医学免疫学课件：pathogenesis of UC and treatments process

1、Pathogenesis of ulcerative colitis and treatments progressIntroductionEpidemiologyGeography, age, and sexGenetic factorsEnvironmental factorsPathophysiologyEpithelial barrierCommensal microfloraAntigen recognitionDysregulation of immunological responsesLeucocyte recruitmentGenetic factorsPathway-bas

2、ed treatmentsReversing dysbiosisTightening the epithelial barrierAnticytokine therapeuticsAntiadhesion therapeuticsContentIntroductionUlcerative colitis (UC)an idiopathic, chronic inflammatory disorderinflammation restricted to the mucosal surfacestarts in the rectum and extends proximally through t

3、he entire colonunpredictable clinical course alternating periods of exacerbation and remissiondisease distribution: from proctitis to left-sided colitis or pancolitisExact etiologies remain uncertainStudies indicate main influencing factorsgenetic abnormalities overly aggressive T-cell responses cau

4、sing defects mucosal barrier functionimmunoregulationbacterial clearanceenvironmental factors onset and reactivation of diseaseEpidemiologyGeographyhighest incidence and prevalence rates: north America and northern Europelowest rates: southern hemisphere and eastern countriesAgemain onset peak betwe

5、en ages 15 and 30 yearssecond smaller peak between ages 50 and 70 yearsSexslight predilection for menGenetic factorssusceptibility loci and risk locigenetic predispositionnot a single mutation but multiple minor traits family historyethnic differencesEnvironmental factorsdeveloped countries vs devel

6、oping countries, urban areas vs rural areasincreasing access to health carebetter medical recordsimproved sanitation ?smokingepisodes of previous gastrointestinal infectionPathophysiologyEpithelial barrierfirst-line defense of the mucosal immune systemproducing antimicrobial peptides badly damagedin

7、creasing permeabilityincreasing uptake of luminal antigensIngrid Ords, et al. Ulcerative colitis. Lancet 2012; 380: 160619Commensal microflorahomoeostatic balanceimportancepathogenesis of the diseaseseverity of intestinal inflammationdisease phenotypebreakdown of the homoeostatic balanceAntigen reco

8、gnitioninteraction with macrophages and dendritic cellspresent antigens to B cells and T cellsPRRs including TLRs on the dendritic cellsagainst pathogensprotection from epithelial injuryincreased expression level like TLR4activation of the transcription factor nuclear factor-B (NF-B) regulates proin

9、flammatoryregulates cell functions in macrophages and T cellsIngrid Ords, et al. Ulcerative colitis. Lancet 2012; 380: 160619Dysregulation of immunological responsesdisturbed T-cells homoeostatic balance Increased NKT in the lamina propriasuperseded by IL-13cytotoxic functionsinduction of apoptosisa

10、lteration of the protein composition of tight junctionselevated TNF-Autoimmunity Reviews 14 (2015) 11611169Lancet 2012; 380: 160619Figure 1: TLRs in human gastrointestinal pathology: health condition and inflammationSimona Frosali, et al. How the Intricate Interaction among Toll-Like Receptors, Micr

11、obiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology. Journal of Immunology Research. Volume 2015, Article ID 489821, 12 pagesLeucocyte recruitmentrelease of chemoattractants CXCL8, CXCL10amplification of the inflammatory responseincreased expression of adhesion moleculesupregula

12、ted by proinflammatory cytokinesmucosal addressin cellular adhesion molecule-1 (MAdCAM-1)promotes leucocyte adhesion and extravasationinteraction with 47 integrinmediates lymphocyte homingIngrid Ords, et al. Ulcerative colitis. Lancet 2012; 380: 160619Figure 2. Schematic representation of pathogenic

13、 mechanisms underlying ulcerative colitisAntonio Di Sabatino, et al. New insights into immune mechanisms underlying autoimmune diseases of the gastrointestinal tract. Autoimmunity Reviews. (2015) 11611169.Treatments progressReversing dysbiosisTightening the epithelial barrierAnticytokine therapeutic

14、sAntiadhesion therapeuticsReversing dysbiosisspecific changes in the gut microbiotaalterations of the major subgroups of bacterianot the involvement of single pathobiontsdifficult to correct abnormalitiesfailure of antibiotics or probiotics fecal microbiota transplantation (FMT)replacing the “dysbio

15、tic flora Infusing donors feces into recipients gastrointestine (GI)through a nasogastric or nasojejunal tubethrough upper or lower GI endoscopyretention enemas (灌肠)re-establish mucosal homeostasisincreased the phylotype richnessoverestimating the effect Table 1.Outcome Measures Comparing Fecal Micr

16、obial Transplantation With PlaceboMoayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology (2015); 149:102109.e6.Figure 3. Similarity of microbial composition in those recei

17、ving FMT vs placebo at the start and end of the trialFigure 4. Similarity of FMT patients stool to the donor they received vs a control donor that they did not receiveMoayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis

18、in a randomized controlled trial. Gastroenterology (2015); 149:102109.e6.Figure 5. Description of the timeline of the use of donors through the trialFigure 6. Taxonomic profiles of donors used in the trialMoayyedi P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in pa

19、tients with active ulcerative colitis in a randomized controlled trial. Gastroenterology (2015); 149:102109.e6.Tightening the epithelial barrierdefects in any of integral parts of the epithelial barrierrestitution of the defective barrier very few efforts have reached the clinical stagephosphatidylc

20、holine (PC) major mucus phospholipidprotective function of colonic mucussubstantially decreased in the mucus of UC patientsreplacement of PC in UC patientsLT-02positive resultsphase III trialsKarner M, Kocjan A, Stein J, et al. First multicenter study of modified release phosphatidylcholine LT-02 in

21、 ulcerative colitis: a randomized, placebo-controlled trial in mesalazine-refractory courses. Am J Gastroenterol 2014;109:104151Figure 7. Primary end-point analysis Figure 8. Further secondary end-point analysesKarner M, Kocjan A, Stein J, et al. First multicenter study of modified release phosphati

22、dylcholine LT-02 in ulcerative colitis: a randomized, placebo-controlled trial in mesalazine-refractory courses. Am J Gastroenterol 2014;109:104151Anticytokine therapeuticsneutralization directed against TNF-several anti-TNF monoclonal antibodiesinfliximab（英夫利昔）adalimumab（阿达木）golimumab（戈利木）induce co

23、mplete and sustainable remissionuseless in a significant proportion of nonrespondersother immunologic pathways existinhibiting JAK kinase activityblocking effects of multiple cytokinesbetter than neutralization of a single cytokinetofacitinib (托法替尼)inhibit differentiation of effector lymphocytessupp

24、ression of innate immune responses induced by LPSAntiadhesion therapeutics target the molecules that mediate leukocyte traffic MAdCAM-1interact with 47 integrin on lymphocytesspecific for recirculation of lymphocytes to the inflamed gutNatalizumab (那他珠单抗)against 4 integrinbind with 47 and 41progress

25、ive multifocal leukoencephalopathy（渐进多灶性白质脑病）Vedolizumabhumanized monoclonal antibodyspecifically blocks 47/MAdCAM-1 bindingonly exerts anti-inflammatory effects on the gutsafetyapproved by the FDA on 20 May 2014Etrolizumabfully humanized monoclonal antibodygut selectivityspecificity for the 7 subun

26、it47 E7E7/E-cadherin interaction for T-cell homing to the intestinereduction of intraepithelial leucocytes in the guttested in a phase II recentlyExpectationEmerge abundance of therapeutic targetsOffer important insightsClearer pathogenic mechanismsMore effective and safer therapiesReference1 Moayye

27、di P, Surette MG, Kim PT, et al. Fecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial. Gastroenterology 2015; 149:102109.e6.2 Karner M, Kocjan A, Stein J, et al. First multicenter study of modified release phosphatidylcholine

28、LT-02 in ulcerative colitis: a randomized, placebo-controlled trial in mesalazinerefractory courses. Am J Gastroenterol 2014;109:104151.3 Giorgos B, Theresa T. P, Fabio C. Pathway-based approaches to the treatment of inflammatory bowel disease. Translational Research 2016;167:104-115.4 Panes J, Su C, Bushmakin AG, Cappelleri JC, Mamolo C, Healey P. Randomized trial of tofacit