genetic factors in animal models of intestinal...

Genetic factors in animal modelsof intestinal inflammation

R BALFOUR SARTOR MD

CLINICAL INVESTIGATORS HAVE

compellingly documented a ge-netic component in ulcerative colitisand Crohn’s disease (1). There is an in-creased incidence of inflammatorybowel disease (IBD) in family members,a predilection for these disorders in cer-tain genetically defined ethnic groups,higher concordance of disease inmonozygotic versus dizygotic twins andfamilial patterns of clinical pheno-types. However, human genetic re-search has not yet provided clinicallyuseful disease susceptibility markersnor an understanding of the immuno-pathogenesis of IBD.

The critical importance of host ge-netic susceptibility in determiningchronicity, aggressiveness and compli-cations of intestinal inflammation isclearly demonstrated by studies in in-bred rodents, transgenic rats, geneknockout mice and spontaneous mu-tants (Table 1). This report summarizesevidence of genetic control of intesti-nal and extraintestinal inflammationin these models, briefly outlines possi-ble immunological mechanisms of en-hanced genetic susceptibility anddiscusses the relevance of these obser-vations to the pathogenesis of humanIBD.

SPONTANEOUSINFLAMMATORY MODELSThe cotton-top tamarin and the

recently developed C3H/HeJ Bir sub-strain mouse develop chronic, sponta-neously relapsing colitis. The mecha-nisms of intestinal inflammation in

PREDISPOSING FACTORS IN IBD: GENETICS AND ANIMAL MODELS

RB SARTOR. Genetic factors in animal models of intestinal inflammation. CanJ Gastroenterol 1995;9(3):147-152. The critical importance of host geneticsusceptibility in determining chronicity, aggressiveness and complications of in-testinal inflammation is clearly demonstrated by studies of inbred rodents, trans-genic rats and spontaneous mutants. Inbred Lewis rats challenged by purifiedbacterial cell wall polymers, indomethacin or small bowel bacterial overgrowthdevelop chronic granulomatous intestinal inflammation with fibrosis and extra-intestinal manifestations, whereas Fischer (major histocompatibility complexidentical to Lewis) and Buffalo rats identically stimulated demonstrate only self-limited enterocolitis with no chronic inflammation, fibrosis, granulomas or ex-traintestinal inflammation. Similar differential patterns of intestinal inflamma-tion are apparent in inbred mouse strains challenged withtrinitrobenzene-sulphonic acid, Citrobacter freundii or backcrossed with T cell re-ceptor deficient (knockout) mice. The dominant role of genetic background ininduction of intestinal inflammation is further documented by spontaneous coli-tis which develops in spontaneously mutant mice, cotton-top tamarins, humanleukocyte antigen-B27/�2 microglobulin transgenic rats and mice with targeteddeletions of certain immunoregulatory cytokine and T lymphocyte genes. Identi-fication of the immunological mechanisms of host genetic susceptibility and thegenetic basis of spontaneous colitis should provide new insights into the patho-genesis of human inflammatory bowel disease.

Key Words: Animal models, Enterocolitis, Experimental colitis, Genetic susceptibil-ity, Intestinal inflammation

Facteurs génétiques dans des modèles animaux d’inflammationintestinale

RÉSUMÉ : La grande importance de la sensibilité génétique de l’hôte dans la dé-termination de la chronicité, de l’agressivité et des complications de l’inflamma-tion de l’intestin est fortement mise en évidence par des études menées chez des

Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill,North Carolina, USA

Correspondence: Dr R Balfour Sartor, Division of Digestive Diseases and Nutrition, School ofMedicine, Department of Medicine, CB# 7080, Room 326 Burnett-Womack Building,University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7080, USA. Telephone(919) 966-0149, Fax (919) 966-6842, e-mail [email protected]

This paper was presented at the Basic Research and Clinical Implications in IBD 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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CAN J GASTROENTEROL VOL 9 NO 3 MAY 1995 147

these animals are unknown, but pre-sumably are the result of a spontaneousgenetic mutation because closely re-lated strains do not develop colitis andaggressive searches have not identifiedenvironmental microbial pathogens.

At least 11 different species and hy-brids of tamarins, a group of NewWorld monkeys, spontaneously de-velop mild chronic colitis with mucosal

atrophy (2). Cotton-top tamarins areunique in that they exhibit acute re-lapsing colitis complicated by adeno-carcinoma of the colon (2-4). Captivecotton-top tamarins frequently de-velop a wasting syndrome character-ized by weight loss, anorexia and diar-rhea. An age-related chronic colitis isalmost universally present by two yearsof age. Underlying chronic colitis isrelatively mild, characterized by athickened mucosa with hyperplastic,elongated crypts, pseudopolyps andmild mononuclear cell infiltration ofthe lamina propria. At any given timeapproximately one-half to two-thirdsof marmosets have histological evi-dence of acute colonic inflammation,with neutrophilic infiltration, crypt ab-scesses and goblet cell depletion, butrarely have ulceration. Adenocarcinomathat complicates chronic colitis is notpreceded by epithelial cell dysplasia oradenomatous polyps. Some tamarinsdevelop chronic periportal inflamma-tion with fibrosis.

The mechanism(s) of intestinal in-flammation in cotton-top tamarins re-mains unclear. The inflammatorymediator profile of increased inter-leukin (IL)-1 and eicosanoids is charac-teristic of intestinal inflammation, andthe colitis responds to sulfasalazine anda 5-lipoxygenase inhibitor (5). Thesemarmosets share several biochemical

and immunological alterations with ul-cerative colitis patients. They have aselective reduction in mucus glycopro-tein fraction IV which does not corre-late with inflammatory activity (6). Inaddition their serum contains antineu-trophil cytoplasmic autoantibodieswhich react with human, but not mar-moset, neutrophils (7), and slightly in-creased concentrations of serumantibodies which stimulate cell-mediated cytotoxicity to colonicepithelial cell-associated components(8). However, the precise genetic al-teration that predisposes these marmo-sets to chronic, relapsing colitis withassociated adenocarcinoma remainsuncharacterized.

C3H/HeJ Bir SUBSTRAINMOUSE COLITIS

Birkenmeier and colleagues (9)have recently described a heritableform of murine colitis. It had becomeapparent that sporadic diarrhea andperianal ulceration were frequent in in-dividual members of the Jackson Labo-ratory C3H/HeJ mouse breeding colonybut that no microbial pathogens weredemonstrable. Selective breeding ofmice that developed diarrhea resultedin a pedigree of mice in which there is a50% incidence of spontaneous colitis.Colitis is more frequent in males (67%incidence) than females (31% inci-dence) and exhibits a seasonal varia-tion (occurring more often in winterthan summer). Inflammation follows abiphasic time course with onset aroundthe time of weaning (three to fiveweeks of age), spontaneous resolutionin most mice and a less predictablechronic phase. Clinical manifestationsinclude occasional diarrhea, fecalblood (not grossly apparent) and peri-anal ulceration. Inflammation is mostfrequently found near the ileocecalvalve but can involve the entire colon.Histological findings include focal lin-ear ulcers and a mixed mononuclearand neutrophilic infiltration. Ex-traintestinal manifestations have notbeen described.

Attempts to identify the presumedspontaneous genetic mutation are inprogress. Like the parent C3H/HeJstrain, monocytes from mice with spon-

rats consanguins, des rats transgéniques et des mutants spontanés. Des rats Lewisconsanguins, exposés à des polymères de la paroi cellulaire purifiée de bactéries, àl’indométhacine ou à des bactéries du grêle, ont développé une inflammation in-testinale granulomateuse chronique avec fibrose et manifestations extra-intestinales, alors que des rats Fisher (complexe majeur d’histocompatibilité sem-blable à ceux des rats Lewis) et des rats Buffalo stimulés de la même façon n’ontmanifesté qu’une entérocolite à résolution spontanée, sans inflammationchronique, fibrose, granulomes ni inflammation extra-intestinale. Des modèlesdifférentiels semblables d’inflammation intestinale apparaissent chez des souchesde souris consanguines exposées à de l’acide trinitrobenzènesulfonique, à Citro-bacter freundii ou soumises à un croisement en retour avec des souris présentant undéficit en récepteurs des cellules T. Le rôle dominant des antécédents génétiquesdans l’induction de l’inflammation de l’intestin s’appuie encore sur la présence decolite spontanée qui se développe chez des souris mutantes, chez des tamarins,chez des rats et de souris rendues transgéniques par une microglobuline de l’an-tigène B27/2 des leucocytes humains avec élisions ciblées de certains gènes deslymphocytes T et des citokines immunorégulatrices. L’identification des mécan-ismes immunologiques de la susceptibilité génétique de l’hôte et de la base géné-tique de la colite spontanée devrait offrir de nouveaux renseignements sur lapathogenèse de la maladie inflammatoire de l’intestin chez l’humain.

TABLE 1Genetic influence on animal modelsof intestinal inflammation

Spontaneous mutations (presumed)Cotton-top tamarin

C3H/HeJ Bir mouse

Genetically engineered modelsHuman leukocyte antigen-B27/�2

microglobulin transgenic rats

Interleukin (IL)-2, IL-10, transforminggrowth factor-beta, alpha-beta-T cell receptor , Gi�2 knockout mice

Differential susceptibility of inbredrodent strains to induced inflammationPeptidoglycan-polysaccharide

enterocolitis

Indomethacin enterocolitis

Small bowel bacterial overgrowth-induced hepatobiliary inflammation

Trinitrobenzene sulphonic acid/ethanolcolitis

Alpha-beta-T cell receptor-deletedcolitis

Citrobacter freundii colitis

148 CAN J GASTROENTEROL VOL 9 NO 3 MAY 1995

SARTOR

taneous colitis are unresponsive tolipopolysaccharide (endotoxin) (10).Comparison of in vitro reactivity of Tlymphocytes derived from parent strainand substrain mice with colonic cyto-kine profiles has not been reported. Inpreliminary studies, serum antibodiesfrom 50% of C3H/HeJ Bir mice reactwith luminal bacterial extracts com-pared with no detectable antibacterialantibodies from serum of C3H/HeJmice (11).

GENETICALLY ENGINEEREDMODELS

Molecular engineering techniquespermit selected genes to be overex-pressed (transgenic) or deleted (embry-onic stem cell recombination) inrodents. These methods have beenpowerful tools to determine the in vivofunction of a targeted gene, and attimes have provided unanticipated re-sults. Deletion of several immunoregu-latory cytokines, including IL-2, IL-10,transforming growth factor (TGF)-beta--1, Gi�2 and alpha or beta T cell recep-tor (TCR) chains, induces spontaneouscolitis (12-15). These studies show thata single mutation of a key immunoregu-latory cytokine, signalling molecule orT lymphocyte protein can lead to spon-taneous intestinal inflammation, andthat the colon is particularly suscepti-ble to injury in immunodeficient hosts.

Overexpression of human leukocyteantigen (HLA)-B27/�2 microglobulin(�2�) in transgenic rats induces a sys-temic inflammatory syndrome inwhich the first manifestation is diar-rhea, followed by arthritis, dermatitis,hair loss, psoriatic nail changes, epidi-dymitis and a wasting syndrome(16,17). Histological patterns of in-flammation include focal chronic gas-tritis and duodenitis, and diffuseinfiltration of the colonic lamina pro-pria by mononuclear cells. Severely in-flamed rats exhibit focal mucosalulcerations and crypt abscesses in thecolon. Cell transfer experiments dem-onstrate that HLA-B27/�2� expressingbone marrow cells mediate the disease,and that B27/�2� protein expressionby nonimmune cells is neither neces-sary nor sufficient to cause disease (18).The absence of colitis, gastritis and ar-

thritis in germ-free B27/�2� transgenicrats, attenuated inflammation in spe-cific pathogen-free rats and inhibitionby metronidazole clearly demonstratethe importance of luminal bacteria ininitiation and perpetuation of intesti-nal inflammation and associated ex-traintestinal disease (19,20). Theincidence and onset of colitis and sys-temic inflammation depend on highcopy numbers of HLA-B27/�2� (17).Compared with induced rat models ofenterocolitis (see below), the inci-dence of intestinal inflammation inLewis and Fischer rats expressingequivalent copy numbers of theHLA-B27/�2� transgene is similar, al-though extraintestinal inflammation issomewhat more frequent and rapid inonset in Lewis than Fischer rats (17).

INDUCED INFLAMMATION ININBRED RODENT STRAINSDifferential susceptibility of inbred

rodents to intestinal and systemic in-flammation powerfully illustrates thekey role of genetic regulation ofchronic inflammation and its compli-cations, including fibrosis.Inbred rat strains: The author usedthree experimental models to demon-strate that, with identical stimuli, in-bred Lewis rats develop chronicrelapsing enterocolitis with extraintes-tinal inflammation and fibrosis whereasinbred Buffalo and Fischer F344 (majorhistocompatibility complex matchedwith Lewis) rats develop only transientintestinal inflammation and no sys-temic manifestations (Table 2). Lewis

rats injected subserosally with the bac-terial cell wall polymer peptidoglycan-polysaccharide (PG-PS) developchronic, spontaneously relapsing,granulomatous enterocolitis with fibro-sis and associated polyarthritis, granu-lomatous hepatitis, leukocytosis andanemia which persists for at least 16weeks (5,21). With identical exposureto PG-PS, Buffalo or Fischer rats exhibitonly transient local inflammation,which resolves by 14 days, with residualdamage and no chronic enterocolitis orextraintestinal manifestations. Out-bred Sprague-Dawley rats developchronic granulomatous enterocolitis,but the chronic intestinal inflamma-tion is less pronounced and there is noextraintestinal disease (22).

In a second model, Lewis ratsinjected subcutaneously with in-domethacin (7.5 mg/kg/day for twodays) developed chronic mid-smallbowel longitudinal ulcers with fibrosisand associated hepatobiliary inflamma-tion, anemia and leukocytosis whichpersisted for at least 77 days, whereasFischer rats had no residual inflamma-tion 14 days after indomethacin (23).Similarly, Lewis rats – but not Buffaloor Fischer rats – developed chronic, fi-brotic hepatobiliary inflammation inresponse to experimental small intesti-nal overgrowth of anaerobic bacteriafollowing surgical creation of jejunalself-filling blind loops (24). In thismodel, Lewis rats develop clinical (he-patomegaly), biochemical (increasedplasma aspartate aminotransferase),histological and cholangiographic evi-

TABLE 2Differential susceptibility of inbred rats to experimental enterocolitis and sys-temic inflammation

High responder Intermediate responders Low respondersLewis Sprague-Dawley Fischer F344

Wistar Buffalo

TABLE 3Differential host susceptibility of inbred mice to experimental colitis

Model High responders Low respondersTrinitrobenzene sulphonic acid/

ethanolBalb/C, C3H/HeN DBA/2, C57/BL

Citrobacter freundii C3H/HeJ DBA/2J

T cell receptor alpha knockout C3H/He Balb/C, C57BL/6


Intestinal inflammation

dence of hepatobiliary inflammationtwo to four weeks after formation of theself-filling blind loops. Wistar rats de-velop similar lesions by eight and 12weeks, but Fischer and Buffalo rats failto develop hepatobiliary injury despitevery similar luminal bacterial concen-trations in all rat strains. Thus, withidentical stimuli, Lewis rats developchronic, spontaneously relapsing in-flammation with extraintestinal in-flammation, but Buffalo and Fischerrats develop transient, self-limited in-flammation with no local or systemiccomplications.

Lewis rats are high responders in anumber of inflammatory models, in-cluding autoimmune encephalitis, thy-roiditis, uveitis and arthritis (adjuvant,collagen and PG-PS-induced) (25,26).Experimental data support two theoriesto explain mechanisms of enhancedsusceptibility to inflammation in Lewisrats: defective acute hypothalamic/pituitary/adrenal responses to IL-1 andPG-PS (27); and disordered regulationof the immune response. In support ofthe latter theory, Lewis rats have an in-creased ratio of cecal IL-1:IL-1ra MRNA

during the chronic phase of PG-PS-i-nduced inflammation relative to resis-tant Buffalo and Fischer rats (21).

Moreover, noninflamed intestinal tis-sues from Lewis, but not Fischer andBuffalo, rats constitutively expressMRNA for tumour necrosis factor andan IL-8-like molecule (28), suggestingthat the mucosal immune system ofthe Lewis rat is in a ‘primed’ state. Theauthor has also demonstrated that Tlymphocytes regulate the chronic, re-lapsing granulomatous phase ofPG-PS-induced enterocolitis and sys-temic inflammation based on observa-tions that Lewis athymic (nude) ratsfail to develop enterocolitis and arthri-tis, and that cyclosporin A preventsand treats chronic intestinal and sys-temic inflammation (29). These resultscomplement the author’s observationsin IBD patients and observations byBristol et al (30) that PG-PS stimulatedperitoneal macrophages from Lewisrats have an increased IL-1:IL-1ra ratiorelative to Buffalo rats. Patients withactive Crohn’s disease and ulcerativecolitis have significantly increasedtissue IL-1:IL-1ra and MRNA protein ra-tios compared with controls (31,32).Inbred mouse strains: Beagley and co-workers (33) have reported that Balb/Cand C3H/HeN mice developed achronic colitis upon repeated weeklyadministration of trinitrobenzene sul-

phonic acid/ethanol enemas, butDBA/2 and C57/BL mice were resistantto chronic inflammation (Table 3).Similarly, C3H/HeJ mice developedmore extensive colonic inflammationand ulcerations than DBA/2J mice fol-lowing experimental infection withCitrobacter freundii, although the twostrains developed similar degrees ofepithelial hyperplasia (34). However,inbred mouse strain susceptibility is notentirely consistent because Mombaertset al (15) found that TCR-alpha chain-deficient mice on the 129/SV back-ground and 129/SVxC3H/He crossesdevelop severe intestinal inflammationmore rapidly (four to six months of age)and with a higher incidence than those129/SV mice crossed with C57BL/6 orBalb/C strain, which develop a less se-vere disease with a slower onset. Theonly mouse strain that displayed consis-tent high susceptibility in these modelswas the C3H/He background (C3H/HeN or C3H/JHeJ), which is the parentstrain for the C3H/HeJ Bir mice thatspontaneously develop colitis (9).

SUMMARY ANDCONCLUSIONS

The studies discussed above clearlydemonstrate that the chronicity, ag-

Initiation Luminal potentiating fac-tors

Genetically determinedimmunoregulation

Inflammatory response Tissue response

Downregulation Resolution, tissue repair Healing, no residualdamage

Normal host

Viral orbacterialinfections,

NSAIDs, toxins

PG-PS, LPS, FMLP,bacterial and dietary

antigens

Acute inflammation

Genetically susceptiblehost

Slow resolution withscarring

Amplification Chronic inflammation,tissue destruction, fibrosis

Secondary immuneevents, irreversible

damage

Figure 1) The influence of genetic susceptibility on chronicity of inflammation is presented. Episodic enteric infections, environment toxins and enhancedmucosal uptake of ubiquitous bacterial constituents induce transient injury in all hosts. The normal response is appropriate suppression of inflammationwith no residual damage (upper arm). However, genetically susceptible hosts amplify the inflammatory response, which leads to chronic tissue damage.FMLP n-formyl-methionyl-leucyl phenylalanine; LPS Lipopolysaccharide, endotoxin; NSAIDs Nonsteroidal anti-inflammatory drugs; PG-PS Peptidoglycan-polysaccharide. Reprinted with permission from: Sartor RB. Microbial factors in the pathogenesis of Crohn’s disease, ulcerative colitis and experimental in-testinal inflammation. In: Kirsner JB, Shorter RG, eds. Inflammatory Bowel Disease, 4th edn. Baltimore: Williams & Wilkins, 1995:96-124


SARTOR

gressiveness and complications of in-duced intestinal inflammation dependon host genetic susceptibility. Further-more, spontaneous mutation or alteredexpression of a single gene can inducespontaneous colitis. Genetically en-gineered models demonstrate that al-teration of any of a number of keyimmunoregulatory cytokine or Tlymphocyte gene products can lead tophenotypically similar intestinal in-flammatory conditions. Furthermore,inbred rodent strains susceptible to in-duced intestinal inflammation exhibitimmunoregulatory defects (Lewis ratsincreased IL-1:IL-1ra ratio and C3H/HeJlipopolysaccharide-unresponsiveness).These observations in animal modelssuggest that human IBD can arise from anumber of mutations of immunoregula-tory molecules, supporting the conceptof genetic heterogeneity for ulcerativecolitis and Crohn’s disease.

The author suggests that geneti-

cally determined defects in immu-noregulation or perhaps mucosalbarrier integrity can alter the delicatebalance among phlogistic luminal bac-terial constituents, dietary antigensand mucosal protective forces, and pro-poses that the genetic susceptibility ofhigh responding hosts (Lewis rats andperhaps IBD patients) is due to an in-ability to downregulate appropri-ately the inflammatory response toubiquitous luminal antigens, probablyof bacterial origin (35). This theorypredicts that events initiating inflam-mation may be nonspecific (self-limited infection, nonsteroidal anti-inflammatory drugs, toxins) and pro-duce acute inflammation of similardegree in all hosts (Figure 1). The nor-mal, genetically resistant host appro-priately downregulates inflammation,which heals with no residual damage.However, the genetically susceptiblehost (Lewis rat, IBD patient), due to de-

fective immunosuppression, ampli-fies the inflammatory response todevelop aggressive tissue injury, fibrosisand extraintestinal inflammation. Bet-ter understanding of genetically deter-mined defects in immunoregulation ofthe Lewis rat, and C3H/HeJ andC3H/HeN mice, and identification ofthe spontaneous genetic mutation(s) ofthe C3H/HeJ Bir mouse should lead tovaluable insights into the genetic regu-lation of experimental chronic intesti-nal and extraintestinal inflammationthat can be rapidly tested in IBD pa-tients.

ACKNOWLEDGEMENTS: This workwas supported by USPHS grants DK 40249,DK 47700 and DK 34987, and the Crohn’sand Colitis Foundation of America. Theauthors gratefully acknowledge the expertsecretarial assistance of Robert Tuttle andShirley Willard.

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