potential human models of inflammatory bowel...

Potential human models ofinflammatory bowel disease

STEPHEN B HANAUER MD

THE ABSENCE OF AN ANIMAL

model that correlates with thecourse of either ulcerative colitis orCrohn’s disease has impeded basic re-search to define the etiopathogenesis ofinflammatory bowel disease (IBD) andclinical research involving potentialtherapeutic agents. Basic progress inanimal (primarily mouse) gene typingaccompanied by both knock-out andtransgenic techniques may, eventually,identify genetic predispositions thatapply to human IBD. Meanwhile, con-tinued clinical research in IBD has elu-cidated many aspects of the immuneand inflammatory cascades contribut-ing to the pathogenesis of ulcerativecolitis and Crohn’s disease, which maytranslate into a better understanding ofthe clinical manifestations and diseasecourse and may promise eventualtherapeutic improvements. Con-currently, new serological markers(eg, antineutrophil cytoplasmic anti-bodies [ANCA]) and genetic pheno-typic markers (eg, human leukocyteantigen [HLA]-DR2) offer potential cor-relates to clinical subgroups that mayclarify aspects of the heterogeneitywithin IBD. The diversity among pa-tients and the evolving epidemiologyof IBD as ethnic populations assumewestern diets and culture (includingsmoking) suggest that an eventual re-classification of IBD is likely. We needto continue to consider these possibili-ties while searching for subsets of hu-man models of IBD. Meanwhile, thereare a number of potential models that

IBD – BASIC SCIENCE: GENETICS, MARKERS AND MODELS

SB HANAUER. Potential human models of inflammatory bowel disease. Can JGastroenterol 1995;9(6):316-318. Similar to animal models of inflammatorybowel disease (IBD), there is no single human model representative of ulcerativecolitis or Crohn’s disease. An optimal human model awaits etiopathogeneticdefinitions and further reclassification or depiction of clinicopathological sce-narios. Current human models can be classified into models depicting risk of dis-ease; preclinical disease; acute inflammation; and miscellaneous IBD. Familystudies are the best means of pursuing patients at risk. Evolving genetic and sero-logical markers may further identify subgroups to assess with permeability probes,leukocyte scans or endoscopy for preclinical disease. Provocation with nonsteroi-dal anti-inflammatory drugs (NSAIDs) may be useful in selected patients becauseNSAID mucosal damage may induce or mimic IBD. Alternative natural history orinterventional studies in patients with human leukocyte antigen (HLA)-B27spondylarthropathy may be useful. The disease margin and pouchitis are modelswithin the disease state of ulcerative colitis as are the aphthous ulcer, anasto-motic margin and diverted fecal stream for Crohn’s disease. Newly defined coliti-des, such as microscopic and collagenous colitis and diversion colitis, also providepotential comparative models to evaluate mucosal immune, inflammatory, re-parative, secretory and absorptive regulation.

Key Words: Crohn’s disease, Genetic models, Human models, Inflammatory boweldisease, Ulcerative colitis

Modèles humains potentiels de maladie inflammatoire del’intestin

RÉSUMÉ : Comme c’est le cas pour les modèles animaux de la maladie inflam-matoire de l’intestin, il n’y a pas de modèle humain distinct représentatif de la co-lite ulcéreuse ou de la maladie de Crohn. Un modèle humain idéal pourra être misau point quand les définitions étiopathogénétiques et autres classifications et de-scriptions des scénarios cliniques ou pathologiques auront été établies. Lesmodèles humains actuels peuvent être classés en deux types dépeignant le risque

University of Chicago Medical Center, Chicago, Illinois, USACorrespondence: Dr SB Hanauer, University of Chicago Medical Center, 5841 Maryland

Avenue, Chicago, IL 60637, USA. Telephone 312-702-1466, fax 312-702-2182, [email protected]

This paper was presented at the Trends in Inflammatory Bowel Disease Therapy meeting,April 6 to 9, 1994, held in Victoria, British Columbia. This paper has also been published inSutherland LR, et al, eds. Inflammatory Bowel Disease: Basic Research, Clinical Implicationsand Trends in Therapy. Boston, Dordrecht and London: Kluwer Academic Publishers, 1994

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316 C�� J G�� V�� 9 N� 6 S��/O�� 1995

can be used to study the pathogenesisand natural history of and therapies forIBD.

RISK FACTORSSeveral risk factors for IBD develop-

ment may be considered as models inpredisposed individuals to distinguishthe susceptibility towards environ-mental exposure, injury or both. Thefamily history of IBD presents the mostavailable means of evaluating potentialcandidates for developing disease.Linkage studies are underway that mayeventually identify patients at risk, asmay serological studies (eg, usingperinuclear antineutrophil cyto-plasmic antibodies [pANCA]). Unfortu-nately, there is no facile means of as-sessing preclinical disease. Therefore,the natural history of relatives withidentified markers such as HLA-DR2 orpANCA should be observed, especiallyin ‘multiplex’ families. Testing theseindividuals affords the potential tomeasure other possible preclinicalmarkers or response parameters. For in-stance, intestinal permeability hasbeen used with variable results in ac-tive and quiescent IBD and as a markerfor preclinical relapse (1) . The originalfinding of increased permeability infamily members of Crohn’s disease pa-tients has not been verified (2); how-ever, the concept of permeability as apotential marker should not be aban-doned. Further, provocative perme-ability testing using nonsteroidalanti-inflammatory drugs (NSAIDs) may

increase the sensitivity of permeabilitystudies (3). The influence of cigarettesmoking on permeability in relatives ofIBD patients could also be explored, es-pecially in relatives of ulcerative colitispatients who may have an increasedrisk of developing clinical disease ifthey have stopped smoking. It would beof great interest to evaluate familymembers documented to have in-creased permeability with additionalstudies such as leukocyte scans or evenileocolonoscopy to rule out preclinicalmucosal/histological disease.

PRECLINICAL MARKERSPreclinical markers of IBD may also

be identified in patients withrecognized predisposing diseases suchas HLA-B27-associated spondylarthritis.Patients with ankylosing spondylitishave a high incidence of associatedileitis with endoscopic and histologicalfeatures that are indistinguishable fromthose of Crohn’s disease (4). Addi-tional studies of mucosal immunefunction in these individuals shouldprovide insight into both initiating (orpredisposing) and amplifying factors(5). Few natural history studies havebeen performed in this subgroup of pa-tients.

NSAID-induced small bowel andcolonic damage have recently been ob-served to mimic many of the mucosal(and potentially clinical) features ofIBD (6). This provides the opportunityto evaluate both a risk factor for IBD insusceptible individuals (eg, relatives)

and the normal reparative mechanismsthat may be absent or deficient (includ-ing eicosanoids, cytokines and growthfactors). Alternative acute models ofidiopathic IBD include enterocolitidesof known etiology such as infectious,ischemic or radiation-induced mucosaldamage where there is the potential tomeasure regulatory immune, inflamma-tory events and tissue repair in healthyindividuals, and in IBD patients andrelatives.

POTENTIAL MODELSPotential models of IBD exist even

within the disease course. In ulcerativecolitis there are two excellent modelsto assess mucosal events: the margin ofdisease and pouchitis. The margin be-tween active inflammation and ‘no-rmal’ mucosa has been inadequatelystudied. Most often patients with distalcolitis are included with pancoliticswhen mediators or histology are exam-ined. The disease margin is a prototypefor defining mucosal abnormalities inthe same individual with an identicalgenetic disposition. Local immune, in-flammatory and regenerative featuresneed to be studied in patients. Like-wise, pouchitis offers another exampleof an aberrant tissue response to (pre-sumably) similar environmental expo-sures in patients with ulcerative colitisand familial polyposis. Genetic disposi-tions can be compared among thesegroups but, even among ulcerative coli-tis patients, the natural history ofpouchitis (beginning with the divertedor naive pouch followed by bacterialproliferation) and the defined risk forsubclinical and clinical disease, as wellas the potential for healing withantibiotic therapy, offer the opportu-nity to study patients in a sequentialfashion (7). It appears that risk factorsmay also predictably be applied to pa-tients before ileal pouch formation,such as the presence of extraintestinalmanifestations or pANCA.

Potential models for the study ofCrohn’s disease also exist within thedisease spectrum and clinical course.The aphthous ulcer occurs in healthyindividuals, in patients with NSAID ex-posure and as isolated findings as a pre-sumed ‘primary’ lesion or event in

de maladie, la maladie préclinique, l’inflammation aiguë et la diversité des MII. Lesuivi auprès des familles est le meilleur moyen de prendre en charge les patients àrisque. L’évolution des marqueurs génétiques et sérologiques peut aider à identi-fier davantage les sous-groupes à évaluer à l’aide de tests de perméabilité, descanographies leucocytaires ou d’endoscopies pour la maladie au stade pré-clinique. Les épreuves de provocation à l’aide d’anti-inflammatoires non stéroïdi-ens peuvent être utiles chez certains patients parce que les lésions de la muqueusecausées par les AINS peuvent provoquer ou imiter les MII. D’autres épreuves axéessur l’histoire naturelle ou sur les résultats d’intervention chez les patients atteintsde spondylarthropathie associée à l’antigène leucocytaire humain (HLA)-B27peuvent être utiles. Les rebords des zones lésées et la pouchite peuvent servir demodèle en présence de colite ulcéreuse, tout comme l’ulcère aphteux, la margeanastomosique et la dérivation fécale dans la maladie de Crohn. Les colites nou-vellement définies, comme la colite microscopique et collagénique et la colite dedérivation offrent également des modèles comparatifs potentiels pour évaluer lesmécanismes immunitaires, inflammatoires, réparateurs, sécréteurs et absorbantsde la muqueuse.

C�� J G�� V�� 9 N� 6 S��/O�� 1995 317

Potential human models of IBD

Crohn’s disease. Further exploration ofthe immunoinflammatory and media-tor events in and around these Crohn’s,infectious or NSAID-induced lesions of-fers additional insight into pathogenicdifferences. Two additional models ofCrohn’s disease include the anasto-motic site and fecal diversion. The pre-disposition for Crohn’s disease to recurat the proximal to the anastomoticmargin affords the potential to monitormucosal events sequentially; this hasrecently been the focus of several inter-ventional studies to prevent prophy-laxis or alter both endoscopic andclinical disease. Similarly, diversion ofthe fecal stream in Crohn’s disease of-

fers an alternative model to study theinflammatory process (8).

A number of newly describedcolitides also need to be examined asmodels for IBD as additional epidemiol-ogical, clinical, histopathological, im-mune and associated factors are ex-plored. The recent recognition ofcollagenous, microscopic diversion andhuman immunodeficiency virus(HIV)-associated enterocolitis affordsthe opportunity to examine potentialsimilarities and differences with theclassic IBD syndromes (9).

CONCLUSIONSIn the examination and evaluation

of these and other potential human

models of IBD it is important not tolimit ourselves to current paradigms ofetiopathogenesis (10). We must behumbled by the recent example of thediscovery of Helicobacter pylori inpeptic ulcer disease. When confrontedwith the current dogma seeking an im-munological ‘truth’ as a predisposingcause of IBD, we should remain open toalternative hypotheses includingdysfunctional epithelium, alternativemicroorganisms (including viral vascu-litis and epithelial bacteria) and mo-lecular mimicry or autoimmunity, anduse these concepts for hypothesis test-ing rather than decreeing them excep-tions to our current conceivedformulations on etiopathogenesis.

REFERENCES1. Hollander D. The intestinal

permeability barrier: a hypothesis asto its regulation and involvement inCrohn’s disease. Scand J Gastroenterol1992;27:721-6.

2. Munkholm P, Langholz E, HollanderD, et al. Intestinal permeability inpatients with Crohn’s disease andulcerative colitis and their first degreerelatives. Gut 1994;35:68-72.

3. Pironi L, Miglioli M, Ruggeri E, et al.Effect of non-steroidal anti-inflammatory drugs (NSAID) onintestinal permeability in first degreerelatives of patients with Crohn’sdisease. Gastroenterology1992;102:A679.

4. Mielants H, Veys EM, Goemaere S,

Cuvelier C, DeVos M. A prospectivestudy of patients with spondylo-arthropathy with special reference toHLA-B27 and to gut histology.J Rheumatol 1993;20:1353-8.

5. Cuvelier CA, DeWever N, Mielants H,DeVos M, Veys EM, Roels H.Expression of T cell receptors alphabeta and gamma delta in the ilealmucosa of patients with Crohn’sdisease and with spondylarthropathy.Clin Exp Immunol 1992;90:275-9.

6. Bjarnason I, Hayllar J, MacPhersonAJ, Russell AS. Side effects ofnonsteroidal anti-inflammatory drugson the small and large intestine inhumans. Gastroenterology1993;104:1832-47.

7. Luukkonen P, Jarvinen H, Tanskanen

M, Kahri A. Pouchitis – recurrence ofthe inflammatory bowel disease? Gut1994;35:243-6.

8. Winslet MC, Allan A, Poxon V,Youngs D, Keighley MRB. Faecaldiversion for Crohn’s colitis: A modelto study the role of the faecal stream inthe inflammatory process. Gut1994;35:236-42.

9. Kingsmore SF, Kingsmore DB, HallBD, Wilson JAP, Gottfried MR, AllenNB. Co-occurrence of collagenouscolitis with seronegative spondyl-arthropathy: Report of a case andliterature review. J Rheumatol1994;20:2153-7.

10. Kuhn TS. The Structure of ScientificRevolutions. Chicago: University ofChicago Press, 1962.

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