisms of activation. Stem Cells 15: 190-7.
Godoy-Ramirez K, Franck K, Mahdavifar S, Andersson L and Gaines H (2004) Optimum culture conditions for specific and nonspecific activation of whole blood and PBMC for intracellular cytokine assessment by flow cytometry. J Immunol Methods 292: 1-15.
Gorelik L, Constant S and Flavell RA (2002) Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 195: 1499-505.
Gorelik L, Fields PE and Flavell RA (2000) Cutting edge: TGF-beta inhibits Th type 2 development through inhibition of GATA-3 expression. J Immunol 165: 4773-7.
Gorelik L and Flavell RA (2002) Transforming growth factor-beta in T-cell biology. Nat Rev Immunol 2: 46-53.
Grunberger D, Banerjee R, Eisinger K, Oltz EM, Efros L, Caldwell M, Estevez V and Nakanishi K (1988) Preferential cytotoxicity on tumor cells by caffeic acid phenethyl ester isolated from propolis. Experientia 44: 230-2.
Guron C, Sudarshan C and Raghow R (1995) Molecular organization of the gene encoding murine transforming growth factor beta 1. Gene 165: 325-6.
Hallsworth MP, Moir LM, Lai D and Hirst SJ (2001) Inhibitors of mitogen-activated protein kinases differentially regulate eosinophil-activating cytokine release from human airway smooth muscle. Am J Respir Crit Care Med 164: 688-97.
Hamelmann E and Gelfand EW (2001) IL-5-induced airway eosinophilia--the key to asthma? Immunol Rev. 179: 182-91.
Hori S and Sakaguchi S (2004) Foxp3: a critical regulator of the development and function of regulatory T cells. Microbes Infect 6: 745-51.
Hori S, Nomura T and Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299: 1057-61.
Horwitz DA, Zheng SG and Gray JD (2003) The role of the combination of IL-2 and TGF-beta or IL-10 in the generation and function of CD4+ CD25+ and CD8+ regulatory T cell subsets. J Leukoc Biol 74: 471-8.
Hsieh CS and Rudensky AY (2005) The role of TCR specificity in naturally arising CD25+CD4+ regulatory T cell biology. Curr Top Microbiol Immunol
Hsu JY, King SL, Kuo BI and Chiang CD (2004) Age of onset and the characteristics of asthma. Respirology 9: 369-72.
Huang MT, Ma W, Yen P, Xie JG, Han J, Frenkel K, Grunberger D and Conney AH (1996) Inhibitory effects of caffeic acid phenethyl ester (CAPE) on 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion in mouse skin and the synthesis of DNA, RNA and protein in HeLa cells. Carcinogenesis 17: 761-5.
Irmak MK, Koltuksuz U, Kutlu NO, Yagmurca M, Ozyurt H, Karaman A and Akyol O (2001) The effect of caffeic acid phenethyl ester on ischemia-reperfusion injury in comparison with alpha-tocopherol in rat kidneys. Urol Res 29: 190-3.
Ilhan A, Koltuksuz U, Ozen S, Uz E, Ciralik H and Akyol O (1999) The effects of caffeic acid phenethyl ester (CAPE) on spinal cord ischemia/reperfusion injury in rabbits. Eur J Cardiothorac Surg 16: 458-63.
Ishizaka T and Ishizaka K (1977) Immunological events at the surface of basophil granulocytes and mast cells which induce degranulation. Scand J Respir Dis Suppl 98: 13-22.
Israel E, Banerjee TR, Fitzmaurice GM, Kotlov TV, LaHive K and LeBoff MS (2001) Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 345: 941-7.
Jeannin P, Lecoanet S, Delneste Y, Gauchat JF and Bonnefoy JY (1998) IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol 160: 3555-61.
Jeffery PK, Wardlaw AJ, Nelson FC, Collins JV and Kay AB (1989) Bronchial biopsies in asthma. An ultrastructural, quantitative study and correlation with hyperreactivity. Am Rev Respir Dis 140: 1745-53.
Jick SS, Vasilakis-Scaramozza C and Maier WC (2001) The risk of cataract among users of inhaled steroids. Epidemiology 12: 229-34.
Jonuleit H, Schmitt E, Schuler G, Knop J and Enk AH (2000) Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 192: 1213-22.
Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J and Enk AH (2002) Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4＋ T helper cells. J Exp Med 196: 255-60.
Kato T and Nariuchi H (2000) Polarization of naive CD4+ T cells toward the Th1 subset by CTLA-4 costimulation. J Immunol 164: 3554-62.
Keane-Myers AM, Gause WC, Finkelman FD, Xhou XD and Wills-Karp M (1998) Development of murine allergic asthma is dependent upon B7-2 costimulation. J Immunol 160: 1036-43.
Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB and Fauci AS (1986) Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 163: 1037-50.
Khattri R, Cox T, Yasayko SA and Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4: 337-42.
Khayyal MT, El-Ghazaly MA, El-Khatib AS, Hatem AM, de Vries PJF, El-Shafei S and Khattab MM (2003) A clinical pharmacological study of the potential beneficial effects of a propolis food product as an adjuvant in asthmatic patients. Fundam Clin Pharmacol 17: 93-102.
Kilav R, Silver J and Naveh-Many T (2001) A conserved cis-acting element in the parathyroid hormone 3'-untranslated region is sufficient for regulation of RNA stability by calcium and phosphate. J Biol Chem 276: 8727-33.
Kim YM, Jung MH, Song HY, Yang HO, Lee ST, Kim JH, Kim YT, Nam JH and Mok JE (2005) Ex vivo expansion of human umbilical cord blood-derived T-lymphocytes with homologous cord blood plasma. Tohoku J Exp Med 205: 115-22.
Kohyama M, Yasogi Y, Nakano N, Ise W, Kaminogawa S and Hozumi N (2005) Ca2+ signaling down-regulates TGF-beta1 gene expression in CD4+ T cells. Biochem Biophys Res Commun 327: 494-9.
Koltuksuz U, Ozen S, Uz E, Aydinc M, Karaman A, Gultek A, Akyol O, Gursoy MH and Aydin E (1999) Caffeic acid phenethyl ester prevents intestinal reperfusion injury in rats. J Pediatr Surg 34: 1458-62.
Kuo ML, Huang JL, Yeh KW, Li PS and Hsieh KH (2001) Evaluation of Th1/Th2 ratio and cytokine production profile during acute exacerbation and convalescence in asthmatic children. Ann Allergy Asthma Immunol 86: 272-6.
Larche M, Till SJ, Haselden BM, North J, Barkans J, Corrigan CJ, Kay AB and Robinson DS (1998) Costimulation through CD86 is involved in airway antigen-presenting cell and T cell responses to allergen in atopic asthmatics. J Immunol 161: 6375-82.
Lawrence DA (1996) Transforming growth factor-beta: a general review. Eur Cytokine Netw 7: 363-74.
Lederer JA, Perez VL, DesRoches L, Kim SM, Abbas AK and Lichtman AH (1996) Cytokine transcriptional events during helper T cell subset differentiation. J Exp Med 184: 397-406.
Letterio JJ and Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16: 137-61.
Leung DY, Hauk P, Strickland I, Travers JB and Norris DA (1998) The role of superantigens in human diseases: therapeutic implications for the treatment of skin diseases. Br J Dermatol 139: 17-29.
Levings MK, Sangregorio R, Sartirana C, Moschin AL, Battaglia M, Orban PC and Roncarolo MG (2002) Human CD25+CD4+ T suppressor cell clones produce transforming growth factor beta, but not interleukin 10, and are distinct from type 1 T regulatory cells. J Exp Med 196: 1335-46.
Liao HF, Chen YY, Liu JJ, Hsu ML, Shieh HJ, Liao HJ, Shieh CJ, Shiao MS and Chen YJ (2003) Inhibitory effect of caffeic acid phenethyl ester on angiogenesis, tumor invasion, and metastasis. J Agric Food Chem 51: 7907-12.
Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, Carr VA and Robinson DS (2004) Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363: 608-15.
Linsley PS and Ledbetter JA (1998) The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 11: 191-212.
Li Z and Li T (1999) Pharmacological study on asthma-relieving decoction (dingchuan tang) treating asthma. Zhong Yao Cai 22: 411-3.
Lukacs NW, Strieter RM, Warmington K, Lincoln P, Chensue SW and Kunkel SL (1997) Differential recruitment of leukocyte populations and alteration of airway hyperreactivity by C-C family chemokines in allergic airway inflammation. J Immunol 158: 4398-404.
Lynch EL, Little FF, Wilson KC, Center DM and Cruikshank WW (2003) Immunomodulatory cytokines in asthmatic inflammation. Cytokine Growth Factor Rev 14: 489-502.
Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M and Morgan WJ (1995) Asthma and wheezing in the first six years of life. N Engl J Med 332: 133-8.
Marquez N, Sancho R, Macho A, Calzado MA, Fiebich BL and Munoz E (2003) Caffeic acid phenethyl ester inhibits T-cell activation by targeting both NF-AT and NF-kappa B transcription factors. J Pharmacol Exp Ther 308: 993-1001.
Matricardi PM, Rosmini F, Riondino S, Fortini M, Ferrigno L and Rapicetta (2000) Exposure to foodbourne and orofecal microbes versus airbourne viruses in relation to atopy and allergic asthma. Br Med J 320: 412-7.
Matsuda JL, Gapin L, Sidobre S, Kieper WC, Tan JT, Ceredig R, Surh CD and Kronenberg M (2002) Homeostasis of V alpha 14i NKT cells. Nat Immuol 3: 966-74.
Matsumoto K, Inoue H, Fukuyama S, Tsuda M, Ikegami T, Kibe A, Yoshiura Y, Komori M, Hamasaki N, Aizawa H and Nakanishi Y (2004a) Decrease of interleukin-10-producing T cells in the peripheral blood of severe unstable atopic asthmatics. Int Arch Allergy Immunol 134: 295-302.
Matsumoto K, Narita S, Rerecich T, Snider DP and O'Byrne PM (2004b) Different profile of interleukin-10 production in circulating T cells from atopic asthmatics compared with healthy subjects. Can Respir J 11: 33-8.
McCartney-Francis NL, Frazier-Jessen M and Wahl SM (1998) TGF-beta: a balancing act. Int Rev Immunol 16: 553-80.
Michaluart P, Masferrer JL, Carothers AM, Subbaramaiah K, Zweifel BS, Koboldt C, Mestre JR, Grunberger D, Sacks PG, Tanabe T and Dannenberg AJ (1999) Inhibitory effects of ceffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation. Cancer Res 59: 2347-52.
Mollenhauer HH, Morre DJ and Rowe LD (1990) Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity. Biochim Biophys Acta 1031: 225-46.
Moore KW, de Waal Malefyt R, Coffman RL and O'Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19: 683-765.
Mosmann TR, Cherwinski H, Bond MW, Giedlin MA and Coffman RL (1986) Two type of murine helper T cell clone I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136: 2348-57.
Mosmann TR and Coffman RL (1989) Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7: 145-73.
Nair MP, Kandaswami C, Mahajan S, Chadha KC, Chawda R, Nair H, Kumar N, Nair RE and Schwartz SA (2002) The flavonoid, quercetin, differentially regulates Th-1 (IFNgamma) and Th-2 (IL4) cytokine gene expression by normal peripheral blood mononuclear cells. Biochim Biophys Acta 1593: 29-36.
Nakamura K, Kitani A and Strober W (2001) Cell contact-dependent immunosuppresion by CD4＋CD25＋regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194: 629-44.
O'Neil-Andersen NJ and Lawrence DA (2002) Differential modulation of surface and intracellular protein expression by T cells after stimulation in the presence of monensin or brefeldin A. Clin Diagn Lab Immunol 9: 243-50.
Natarajan K, Singh S, Burke TR Jr, Grunberger D and Aggarwal BB (1996) Caffeic acid phenethyl ester is a potent and specific inhibitor of activation of nuclear transcription factor NF-kappa B. Proc Natl Acad Sci USA 93: 9090-5.
National Asthma Education and Prevention Program (1997) Expert Panel No. 2: Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, NIH Publication 97-4051.
National Asthma Education and Prevention Program (2002) Update on Selected Topics: Guidelines for the diagnosis and management of asthma. National Heart, Lung, and Blood Institute, NIH Publication 02-5074.
Noma T, Sugawara Y, Ogawa N, Saeki T, Yamaguchi K and Kawano Y (2004) Dermatophagoides-induced interleukin-10 production by peripheral blood lymphocytes from patients with asthma in remission. Pediatr Allergy Immunol 15: 459-68.
Oliveira SH and Lukacs NW (2003) The role of chemokines and chemokine receptors in eosinophil activation during inflammatory allergic reactions. Braz J Med Biol Res 36: 1455-63.
Ohta K and Yamashita N (1999) Apoptosis of eosinophils and lymphocytes in allergic inflammation. J Allergy Clin Immunol 104: 14-21.
Orsolic N and Basic (2003) Immunomodulation by water-soluble derivative of propolis: a factor of antitumor reactivity. J Ethnopharmacol 84: 265-73.
Ou LS, Goleva E, Hall C and Leung DY (2004) T regulatory cells in atopic dermatitis and subversion of their activity by superantigens. J Allergy Clin Immunol 113: 756-63.
Owen CE (2002) Anti-immunoglobulin E therapy for asthma. Pulm Pharmacol Ther 15: 417-25.
Owen WF Jr, Rothenberg ME, Silberstein DS, Gasson JC, Stevens RL, Austen KF and Soberman RJ (1987) Regulation of human eosinophil viability, density, and function by granulocyte/macrophage colony-stimulating factor in the presence of 3T3 fibroblasts. J Exp Med 166: 129-41.
Pala P, Hussell T and Openshaw PJ (2000) Flow cytometric measurement of intracellular cytokines. J Immunol Methods 243: 107-24.
Park JH, Lee JK, Kim HS, Chung ST, Eom JH, Kim KA, Chung SJ, Paik SY and Oh HY (2004) Immunomodulatory effect of caffeic acid phenethyl ester in Balb/c mice. Int Immunopharmacol 4: 429-36.
Punnonen J, Aversa G, Cocks BG, McKenzie AN, Menon S, Zurawski G, de Waal Malefyt R and de Vries JE (1993) Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 90: 3730-4.
Ramakrishnan M, Musa NL, Li J, Liu PT, Pestell RG and Hershenson MB (1998) Catalytic activation of extracellular signal-regulated kinases induces cyclin D1 expression in primary tracheal myocytes. Am J Respir Cell Mol Bio 18: 736-40.
Rao PE, Petrone AL and Ponath PD (2005) Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF-beta. J Immunol 174: 1446-55.
Robinson DS, Larche M and Durham SR (2004) Tregs and allergic disease. J Clin Invest 114: 1389-97.
Roche WR, Beasley R, Williams JH and Holgate ST (1989) Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1: 520-4.
Romagnani S (1994) Lymphokine production by human T cells in disease states. Annu Rev Immunol 12: 227-57.
Rostaing L, Tkaczuk J, Durand M, Peres C, Durand D, de Preval C, Ohayon E and Abbal M (1999) Kinetics of intracytoplasmic Th1 and Th2 cytokine production assessed by flow cytometry following in vitro activation of peripheral blood mononuclear cells. Cytometry 35: 318-28.
Sakaguchi S (2003) The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery. J Clin Invest 112: 1310-2.
Schall TJ, Bacon K, Toy KJ and Goeddel DV (1990) Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature 347: 669-71.
Schluesener H, Jung S and Salvetti M (1990) Susceptibility and resistance of human autoimmune T cell activation to the immunoregulatory effects of transforming growth factor (TGF) beta 1, beta 2, and beta 1.2. J Neuroimmunol 28: 271-6.
Schmidt-Weber CB and Blaser K (2004) Regulation and role of transforming growth factor-beta in immune tolerance induction and inflammation. Curr Opin Immunol 16: 709-16.
Schubert LA, Jeffery E, Zhang Y, Ramsdell F and Ziegler SF (2001) Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 276: 37672-9.
Secrist H, Chelen CJ, Wen Y, Marshall JD and Umetsu DT (1993) Allergen immunotherapy decreases interleukin 4 production in CD4+T cells from allergic individuals. J Exp Med 178: 2123-30.
Shimizu J, Yamazaki S, Takahashi T, Ishida Y and Sakaguchi S (2002) Stimulation of CD25＋CD4＋regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3: 135-42.
Solèr M, Matz J, Townley R, Buhl R, O’Brien J, Fox H, Thurlwell J, Gupta N and Della Cioppa G (2001) The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 18: 254-61.
Sornasse T, Larenas PV, Davis KA, de Vries JE and Yssel H (1996) Differentiation and stability of T helper 1 and 2 cells derived from naive human neonatal CD4+ T cells, analyzed at the single-cell level. J Exp Med 184: 473-83.
Strachan DP (1989) Hay fever, hygiene, and household size. BMJ 299: 1259-60.
Song YS, Park EH, Hur GM, Ryu YS, Lee YS, Lee JY, Kim YM and Jin C (2002) Caffeic acid phenethyl ester inhibits nitric oxide synthase gene expression and enzyme activity. Cancer Lett 175: 53-61.
Sud'ina GF, Mirzoeva OK, Pushkareva MA, Korshunova GA, Sumbatyan NV and Varfolomeev SD (1993) Caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties. FEBS Lett 329: 21-4.
Su ZZ, Grunberger D and Fisher PB (1991) Suppression of adenovirus type 5 E1A-mediated transformation and expression of the transformed phenotype by caffeic acid phenethyl ester (CAPE). Mol Carcinog 4: 231-42.
Su ZZ, Lin J, Grunberger D and Fisher PB (1994) Growth suppression and toxicity induced by caffeic acid phenethyl ester (CAPE) in type 5 adenovirus-transformed rat embryo cells correlate directly with transformation progression. Cancer Res 54: 1865-70.
Su ZZ, Lin J, Prewett M, Goldstein NI and Fisher PB (1995) Apoptosis mediates the selective toxicity of caffeic acid phenethyl ester (CAPE) toward oncogene-transformed rat embryo fibroblast cells. Anticancer Res 15: 1841-8.
Takahata Y, Nomura A, Takada H, Ohga S, Furuno K, Hikino S, Nakayama H, Sakaguchi S and Hara T (2004) CD25+CD4+ T cells in human cord blood: an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Exp Hematol 32: 622-9.
Teng YT, Gorczynski RM and Hozumi N (1998) The function of TGF-beta-mediated innocent bystander suppression associated with physiological self-tolerance in vivo. Cell Immunol 190: 51-60.
Thornton CA, Upham JW, Wikstrom ME, Holt BJ, White GP, Sharp MJ, Sly PD and Holt PG (2004) Functional maturation of CD4+CD25+CTLA4+CD45RA+ T regulatory cells in human neonatal T cell responses to environmental antigens/allergens. J Immunol 173: 3084-92.
Thornton AM and Shevach EM (1998) CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188: 287-96.
Trinchieri G (2001) Regulatory role of T cells producing both interferon gamma and interleukin 10 in persistent infection. J Exp Med 194: F53-7.
Tomas-Barbran FA, Cristina-Vignera C, Vit-Olivier P, Ferreres F and Tomas-Lorente F (1993) Phytochemial evidence for the botanical origin of tropical propolis from Venezuela. Phytochemistry 34: 191-6.
Umetsu DT, Akbari O and Dekruyff RH (2003) Regulatory T cells control the development of allergic disease and asthma. J Allergy Clin Immunol 112: 480-7.
Van der Pouw-Kraan T, Van Kooten C, Rensink I and Aarden L (1992) Interleukin (IL)-4 production by human T cells: differential regulation of IL-4 vs. IL-2 production. Eur J Immunol 22: 1237-41.
Verhoef CM, Van Roon JA, Vianen ME, Glaudemans CA, Lafeber FP and Bijlsma JW (1999) Lymphocyte stimulation by CD3-CD28 enables detection of low T cell interferon-gamma and interleukin-4 production in rheumatoid arthritis. Scand J Immunol 50: 427-32.
Wahl SM, Vazquez N and Chen W (2004) Regulatory T cells and transcription factors: gatekeepers in allergic inflammation. Curr Opin Immunol 16: 768-74.
Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH and Ziegler SF (2003) Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25- T cells. J Clin Invest 112: 1437-43.
Weiner HL (2001) Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 182: 207-14.
Wierenga EA, Snoek M, Jansen HM, Bos JD, van Lier RAW and Kapsenberg ML (1991) Human atopen-specific type 1 and 2 T helper cell clones. J Immunol 147: 2942-9.
Wong CK, Ho CY, Ko FW, Chan CH, Ho AS, Hui DS and Lam CW (2001) Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-gamma, IL-4, IL-10 and IL-13) in patients with allergic asthma. Clin Exp Immunol 125: 177-83.
Woolcock AJ and Peat JK (1997) Evidence for the increase in asthma worldwide. Ciba Found Aymp 206: 122-34.
Wu CY, Demeure C, Kiniwa M, Gately M and Delespesse G (1993) IL-12 induces the production of IFN-gamma by neonatal human CD4 T cells. J Immunol 151: 1938-49.
Yssel H, De Waal Malefyt R, Roncarolo MG, Abrams JS, Lahesmaa R, Spits H and de Vries JE (1992) IL-10 is produced by subsets of human CD4+ T cell clones and peripheral blood T cells. J Immunol 149: 2378-84.
Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S, Maeda M, Onodera M, Uchiyama T, Fujii S and Sakaguchi S (2004) Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 16: 1643-56.
Zhang X, Wang L and Shi Q (2003) Effect of fluticasone inhalation combined with xiao-qing-long decoction on pulmonary function and serum interleukin-16 level in asthma patients. Zhongguo Zhong Xi Yi Jie He Za Zhi 23: 426-9.
Zheng SG, Wang JH, Gray JD, Soucier H and Horwitz DA (2004) Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 172: 5213-21.
Zhou L and Hershenson MB (2003) Mitogenic signaling pathways in airway smooth muscle. Respir Physiol Neurobio 137: 295-308.