Inflammatory Bowel Disease A model for translational medicine. D P Jewell Professor Emeritus of Gastroenterology University of Oxford

Transcription

1 Inflammatory Bowel Disease A model for translational medicine D P Jewell Professor Emeritus of Gastroenterology University of Oxford

2 Samuel Wilks 1859, Pathological Treatises of Guy s Hospital

3 The London Teaching Hospitals Experience 300 cases Aetiology debated:- - bacterial (Hawkins) - tinned foods / preservatives (Phillips) - psychosomatic (Claye-Shaw) Allchin 1909

4 Sir Arthur Hurst Sir Arthur Hurst

5 Ulcerative colitis - the Early Days Hurst (1921) described:- gradual onset limited distal disease tended to present as constipation sigmoidoscopically identical to bacillary dysentery but distinct from amoebiasis

6 Ulcerative colitis - the Early Days Treatment: bed rest low-fibre diet soured milk colonic irrigation - albargin (silver nucleinate) - tannic acid antidysenteric serum Hurst 1921

7 Anti-dysenteric antiserum for UC IV antiserum: 20, 40, 60, 80 and 100mls on consecutive days Adrenaline for anaphylaxis Relapse much less frequent if treatment continued until mucosal healing Dramatic effect Hurst 1935 Splendid results Crohn and Rosenak 1935

8 Dr Crohn

9 Mycobacteria and Crohn s Disease 1940s - failure to detect M. tuberculosis culture of M paratuberculosis ( Thayer ) detection of M para in tissue using molecular techniques ( Hermon Taylor ) 1990s % CD, 18% UC, 10-12% controls shown to be positive for IS900 insert of M para failure of antimycobacterial therapy over 2 years ( Selby et al )

10 Bacteria and Crohn s disease Entero-invasive E coli in 60% of ileal disease Reduced populations of bifidobacteria and Faecalibacterium prausnitzii in the faecal microbiota Reduced urinary hippurate on metabolomic analysis ( Williams et al 2009 )

11 Aetiopathogenesis of UC and CD Genetic v Environment Polygenic Childhood Heritability Bacteria CD 30-40% Food UC 10-15% Drugs Appendicitis

12 Meta-analysis of Genome - wide association studies Discovery panel CD 6,333 Controls 15,056 UC 6,782 Controls 20,099 Replication panel CD 14,934 Controls 13,647 UC 7,765 Controls 9,177

13 How many genes? CD 105 genes UC 49 genes Of 154 IBD-associated genes, at least 30 are shared between CD and UC

14 Role of genetic variants in IBD Adaptive immune response HLA Class 2 T cell function - IL 12, IL 23, IL 17, IL 23R - IL 10, ETS1 Innate immune response ( CD ) NOD 2, TLR 4, NALP 3 Autophagy ( CD ) NOD 2, ATG16L1, IRGM, DAP Epithelial barrier function ( UC ) GNA12, HNF4, CDH1, LAMB1

15 AUTOPHAGY Constitutive process for regulating intracellular homeostasis and organelle turnover Breakdown of bacteria: E coli, Salmonella, Listeria, M tuberculosis Important for adaptive as well as innate immunity.

16 During nutrient starvation increased autophagy leads to breakdown of non-vital components During infection autophagy plays a role in destruction of some bacteria in cells Programmed cell death-autophagy results in total destruction of the cell Antigen presentation-antigen loading compartments for MHC II molecules receive input from autophagosomes

17 Crohn s disease and autophagy Nod2 and Atg16L1 are involved in the formation of autophagosomes, the killing of bacteria and increased HLA Class 2 antigens on cell surfaces Mutations in both genes inhibit autophagy in dendritic cells DAP1 gene, mutated in UC, is a regulator of mtor which initiates the formation of the autophagosome Cooney et al 2010, Fritz et al 2011

18 /G in the colon The Gut Flora 2. At least 500 species using 16S rrna techniques 3. No specific pathogen detected for UC but 5-10% with bacillary dysentery may progress to UC 4. Prebiotics and probiotics (E. coli Nissle, VSL#3, Lactobacilli) may benefit UC and pouchitis. 5. Crohn s disease - EIEC, reduced F prausnitzii

19 The Hygiene Hypothesis 1. Increased allergy results from decreased exposure to infections in early life (small family size, clean environment) (Strachan 1989) 2. Some support for better living conditions in childhood associated with increased risk of IBD later in life (Gent et al) 3. Mechanisms include altering TH1/TH2 balance, induction of T reg cells 4. Basis of using ova of Trichuis suis as therapy to stimulate a down-regulating TH2 response.

20 Incidence per 100, Ulcerative colitis Crohn's disease Year

21 Incidence of IBD in Children UC (n=148) CD (n=102) Cases/100,000/year Hildebrand et al 2003

22 Management Strategy Rapid induction of remission UC - 5ASA, corticosteroids CD - corticosteroids Maintenance of remission UC - 5ASA CD - azathioprine Select patients for surgery Patient education

23 New therapies for IBD Inhibitors of Th Polarization: Anti-interferon antibody Anti-IL 2 antibody Anti-IL 12p40 antibody Anti-IL-23 IL-10 Inhibitors of Lymphocyte Trafficking: Antisense ICAM-1 Anti 4 integrin antibody Anti 4 7 integrin antibody Antigen Processing & Presentation, Activation of Macrophages Antigen Recognition & Activation of CD4+ T-Cells Th1/Th2 Imbalance Production of Proinflammatory Cytokines Recruitment, migration, & adhesion of inflammatory cells Inflammation & Injury Repair & Restitution CTLA-4 Ig Anti-CD3 Anti-TNF Agents Anti-IL6 Epidermal GF

24 Anti-TNF - a milestone for therapy Targan et al NEJM 1997 A single infusion of ca2 antibody to TNF alpha induced a response in 65% of patients with active CD not responding to standard treatment.

25 Accent

26 Best use of anti-tnf Induction followed by maintenance Combine with thiopurines or methotrexate for 6 months Loss of response may be restored by increasing dose or changing to another anti-tnf

27 Anti-TNF for Crohn s Disease Chronic active disease Trial Clinical practice 64% response rate - 33% remission rate 60 70% response Fistula healing Trial Clinical Practice - 62% response % response BUT 30% fail to respond, 50% lose response over 5 years

28 Immune mechanisms in CD Epithelial cells Macrophage DC IL-1 IL- 6 TNF- TNF- IFN- Fais S, J Interferon Res 1994 Fuss IJ, J Immunol 1996 Monteleone G, Gastro 1997 IL-12 Th1 IL-2

29 (Anti-p40 subunit)

30 Sandborn et al 2008

31 Sandborn et al 2008

32 Manipulating lymphocyte homing Leucocytapheresis Inhibit chemotaxis ( CCR9 antagonist - Traficet ) Block integrins on lymphocyte surface Anti- 4, natalizumab Anti- 4 7, MLN-02 Promising Phase 2 trials anti-sense ICAM1. Negative CD. Effective for distal UC and chronic pouchitis

33 Percent of patients ENACT-2: Maintenance of Sustained Clinical Remission p=0.217 p<0.05 p< Natalizumab 300mg (n=130) Placebo (n=120) 44% 26% Contingent primary endpoint 39% Start Time (months) ENACT-2 15 %

34 Patient s outlook At any one time - 75% in remission Biologics have dramatically reduced time in hospital and need for surgery Quality of life is normal while in remission Expectancy of life near normal Can DNA micro-arrays allow clinical course to be predicted? Understanding pathogenesis has allowed new therapies - refractory disease,?early introduction into management