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1. Lifestyle, behaviour, and environmental modification for the management of patients with inflammatory bowel diseases: an International Organization for Study of Inflammatory Bowel Diseases consensus

Author

Abreu, M, Ahuja, V, Allez, M, Ananthakrishnan, A, Bemelman, W, Bernstein, C, Braun, J, Chowers, Y, Colombel, J-F, Danese, S, D'Haens, G, D'Hoore, A, Dignass, A, Dotan, I, Dubinsky, M, Ekbom, A, Fleshner, P, Gasche, C, Gassull, MA, Gearry, R, Ghosh, S, Gibson, P, Griffiths, A, Halfvarson, J, Hanauer, S, Harpaz, N, Hart, A, Hibi, T, Kamm, M, Kaplan, G, Kaser, A, Korelitz, B, Kotze, P, Koutroubakis, I, Kruis, W, Lakatos, P, Lewis, J, Lindsay, J, Loftus, E, Louis, E, Lukas, M, Magro, F, Mahadevan, U, Mantzaris, G, Mary, J-Y, McGovern, D, Moum, B, Munkholm, P, Neurath, M, Ng, S, O'Morain, C, Oresland, T, Panaccione, R, Panes, J, Panis, Y, Pemberton, J, Peyrin-Biroulet, L, Prantera, C, Rachmilewitz, D, Ran, Z, Reinisch, W, Remzi, F, Rhodes, J, Riddell, R, Rogler, G, Rubin, D, Sachar, D, Sandborn, W, Sands, B, Sartor, B, Schoelmerich, J, Schreiber, S, Siegel, C, Siegmund, B, Silverberg, M, Söderholm, J, Sood, A, Spinelli, A, Stange, E, Steinwurz, F, Targan, S, Travis, S, Turner, D, Tysk, C, Vatn, M, Vermeire, S, Watanabe, M, Yamamoto, T, Yamamoto-Furusho, J, Ananthakrishnan, Ashwin N, Kaplan, Gilaad G, Bernstein, Charles N, Burke, Kristin E, Lochhead, Paul J, Sasson, Alexa N, Agrawal, Manasi, Tiong, Jimmy Ho Tuan, Steinberg, Joshua, Kruis, Wolfgang, Steinwurz, Flavio, Ahuja, Vineet, Ng, Siew C, Rubin, David T, Colombel, Jean-Frederic, and Gearry, Richard

Published
2022
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2. Author Correction: Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease (Nature Communications, (2020), 11, 1, (995), 10.1038/s41467-019-14275-y)

Author

Serra E. G., Schwerd T., Moutsianas L., Cavounidis A., Fachal L., Pandey S., Kammermeier J., Croft N. M., Posovszky C., Rodrigues A., Russell R. K., Barakat F., Auth M. K. H., Heuschkel R., Zilbauer M., Fyderek K., Braegger C., Travis S. P., Satsangi J., Parkes M., Thapar N., Ferry H., Matte J. C., Gilmour K. C., Wedrychowicz A., Sullivan P., Moore C., Sambrook J., Ouwehand W., Roberts D., Danesh J., Baeumler T. A., Fulga T. A., Carrami E. M., Ahmed A., Wilson R., Barrett J. C., Elkadri A., Griffiths A. M., Zurek M., Strisciuglio C., Elawad M., Lo B., Arancibia-Carcamo C., Bailey A., Barnes E., Bird-Lieberman E. L., Brain O., Braden B., Collier J., East J., Howarth L., Keshav S., Klenerman P., Leedham S., Palmer R., Powrie F., Simmons A., Walker M., Tolkien Z., Kaptoge S., Allen D., Mehenny S., Mant J., Di Angelantonio E., Thompson S. G., Yilmaz B., Juillerat P., Geuking M., Wiest R., Macpherson A. J., Bravo F. D., Brugger L., Carstens O., Bigler U. G., Heimgartner B., Rusticeanu M., Schmid-Uebelhart S., Strebel B., Tatu A., Tutuian R., Oyas O., Ramon C., Stelling J., Franc Y., Fournier N., Pittet V. E. H., Burnand B., Egger M., Golay D., Marot A., Musso L., Rossel J. -B., Seematter V., Sommer J., Vulliamy R., Michetti P., Maillard M. H., Keller C., Nydegger A., Schoepfe A., Archanioti E., Ezri J., Fraga M., Schoepfer A., Muller C., Rogler G., Biedermann L., Blattmann M., Burk S., Dora B., Fried M., Misselwitz B., Mullhaupt B., Obialo N., Pohl D., Raschle N., Scharl M., Vavricka S., Von Kanel R., Zeitz J., Abdelrahman K., Ademi G., Borovicka J., Brand S., Frei R., Haarer J., Knellwolf-Grieger C., Krieger-Grubel C., Kunzler P., Meyenberger C., Meyer P., Rohrich N., Sawatzki M., Schelling M., Semadeni G. -M., Sulz M., Zimmermann D., Aepli P., Criblez D. H., Hess C., Richterich J. -P., Spalinger J., Staudenmann D., Stulz A., Wohrle S., Thomas A., Anderegg C., Kohler H., Kusche R., Antonino A. -T., Arrigoni E., Bengoa J. M., Cunningham S., de Saussure P., Girard L., de Jong D. B., Basturk P., Brunner S., Degen L., Hruz P., Bakker C. K. -D., Niess J., Balsiger B., Haldemann J., Saner G., Seibold F., Bauerfeind P., Becocci A., Belli D., Binek J., Hengstler P., Boehm S., Boldanov T., Buhr P., Koller R., Rueger V., Senning A., Burri E., Buyse S., Cao D. -T., D'Angelo F., Delarive J., Doerig C., Hessler R., Preissler C., Rentsch R., Risti B., Ritz M. A., Steuerwald M., Vogtlin J., Sagmeister M., Sauter B., Schibli S., Sokollik C., Schlauri H., Schnegg J. -F., Seirafi M., Spangenberger H., Stadler P., Staub P., Stenz V., Tempia-Caliera M., Thorens J., Truninger K., Urfer P., Viani F., Vouillamoz D., Zander S., Wyli T., Jostins L., Kennedy N. A., Ahmad T., Lamb C. A., Edwards C., Hart A., Hawkey C., Mansfield J. C., Mowat C., Newman W. G., Tremelling M., Lee J. C., Prescott N. J., Mathew C. G., Lees C. W., McGovern D. P. B., Targan S. R., Botwin G., Mengesha E., Fleshner P., Landers C., Li D., Rioux J. D., Bitton A., Cote-Daigneault J., Daly M. J., Xavier R., Morris K., Boucher G., Cho J. H., Abraham C., Merad M., Sands B., Peter I., Hao K., Itan Y., Duerr R. H., Konnikova L., Schwartz M. B., Proksell S., Johnston E., Miladinova V., Chen W., Brant S. R., Datta L., Silverberg M. S., Schumm L. P., Birch S., Giri M., Gettler K., Sharma Y., Stevens C., Lazarev M., Haritunians T., Snapper S. B., Shah N., Muise A. M., Wilson D. C., Uhlig H. H., Anderson C. A., Serra, E. G., Schwerd, T., Moutsianas, L., Cavounidis, A., Fachal, L., Pandey, S., Kammermeier, J., Croft, N. M., Posovszky, C., Rodrigues, A., Russell, R. K., Barakat, F., Auth, M. K. H., Heuschkel, R., Zilbauer, M., Fyderek, K., Braegger, C., Travis, S. P., Satsangi, J., Parkes, M., Thapar, N., Ferry, H., Matte, J. C., Gilmour, K. C., Wedrychowicz, A., Sullivan, P., Moore, C., Sambrook, J., Ouwehand, W., Roberts, D., Danesh, J., Baeumler, T. A., Fulga, T. A., Carrami, E. M., Ahmed, A., Wilson, R., Barrett, J. C., Elkadri, A., Griffiths, A. M., Zurek, M., Strisciuglio, C., Elawad, M., Lo, B., Arancibia-Carcamo, C., Bailey, A., Barnes, E., Bird-Lieberman, E. L., Brain, O., Braden, B., Collier, J., East, J., Howarth, L., Keshav, S., Klenerman, P., Leedham, S., Palmer, R., Powrie, F., Simmons, A., Walker, M., Tolkien, Z., Kaptoge, S., Allen, D., Mehenny, S., Mant, J., Di Angelantonio, E., Thompson, S. G., Yilmaz, B., Juillerat, P., Geuking, M., Wiest, R., Macpherson, A. J., Bravo, F. D., Brugger, L., Carstens, O., Bigler, U. G., Heimgartner, B., Rusticeanu, M., Schmid-Uebelhart, S., Strebel, B., Tatu, A., Tutuian, R., Oyas, O., Ramon, C., Stelling, J., Franc, Y., Fournier, N., Pittet, V. E. H., Burnand, B., Egger, M., Golay, D., Marot, A., Musso, L., Rossel, J. -B., Seematter, V., Sommer, J., Vulliamy, R., Michetti, P., Maillard, M. H., Keller, C., Nydegger, A., Schoepfe, A., Archanioti, E., Ezri, J., Fraga, M., Schoepfer, A., Muller, C., Rogler, G., Biedermann, L., Blattmann, M., Burk, S., Dora, B., Fried, M., Misselwitz, B., Mullhaupt, B., Obialo, N., Pohl, D., Raschle, N., Scharl, M., Vavricka, S., Von Kanel, R., Zeitz, J., Abdelrahman, K., Ademi, G., Borovicka, J., Brand, S., Frei, R., Haarer, J., Knellwolf-Grieger, C., Krieger-Grubel, C., Kunzler, P., Meyenberger, C., Meyer, P., Rohrich, N., Sawatzki, M., Schelling, M., Semadeni, G. -M., Sulz, M., Zimmermann, D., Aepli, P., Criblez, D. H., Hess, C., Richterich, J. -P., Spalinger, J., Staudenmann, D., Stulz, A., Wohrle, S., Thomas, A., Anderegg, C., Kohler, H., Kusche, R., Antonino, A. -T., Arrigoni, E., Bengoa, J. M., Cunningham, S., de Saussure, P., Girard, L., de Jong, D. B., Basturk, P., Brunner, S., Degen, L., Hruz, P., Bakker, C. K. -D., Niess, J., Balsiger, B., Haldemann, J., Saner, G., Seibold, F., Bauerfeind, P., Becocci, A., Belli, D., Binek, J., Hengstler, P., Boehm, S., Boldanov, T., Buhr, P., Koller, R., Rueger, V., Senning, A., Burri, E., Buyse, S., Cao, D. -T., D'Angelo, F., Delarive, J., Doerig, C., Hessler, R., Preissler, C., Rentsch, R., Risti, B., Ritz, M. A., Steuerwald, M., Vogtlin, J., Sagmeister, M., Sauter, B., Schibli, S., Sokollik, C., Schlauri, H., Schnegg, J. -F., Seirafi, M., Spangenberger, H., Stadler, P., Staub, P., Stenz, V., Tempia-Caliera, M., Thorens, J., Truninger, K., Urfer, P., Viani, F., Vouillamoz, D., Zander, S., Wyli, T., Jostins, L., Kennedy, N. A., Ahmad, T., Lamb, C. A., Edwards, C., Hart, A., Hawkey, C., Mansfield, J. C., Mowat, C., Newman, W. G., Tremelling, M., Lee, J. C., Prescott, N. J., Mathew, C. G., Lees, C. W., Mcgovern, D. P. B., Targan, S. R., Botwin, G., Mengesha, E., Fleshner, P., Landers, C., Li, D., Rioux, J. D., Bitton, A., Cote-Daigneault, J., Daly, M. J., Xavier, R., Morris, K., Boucher, G., Cho, J. H., Abraham, C., Merad, M., Sands, B., Peter, I., Hao, K., Itan, Y., Duerr, R. H., Konnikova, L., Schwartz, M. B., Proksell, S., Johnston, E., Miladinova, V., Chen, W., Brant, S. R., Datta, L., Silverberg, M. S., Schumm, L. P., Birch, S., Giri, M., Gettler, K., Sharma, Y., Stevens, C., Lazarev, M., Haritunians, T., Snapper, S. B., Shah, N., Muise, A. M., Wilson, D. C., Uhlig, H. H., and Anderson, C. A.

Published
2022

3. Large-scale sequencing identifies multiple genes and rare variants associated with Crohn’s disease susceptibility

Author

Sazonovs, A., Stevens, C.R., Venkataraman, G.R., Yuan, K., Avila, B., Abreu, M.T., Ahmad, T., Allez, M., Ananthakrishnan, A.N., Atzmon, G., Baras, A., Barrett, J.C., Barzilai, N., Beaugerie, L., Beecham, A., Bernstein, C.N., Bitton, A., Bokemeyer, B., Chan, A., Chung, D., Cleynen, I., Cosnes, J., Cutler, D.J., Daly, A., Damas, O.M., Datta, L.W., Dawany, N., Devoto, M., Dodge, S., Ellinghaus, E., Fachal, L., Farkkila, M., Faubion, W., Ferreira, M., Franchimont, D., Gabriel, S.B., Ge, T., Georges, M., Gettler, K., Giri, M., Glaser, B., Goerg, S., Goyette, P., Graham, D., Hamalainen, E., Haritunians, T., Heap, G.A., Hiltunen, M., Hoeppner, M., Horowitz, J.E., Irving, P., Iyer, V., Jalas, C., Kelsen, J., Khalili, H., Kirschner, B.S., Kontula, K., Koskela, J.T., Kugathasan, S., Kupcinskas, J., Lamb, C.A., Laudes, M., Levesque, C., Levine, A.P., Lewis, J.D., Liefferinckx, C., Loescher, B.S., Louis, E., Mansfield, J., May, S., McCauley, J.L., Mengesha, E., Mni, M., Moayyedi, P., Moran, C.J., Newberry, R.D., O'Charoen, S., Okou, D.T., Oldenburg, B., Ostrer, H., Palotie, A., Paquette, J., Pekow, J., Peter, I., Pierik, M.J., Ponsioen, C.Y., Pontikos, N., Prescott, N., Pulver, A.E., Rahmouni, S., Rice, D.L., Saavalainen, P., Sands, B., Sartor, R.B., Schiff, E.R., Schreiber, S., Schumm, L.P., Segal, A.W., Seksik, P., Shawky, R., Sheikh, S.Z., Silverberg, M.S., Simmons, A., Skeiceviciene, J., Sokol, H., Solomonson, M., Somineni, H., Sun, D., Targan, S., Turner, D., Uhlig, H.H., Meulen, A.E. van der, Vermeire, S., Verstockt, S., Voskuil, M.D., Winter, H.S., Young, J., Duerr, R.H., Franke, A., Brant, S.R., Cho, J., Weersma, R.K., Parkes, M., Xavier, R.J., Rivas, M.A., Rioux, J.D., McGovern, D.P.B., Huang, H.L., Anderson, C.A., Daly, M.J., Belgium IBD Consortium, Cedars-Sinai IBD, International IBD Genetics Consortium, NIDDK IBD Genetics Consortium, NIHR IBD BioResource, Regeneron Genetics Center, SHARE Consortium, SPARC IBD Network, UK IBD Genetics Consortium, Interne Geneeskunde, MUMC+: MA Maag Darm Lever (9), RS: NUTRIM - R2 - Liver and digestive health, Gastroenterology and Hepatology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI)

Subjects
Crohn Disease, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) have identified hundreds of loci associated with Crohn's disease (CD). However, as with all complex diseases, robust identification of the genes dysregulated by noncoding variants typically driving GWAS discoveries has been challenging. Here, to complement GWASs and better define actionable biological targets, we analyzed sequence data from more than 30,000 patients with CD and 80,000 population controls. We directly implicate ten genes in general onset CD for the first time to our knowledge via association to coding variation, four of which lie within established CD GWAS loci. In nine instances, a single coding variant is significantly associated, and in the tenth, ATG4C, we see additionally a significantly increased burden of very rare coding variants in CD cases. In addition to reiterating the central role of innate and adaptive immune cells as well as autophagy in CD pathogenesis, these newly associated genes highlight the emerging role of mesenchymal cells in the development and maintenance of intestinal inflammation.Large-scale sequence-based analyses identify novel risk variants and susceptibility genes for Crohn's disease, and implicate mesenchymal cell-mediated intestinal homeostasis in disease etiology.

Published
2022

14. Ustekinumab as induction and maintenance therapy for Ulcerative Colitis

Author

Sands, B, Sandborn, W, Panaccione, R, O'Brien, C, Zhang, H, Johanns, J, Adedokun, O, Li, K, Peyrin-Biroulet, L, Van Assche, G, Danese, S, Targan, S, Abreu, M, Hisamatsu, T, Szapary, P, Marano, C, UNIFI Study Group, Biancone, L, inclusa nell’ UNIFI Study Group, and vedi articolo e, P

Subjects
Settore MED/12
Published
2019

24. Summary

Author

RUTGEERTS, P. J. and TARGAN, S. R.

Published
1999

30. Safety, tolerance and activity of multiple doses of subcutaneous recombinant human interleukin-10 (rHuIL-10) in patients with mild to moderate active Crohn's disease 11.02

Author

Fedorak, R. N., Gangl, A., Elson, C. O., Gasche, C., Rutgeerts, P., D'Haens, G., Schreiber, S., Wild, G., Hanauer, S. B., Sninsky, C. A., Wilson, J. H. P., Tilg, H., Isaacs, K., Jacyna, M., Colombel, J. F., Desreumaux, P., van Deventer, S. J. H., Wright, J. P., Irvine, E. J., Levine, D. S., Tremaine, W. J., Laschner, B. A., Warner, A. S., McDermott, R., Mayer, L., Koningsberger, J. C., van Gossum, A., Befrits, R., Deusch, K., Targan, S., Gibson, P., Cohard, M., Grint, P., Kilian, A., and LeBeaut, A.

Published
1997

32. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease

Author

Feagan, BG, Sandborn, WJ, Gasink, C, Jacobstein, D, Lang, Y, Friedman, JR, Blank, MA, Johanns, J, Gao, L-L, Miao, Y, Adedokun, OJ, Sands, BE, Hanauer, SB, Vermeire, S, Targan, S, Ghosh, S, de Villiers, WJ, Colombel, J-F, Tulassay, Z, Seidler, U, Salzberg, BA, Desreumaux, P, Lee, SD, Loftus, EV, Dieleman, LA, Katz, S, and Rutgeerts, P

Abstract

BACKGROUND\ud Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and inter-leukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn’s disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.\ud METHODS\ud We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed \ud these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn’s Disease Activity Index [CDAI] score of ≥100 points or a CDAI score

Published
2016

34. Long‐term efficacy and safety of ustekinumab for Crohn's disease through the second year of therapy.

Author

Sandborn, W. J., Rutgeerts, P., Gasink, C., Jacobstein, D., Zou, B., Johanns, J., Sands, B. E., Hanauer, S. B., Targan, S., Ghosh, S., de Villiers, W. J. S., Colombel, J.‐F., and Feagan, B. G.

Subjects
CROHN'S disease, MONOCLONAL antibodies, DRUG efficacy, RANDOMIZED controlled trials, PLACEBOS
Abstract

Summary: Background: In Phase 3 studies of ustekinumab, a fully human monoclonal IL‐12/23p40 antibody approved for moderate‐to‐severe Crohn's disease, patients entered a long‐term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM‐UNITI maintenance are reported. Methods: UNITI‐1 (TNF‐antagonist failures) and UNITI‐2 (conventional therapy failures) patients (N = 1281) entered IM‐UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose‐adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8–32). All Week 44 completers could enter the long‐term extension without further dose adjustment. Placebo patients discontinued following study unblinding. Results: A total of 718 patients (all treated) entered the long‐term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient‐years) were similar among all placebo and ustekinumab patients (Week 0‐96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed. Conclusions: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355. [ABSTRACT FROM AUTHOR]

Published
2018
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35. Ustekinumab induction and maintenance therapy in refractory Crohn's disease

Author

Sandborn, Wj, Gasink, C, Gao, Ll, Blank, Ma, Johanns, J, Guzzo, C, Sands, Be, Hanauer, Sb, Targan, S, Rutgeerts, P, Ghosh, S, de Villiers WJ, Panaccione, R, Greenberg, G, Schreiber, S, Lichtiger, S, Feagan, Bg, Haas, T, Kaser, A, Vogelsang, H, Brown, S, Florin, T, Gibson, Pg, Hetzel, D, Leong, R, Pavli, P, Radford-Smith, G, Sparrow, M, Baert, F, D'Haens, G, D'Heygere, F, Franchimont, D, Louis, E, Mana, F, Moreels, T, Vermeire, S, Anderson, F, Axler, J, Greenbloom, S, Bitton, A, Fedorak, Rn, Larkai, E, Marshall, J, Singh, R, Abitbol, V, Allez, M, Lemann, M, Bonaz, B, Colombel, Jf, Dupas, Jl, Hebuterne, X, Laharie, D, Lerebours, E, Moreau, J, Bokemeyer, B, Holler, B, Howaldt, Sp, Krummenerl, T, Kucharzik, T, Ochsenkühn, T, Raedler, A, Schiefke, I, Seidler, U, Sturm, A, Zeitz, M, Eliakim, A, Fishman, S, Konikoff, Fm, Lavy, A, Niv, Y, Nussinson, E, Rachmilewitz, D, Andriulli, A, Annese, V, Biancone, L, Corazza, Gr, Danese, S, Sturniolo, Gc, Terrosu, G, Sorrentino, D, Hommes, Dw, Jansen, Jm, Otten, Mh, Pierik, M, Ponsioen, Cy, Stokkers, P, van Bodegraven AA, Van der Woude, J, Calvet Calvo, X, Casellas, F, Garcia López, S, Garcia-Planella, E, Ginard-Vincens, D, López San Román, A, Muñoz Nuñez, F, Pérez Gisbert, J, Vera, Mi, Rodrigo, J, Riestra-Menendez, S, Arnott, I, Bloom, S, Campbell, Ss, Harbord, Mw, Mansfield, Jc, Nwokolo, C, Parkes, M, Probert, Cs, Aberra, Fn, Abraham, Bp, Abreu, Mt, Amontree, Js, Barish, Cf, Barto, Ae, Behm, B, Birbara, Ca, Bologna, S, Dryden GW Jr, Eisner, Ms, Ertan, A, Fogel, R, Gagneja, Hk, Ginsburg, P, Goff, Js, Gordon, G, Hamilton, Jw, Hanson, Js, Hardi, R, Hemaidan, A, Higgins, P, Holderman, W, Hornbuckle, K, Ibegbu, E, Isaacs, Kl, Katz, Ja, Katz, S, Kaufman, Bp, Kavanaugh, Af, Khurana, Sk, Lashner, B, Lawrence, S, Hansen, Rn, Lee, S, Leighton, Ja, Leman, Bi, Levenson, Sd, Lowe, Je, Marcuard, Sp, Matsuyama, Rm, Mcnair, Ae, Melmed, G, Miller, Km, Miner PB Jr, Mutlu, Ea, Keshavarzian, A, Narayen, V, Noar, Md, Patel, Ph, Patrick, Tj, Peck, A, Peterson, Ka, Phillips, Rw, Picco, Mf, Randall, C, Richards, Rj, Safdi, Ma, Scherl, Eh, Schwartz, Da, Schwartz, Hi, Schwartz, Jl, Sedghi, S, Shafran, I, Siegel, Ca, Sninsky, Ca, Stern, M, Suiter, D, Swaminath, A, Terdiman, Jp, Mahadevan, U, Thomson, C, Valentine, J, Vasudeva, R, Vecchio, Ja, Wolf, Dc, Yajnik, V, Yabkowski, J, Yen, E., AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology, and Other departments

Subjects
Male, Oncology, MONOCLONAL-ANTIBODY, Drug Resistance, Disease, Severity of Illness Index, Crohn Disease, Maintenance therapy, IL-23, Adult, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Double-Blind Method, Female, Humans, Induction Chemotherapy, Maintenance Chemotherapy, Middle Aged, Remission Induction, Tumor Necrosis Factors, Ustekinumab, Monoclonal, Humanized, Settore MED/12 - Gastroenterologia, Crohn's disease, EXPERIMENTAL COLITIS, General Medicine, medicine.drug, medicine.medical_specialty, MONOCLONAL-ANTIBODY, RANDOMIZED-TRIAL, EXPERIMENTAL COLITIS, CERTOLIZUMAB PEGOL, INFLAMMATION, IL-23, INTERLEUKIN-12, ADALIMUMAB, INFLIXIMAB, DISCOVERY, Antibodies, CERTOLIZUMAB PEGOL, INFLAMMATION, Refractory, Internal medicine, INFLIXIMAB, medicine, business.industry, Induction chemotherapy, medicine.disease, RANDOMIZED-TRIAL, INTERLEUKIN-12, Clinical trial, DISCOVERY, Immunology, Tumor Necrosis Factor Inhibitors, business, ADALIMUMAB
Abstract

BACKGROUND In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown. METHODS We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks. RESULTS The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P = 0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P = 0.03) and response (69.4% vs. 42.5%, P < 0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab. CONCLUSIONS Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.)

Published
2012

36. Detection of Antisynthetic Mannoside Antibodies (AΣMA) Reveals Heterogeneity in the ASCA Response of Crohn's Disease Patients and Contributes to Differential Diagnosis, Stratification, and Prediction

Author

Khoury, P. V. E, Colombel, J.F., Sofie Joossens, Ph.D., Standaert-Vitse, A., Collot, M., Halfvarson, J., Ayadi, A., Landers, C.J., Vermeire, S., Rutgeerts, P., Targan, S. R., Chamaillard, M., Mallet, Jean-Maurice, Sendid, B., Poulain, D., Physiopathologie des Candidoses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Physiopathologie des Maladies Inflammatoires de l'Intestin, Division of Gastroenterology, University Hospital Gasthuisberg, Biomolécules : synthèse, structure et mode d'action (UMR 8642) (BIOSYMA), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Örebro University Hospital [Örebro, Sweden], Laboratoire de Parasitologie et Mycologie, École de Médecine, École de Médecine, Inflammatory Bowel Disease Center,, Cedars-Sinai Medical Center, Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
[CHIM.ORGA]Chemical Sciences/Organic chemistry, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2007

37. International collaboration provides convincing linkage replication in complex disease through analysis of a large pooled data set: Crohn disease and chromosome 16

Author

Cavanaugh, J. A., Bryce, M. E., Stanford, P. M., Pavli, P., Vermeire, S., Peeters, M., Vlietinck, R., Rutgeerts, P., Rioux, J. D., Silverberg, M. S., Steinhart, A. H., Siminovitch, K. A., Hugot, J. P., Lesage, S., Zouali, H., Paavola, P., Halme, L., Färkkilä, M., Kontula, K., Annese, V., Forabosco, P., Fortina, P., Latiano, A., Van Heel, D., Parkes, M., Lench, N., Jewell, D., Brant, S. R., Bailey-Wilson, J. E., Panhuysen, C. I. M., Bayless, T. M., Cho, J. H., Bonen, D. K., Kirschner, B. S., Hanauer, S. B., Yang, H., Taylor, K., Targan, S. R., Rotter, J. I., Silver, J., Gulwani-Akolkar, B., Akolkar, P., Lin, X. -Y., Duerr, R. H., Zhang, L., Achkar, J. P., Baldassano, R. N., Daly, M. J., and Risch, N.

Subjects
Male, Genetic Linkage, International Cooperation, Ulcerative, 0302 clinical medicine, Chromosome Mapping, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 16, Colitis, Ulcerative, Crohn Disease, European Continental Ancestry Group, Family Characteristics, Female, Genetic Heterogeneity, Genetic Markers, Genetic Predisposition to Disease, Genotype, Humans, Jews, Lod Score, Microsatellite Repeats, Models, Genetic, Nuclear Family, Reproducibility of Results, Statistics, Nonparametric, Genetics, Genetics (clinical), Models, Pair 12, Genetics(clinical), 0303 health sciences, Statistics, Articles, Colitis, 3. Good health, symbols, Microsatellite, 030211 gastroenterology & hepatology, Human, Locus (genetics), Biology, White People, Chromosomes, 03 medical and health sciences, symbols.namesake, Chromosome 16, Genetic, Genetic linkage, Nonparametric, Genotyping, Chromosome 12, 030304 developmental biology, Genetic heterogeneity, Pair 16, Mendelian inheritance
Abstract

Numerous familial, non-Mendelian (i.e., complex) diseases have been screened by linkage analysis for regions harboring susceptibility genes. Except for rare, high-penetrance syndromes showing Mendelian inheritance, such as BRCA1 and BRCA2, most attempts have failed to produce replicable linkage findings. For example, in multiple sclerosis and other complex diseases, there have been many reports of significant linkage, followed by numerous failures to replicate. In inflammatory bowel disease (IBD), linkage to two regions has elsewhere been reported at genomewide significance levels: the pericentromeric region on chromosome 16 (IBD1) and chromosome 12q (IBD2). As with other complex diseases, the subsequent support for these localizations has been variable. In this article, we report the results of an international collaborative effort to investigate these putative localization by pooling of data sets that do not individually provide convincing evidence for linkage to these regions. Our results, generated by the genotyping and analysis of 12 microsatellite markers in 613 families, provide unequivocal replication of linkage for a common human disease: a Crohn disease susceptibility locus on chromosome 16 (maximum LOD score 5.79). Despite failure to replicate the previous evidence for linkage on chromosome 12, the results described herein indicate the need to further investigate the potential role of this locus in susceptibility to ulcerative colitis. This report provides a convincing example of the collaborative approach necessary to obtain the sample numbers required to achieve statistical power in studies of complex human traits.

Published
2001

38. Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease

Author

Kleoudis, C. S., Hanauer, S. B., Targan, S. R., Feagan, B. G., Tremaine, W. J., Fedorak, R. N., Wolf, D. C., McDonald, J. W.D., Isaacs, K. L., Sutherland, L. R., Lipsky, J. J., Murdock R.H., Jr, Sandborn, W. J., Gordon, S., Pike, M. G., Sninsky, C. A., and Mays, D. C.

Abstract

Background & Aims: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. Methods: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of ≤150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. Results: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. Conclusions: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.GASTROENTEROLOGY 1999;117:527-535

Published
1999
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40. A protein-truncating R179X variant in RNF186 confers protection against ulcerative colitis

Author

Rivas, Manuel A., Graham, Daniel, Sulem, Patrick, Stevens, Christine, Desch, A. Nicole, Goyette, Philippe, Gudbjartsson, Daniel, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Degenhardt, Frauke, Mucha, Sören, Kurki, Mitja I., Li, Dalin, D'Amato, Mauro, Annese, Vito, Vermeire, Severine, Weersma, Rinse K., Halfvarson, Jonas, Paavola-Sakki, Paulina, Lappalainen, Maarit, Lek, Monkol, Cummings, Beryl, Tukiainen, Taru, Haritunians, Talin, Halme, Leena, Koskinen, Lotta L. E., Ananthakrishnan, Ashwin N., Luo, Yang, Heap, Graham A., Visschedijk, Marijn C., Barrett, J, de Lange, K, Edwards, C, Hart, A, Hawkey, C, Jostins, L, Kennedy, N, Lamb, C, Lee, J, Lees, C, Mansfield, J, Mathew, C, Mowatt, C, Newman, W, Nimmo, E, Parkes, M, Pollard, M, Prescott, N, Randall, J, Rice, D, Satsangi, J, Simmons, A, Tremelling, M, Uhlig, H, Wilson, D, Abraham, C, Achkar, J.P, Bitton, A, Boucher, G, Croitoru, K, Fleshner, P, Glas, J, Kugathasan, S, Limbergen, J.V, Milgrom, R, Proctor, D, Regueiro, M, Schumm, P.L, Sharma, Y, Stempak, J.M, Targan, S.R, Wang, M.H, MacArthur, Daniel G., Neale, Benjamin M., Ahmad, Tariq, Anderson, Carl A., Brant, Steven R., Duerr, Richard H., Silverberg, Mark S., Cho, Judy H, Palotie, Aarno, Saavalainen, Päivi, Kontula, Kimmo, Färkkilä, Martti, McGovern, Dermot P. B., Franke, Andre, Stefansson, Kari, Rioux, John D., Xavier, Ramnik J., Daly, Mark J., Barrett, J., de Lane, K., Edwards, C., Hart, A., Hawkey, C., Jostins, L., Kennedy, N., Lamb, C., Lee, J., Lees, C., Mansfield, J., Mathew, C., Mowatt, C., Newman, B., Nimmo, E., Parkes, M., Pollard, M., Prescott, N., Randall, J., Rice, D., Satsangi, J., Simmons, A., Tremelling, M., Uhlig, H., Wilson, D., Abraham, C., Achkar, J. P., Bitton, A., Boucher, G., Croitoru, K., Fleshner, P., Glas, J., Kugathasan, S., Limbergen, J. V., Milgrom, R., Proctor, D., Regueiro, M., Schumm, P. L., Sharma, Y., Stempak, J. M., Targan, S. R., and Wang, M. H.

Abstract

Protein-truncating variants protective against human disease provide in vivo validation of therapeutic targets. Here we used targeted sequencing to conduct a search for protein-truncating variants conferring protection against inflammatory bowel disease exploiting knowledge of common variants associated with the same disease. Through replication genotyping and imputation we found that a predicted protein-truncating variant (rs36095412, p.R179X, genotyped in 11,148 ulcerative colitis patients and 295,446 controls, MAF=up to 0.78%) in RNF186, a single-exon ring finger E3 ligase with strong colonic expression, protects against ulcerative colitis (overall P=6.89 × 10−7, odds ratio=0.30). We further demonstrate that the truncated protein exhibits reduced expression and altered subcellular localization, suggesting the protective mechanism may reside in the loss of an interaction or function via mislocalization and/or loss of an essential transmembrane domain.

Published
2016
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41. Development of hydrocephalus in a patient with Joubert syndrome

Author

Genel, F., Atlihan, F., Ozdemir, D., and Targan, S.

Abstract

Sir, Joubert syndrome is a rare autosomal-recessive condition characterized by dysgenesis of the cerebellar vermis, hypotonia, ataxia, abnormal eye movements, mental retardation, episodic hyperpnoea and apnoea. (1) We report a [...]

Published
2004

43. P300 Health related quality of life results through week 22 from the CERTIFI study, a multicenter, randomized, double-blind, placebo-controlled Phase2b study of ustekinumab in patients with moderately to severely active Crohn's disease

Author

Feagan, B., Gasink, C., Gao, L.-L., Blank, M., Johanns, J., Guzzo, C., Chiou, C.-F., Sandborn, W., Hanauer, S.B., Targan, S., Rutgeerts, P., Ghosh, S., De Villiers, W., Panaccione, R., Greenberg, G., Schreiber, S., Lichtiger, S., and Sands, B.

Published
2012
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44. Isolation of spontaneous and interferon inducible natural killer like cells from human colonic mucosa: lysis of lymphoid and autologous epithelial target cells.

Author

Targan, S., Britvan, Leora, Kendal, R., Vimadalal, Shirin, and Soll, A.

Subjects
*GLYCOPROTEINS, *ANTINEOPLASTIC agents, *INTERFERONS, *LYMPHOKINES, *EPITHELIAL cells, *KILLER cells
Abstract

Viable mononuclear and epithelial cells were dispersed from human colonic tissue by treatment with collagenase and ethylene diamino-tetra acetate (EDTA) and separated by centrifugal elutriation. Using a single cell cytotoxic assay, functional endogenous and interferon responsive mononuclear cytotoxic cells were detected. Compared to peripheral blood lymphocyte associated killer cells that had been exposed to similar treatment, these colonic killer cells demonstrated lower efficiency cytotoxicity of Molt-4 target cells. Furthermore, inefficient, but interferon responsive cytotoxic cells were present which bound and lysed freshly isolated autologous epithelial cells. The cytotoxicity of these colonic mononuclear natural killer (NK) like cells appeared specific in that cells bound but did not lyse NK resistant Raji cells, even after interferon activation. [ABSTRACT FROM AUTHOR]

Published
1983

45. Activation of human NKCC by moderate exercise: increased frequency of NK cells with enhanced capability of effector-target lytic interactions.

Author

Targan, S., Britvan, Leora, and Dorey, F.

Subjects
*GLYCOPROTEINS, *KILLER cells, *ANTIVIRAL agents, *INTERFERONS, *GLYCOCONJUGATES, *CELL-mediated cytotoxicity
Abstract

In the present study we examined the mechanism of human natural killer cellular cytotoxicity (NKCC) augmentation by 5 mm of moderate exercise and its interrelationship to in vitro interferon (IFN) activation. Cytotoxicity was measured by employing both a single-cell cytotoxic assay and a standard 3-hr chromium-51 (51Cr) release assay. The former was used to assess changes at the single NK cell-target cell level and the latter to assess changes in overall lytic capacity of a given population of NK cells. Several findings were obtained: (1) moderate exercise augmented NKCC in vivo by recruiting a `new' population of active cytotoxic N K cells. (2) This `new' population of active cells probably was derived from cells which can bind targets but are non-cytotoxic. (3) In a standard 51Cr-release assay, additional augmentation of these exercise-activated cells occurred in vitro following exposure to interferon. (4) This additional increase in cytotoxicity produced no alteration in the frequency of killer cells as viewed at the single cell level. (5) Thus interferon's capacity to increase further the overall lytic ability of exercise-activated NK cells was not due to its activation of an additional subset of pre-NK cells, but due to its increasing the capacity of effector target lytic interactions (recycling) of the same set of NK and pre-NK cells. [ABSTRACT FROM AUTHOR]

Published
1981

46. Spontaneous and lectin-dependent cellular cytotoxicity by lymphocyte subpopulations against cell lines susceptible or resistant to spontaneous cytotoxicity.

Author

Jondal, M. and Targan, S.

Subjects
*CELL lines, *LECTINS, *LYMPHOCYTES, *CELLS, *CELL receptors, *CELL culture
Abstract

In the present study we have investigated whether cell lines, which are resistant to spontaneous cytotoxicity, can be killed by lectin-dependent cellular cytotoxicity (LDCC), the expression of EAC: (7S) receptors on LDCC effector cells, and the relationship between spontaneous cytotoxicity and LDCC when EAC (7S) receptor-positive or -negative subpopulations are tested against different target cell lines. We found that target cells which are resistant to spontaneous cytotoxicity can, indeed, be killed by LDCC, and that there is an inverse relationship between spontaneous cytotoxicity and LDCC, both when unfractionated lymphocytes were tested against different target cells and when fractionated cells were tested against cell lines highly susceptible to spontaneous cytotoxicity. The implications of these findings, in relation to the relative specificity of the spontaneous cytotoxicity system, are discussed. [ABSTRACT FROM AUTHOR]

Published
1978

47. The CD8+ Leu-7+ subset of T cells in Crohn's disease: distinction between cytotoxic and covert suppressor functions.

Author

Deem, R. L., Targan, S. R., Niederlehner, A., and Shanahan, F.

Subjects
*T cells, *CROHN'S disease, *IMMUNOGLOBULINS, *POKEWEED mitogens, *MITOGENS, *LYMPHOCYTES
Abstract

An expanded T cell subpopulation (CD8' Leu-7') has previously been reported in the peripheral blood of patients with Crohn's disease. This subpopulation of T cells was associated with a 'covert suppressor' function, particularly in patients with mild/early Crohn's disease, suppressing immunoglobulin production in vitro when cultured in the presence of pokeweed mitogen. T cells with the same CD8 ' Leu-7+ phenotype have also been shown to exhibit non-major histocompatability complex restricted cytotoxicity when triggered by anti-CD3 antibodies, and this cytotoxic activity has also been shown to be elevated in patients with Crohn's disease. Because cytotoxic cells can have immunoregulatory properties, we investigated the possible relationship between the cytotoxic and 'covert suppressor" functions of the CD8' Leu-7' subset of T lymphocytes in patients with mildly active Crohn's disease. Although the correlation between T cell cytotoxic activity and the CD8' Leu-7' cells was confirmed, no evidence for covert suppressor activity was found; there were no significant differences between the amount of IgM secreted by B cells from normal subjects and patients with Crohn's disease when cultured with T cells at increasing T: B ratios. In addition, IgM production by peripheral blood B cells did not correlate with either the number of CD8' Leu-7+ cells or with the level of cytotoxic T cell activity. Furthermore, when B cells and CD4+ T cells were co-cultured with increasing numbers of CD8+ T cells, there was no evidence for excessive suppressor T cell activity in Crohn's disease. Although some patients exhibited low levels of IgM production, this was due to diminished B cell function, rather than excessive T suppressor activity or defective T helper activity. We conclude that the CD8' Leu-7+ T cell subset is associated with cytotoxic but not with enhanced or covert suppressor activity in Crohn's disease. The previously described covert suppressor function attributed to cells with this phenotype in Crohn's disease was not found to account for diminished B cell responsiveness in vitro and is unlikely to be of major pathophysiologic significance in the majority of patients. [ABSTRACT FROM AUTHOR]

Published
1990

48. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews.

Author

Yang, H, McElree, C, Roth, M P, Shanahan, F, Targan, S R, and Rotter, J I

Abstract

The Jewish population has an increased frequency of inflammatory bowel disease compared with their non-Jewish neighbours. Genetic factors have been implicated in the aetiology of this disorder and may contribute to ethnic differences. This study determined the familial empirical risks for inflammatory bowel disease in the first degree relatives of inflammatory bowel disease probands (for both Jews and non-Jews) for the purpose of accurate genetic counselling and genetic analysis. A total of 527 inflammatory bowel disease patients from Southern California (291 Jews and 236 non-Jews) were questioned about inflammatory bowel disease in their first degree relatives (a total of 2493 individuals). Since inflammatory bowel disease has a variable and late age of onset, age specific incidence data were used to estimate the life time risks and to make valid comparisons between the different groups. In the first degree relatives of non-Jewish probands, the life time risks for inflammatory bowel disease were 5.2% and 1.6% when probands had Crohn's disease and ulcerative colitis respectively. These values were consistently lower than the corresponding risks for relatives of Jewish patients -7.8% and 4.5% for Crohn's disease and ulcerative colitis probands respectively (p value for comparison between Jews and non-Jews: 0.028; between ulcerative colitis and Crohn's disease: 0.005). These data provide the requisite basis for genetic counselling for these disorders in the white American population. In addition, these different empirical risks for relatives of Jewish and non-Jewish probands allow rejection of single Mendelian gene models for inflammatory bowel disease, but are consistent with several alternative genetic models. [ABSTRACT FROM PUBLISHER]

Published
1993

49. Triggered human mucosal T cells release tumour necrosis factor-alpha and interferon-gamma which kill human colonic epithelial cells.

Author

Deem, R. L., Shanahan, F., and Targan, S. R.

Subjects
TUMOR necrosis factors, EPITHELIAL cells, T cells, INTERFERONS, LYMPHOKINES, INFLAMMATORY bowel diseases
Abstract

T cell activation can lead to local tissue injury in organ culture studies of human fetal Jejunum, either directly through cytotoxicity or indirectly by the release of cytotoxic cytokines. The goal of this study was to establish in vitro whether cytotoxic cytokines can be released by isolated colonic T cells and what cytokine interactions are required for killing of human colonic epithelial cells. Cytokine-containing supernatants were induced by incubating unseparated lamina propria lymphocytes (LPL) or mucosal T cell subpopulations (separated by indirect panning) with anti-CD3 and/or K562 target cells for 18 h at 37°C. Cytokines were measured by cytotoxicity assays using 1.929 (murine fibroblast) and HT-29 (human colonic tumour) lines us target cells in combination with blocking anti-cytokine antibodies. Supernatants derived from unseparated, CD4+ (> 95% pure) and CD8+ (7 > 90% pure) LPL were cytotoxic to L929 targets (350 U/ml, 230 U/ml and 100 U/ml tumour necrosis factor-alpha, respectively). All or nearly all of the cytotoxicity was due to the presence of tumour necrosis factor-alpha (little or no tumour necrosis factor-beta was detected). These same supernatants were cytotoxic (up to 32% lysis at 1/4 dilution) to HT-29 targets in a 48-h 111In release assay. Recombinant tumour necrosis factor-alpha and interferon-gamma alone produced minimal killing of HT-29, but together killed the HT-29 target cells. Anti-tumour necrosis factor-alpha or anti-interferon-gamma alone blocked killing of HT-29 target cells by LPL-derived supernatants, although anti-tumour necrosis factor-beta had no effect upon killing of HT-29. These results demonstrate that human LPL T cells, triggered by addition of anti-CD3 and target cells, produce tumour necrosis factor-alpha and interferon-gamma, both of which are required for optimal killing of HT-29. Simultaneous release of these cytokines in the vicinity of epithelial cells during immune responses could play an important role in the mucosal damage in chronic inflammatory states such as inflammatory bowel disease. [ABSTRACT FROM AUTHOR]

Published
1991

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