克罗恩病研究进展资料.ppt

克罗恩病研究进展彭 孝 纬福建省立医院 福建省胃肠病研究所,,,流行病学研究概况,发病率分别为 4-12/105 近20年来CD增加明显欧美多见,中国和亚洲国家少见,青壮年多见,儿童和老年人少见,流行病学研究概况,经济发达地区的发病危险性高于落后地区城市地区高于农村当人群从疾病低发区移居到高发区后,发病率也会上升,亚洲国家克罗恩病发病率在上升,国内近15年克罗恩病病例数,小计 2910,提高城市化：公共卫生水平,增加CD的发病率饮用热水成为习惯：OR 5.0 (95%CI1.4-17.3)不再使用公共浴室：OR 3.3 (95%CI1.3–8.3)儿童期胃肠道感染可能是 CD的保护因素? Gent Lancet 1994,克 罗 恩 病,病因、发病机制迄今未明主要集中在环境、遗传和免疫异常等方面Genetic Linkages and CD,Chr. 16q12 - IBD1 NOD2 6p - IBD3 MHC Ⅰ和Ⅱ 14q - IBD4 TCR α/β复合体5q - IBD5 IL-3,IL-4,IL-519p - IBD6 TB4H,C3Others:- Chr 1, 2, 3, 7, X,NOD2 基因,NOD2/CARD15基因——CD相关基因Hugot等1996年发现在IBD1位点仅见于CD而非UC，约20%-30%的CD患者欧美澳三洲12个研究组613个家庭研究证实,,NOD2基因产物是一种细胞内的内毒素结合蛋白 ,野生型能清除入侵病原体.NOD2突变可引起肠道菌群改变导致的免疫激活异常 NOD2突变还可使细胞凋亡机制失常导致CD慢性炎症和组织破坏突变杂合子患病危险性增加3倍,纯合子增加23倍.,,NOD2突变破坏了细胞对细菌的天然(先天性)免疫反应特异性获得性免疫反应增强引起CD的组织损伤编码蛋白在单核细胞表达可使NF-κB活化，对LPS反应,免 疫 异 常,细胞中介免疫反应异常T细胞中心地位，激活后产生各种细胞因子、炎性介质，引起和放大粘膜炎症--Th1类型免疫反应遗传决定因素使普通肠菌抗原引起上调的Ｔ细胞免疫反应,克罗恩病的粘膜免疫反应,Role for Targeted Biologic Therapy in Crohn’s Disease (CD),Disease Mechanisms: Chronic Immune ActivationNatural History of Crohn’s Disease: Chronic ProgressionMonoclonal Antibodies for the Treatment of CD,,Etiology of CD: Chronic Activation of the Mucosal Immune Response,Environmental factors,Genetic factors,T cell,Th1 cell,TNF-,IL-12,IFN-,Macrophage,Inflammation,Th1 cell,Th1 cell,Th1 cell,TNF-,IFN-,IL-12,Crohn’s disease state,Normal state,Chronic uncontrolled inflammation due to Th1 cell apoptotic defect,Normal controlled inflammation via apoptosis of Th1 cells (programmed cell death),Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Ina K et al. J Immunol. 1999;163:1081-1090; Podolsky DK. N Engl J Med. 2002;347:417-429,Cytokine Imbalance in Chronic Inflammation,,Pro-inflammatory,Anti-inflammatory,,adapted from Papachristou G et al. Pract Gastroenterol. 2004;28:18-30.,Key Inflammatory Mediators in CD,Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Podolsky DK. N Engl J Med. 2002;347:417-429,Interleukin 12 (IL-12) Promotes Th1 Responses in CD,Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Podolsky DK. N Engl J Med. 2002;347:417-429,,,,,,,,,IL-12,,IFN,Th1 cell,,,Differentiation,Gately MK et al. Annu Rev Immunol. 1998;16:495-521,,,,,Additional Mechanisms for IL-12-induced Th1 Reponses,,,,Clinical Evidence of Increased Expression of IL-12 in CD,,Kakazu T et al. Am J Gastroenterol. 1999;94: 2149-2155.Colpaert S et al. Eur Cytokine Netw. 2002;13: 431-437.Berrebi D et al. Am J Pathol. 1998;152:667-672.,Parronchi P et al. Am J Pathol. 1997;150:823-832.Monteleone G et al. Gastroenterology. 1997;112: 1169-1178.Nielsen OH et al. Scand J Gastroenterol. 2003;38:180-185.,Tumor Necrosis Factor (TNF) Sustains Th1 Responses in CD,Gately MK et al. Annu Rev Immunol. 1998;16:495-521; Podolsky DK. N Engl J Med. 2002;347:417-429,TNF Promotes CD Activity and Pathogenesis Through Multiple Pathways,Adapted from Holtmann et al. Z Gastroenterol. 2002;40:587-600.,Tissue destruction & inflammation,Macrophage,TNF-,TNF-,TNF-,IFN-,IL-12,Activated T cell,Th1 cell,Coagulation (increased production of thrombin),Ulcer,Inflammation,Inflammatory cells,Clinical Evidence of Increased Expression of TNF in CD,Braegger CP al. Lancet. 1992;339:89-91.Reinecker HC et al. Clin Exp Immunol. 1993; 94:174-181Murch SH et al. Gut. 1993;34:1705-1709.,,Breese EJ et al. Gastroenterology. 1994;106:1455-1466.MacDonald TT et al. Clin Exp Immunol. 1990;81: 301-305.Cappello M et al. Gut. 1992;33:1214-1219.,Current Concepts in Crohn’s Disease (CD),Disease Mechanisms: Chronic Immune ActivationNatural History of Crohn’s Disease: Chronic ProgressionMonoclonal Antibodies for the Treatment of CD,,The Likelihood for Disease Complications in CD Increases Over Time,,Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250.,Number of patients at risk:,2002 552 229 95 37,,,0,12,24,36,48,60,72,84,96,108,120,132,144,156,168,180,192,204,216,228,240,0,10,20,30,40,50,60,70,80,90,100,,,,,,,,,,,Months,Cumulative probability %,,,,,,,,,,,,,,,,,,,,,,,penetrating,inflammatory,stricturing,Occurrence of a stricturing and/or penetrating complication was assessed retrospectively in 2,002 consecutive CD patients (1974–2000)The estimated risks for penetrating CD at 5 and 20 years after diagnosis are 40% and 70%,Most Patients Will Progress to Surgery,Data on initial intestinal resection and postoperative recurrence were evaluated retrospectively in a population-based cohort of 1,936 CD patients (1955–1989)It is estimated that 75% of CD patients will require at least 1 intestinal resectionNearly 50% of these patients will have a clinical relapse,Bernell O et al. Ann Surg. 2000;231:38-45.,,,,,,,,,,,,,,,,,,,,0,2,4,6,8,10,12,14,0,20,40,60,80,100,Time (years),,,,,,,Cumulative risk of surgery (%),,,,,,,,,,,,,,,,,,,,,,,,0,2,4,6,8,10,12,14,0,20,40,60,80,100,Time (years),,,,,,,Cumulative risk of recurrence (%),,,,,Risk of First Resection,Risk of Recurrence After First Resection,。