Skip to main content
PMC home page
The American Journal of Pathology logoLink to The American Journal of Pathology
. 1997 Mar;150(3):823–832.

Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn's disease.

P Parronchi 1, P Romagnani 1, F Annunziato 1, S Sampognaro 1, A Becchio 1, L Giannarini 1, E Maggi 1, C Pupilli 1, F Tonelli 1, S Romagnani 1
PMCID: PMC1857889  PMID: 9060820

Abstract

Crohn's disease (CD) is a chronic bowel inflammatory disorder in which the pathogenic role of immune alterations has been suggested, but the immunologic mechanisms responsible for the inflammatory reaction are still poorly understood. We investigated the profile of cytokine secretion by T-cell clones generated from gut tissue specimens of four patients with active CD, five patients with ulcerative colitis, and four patients with noninflammatory gut disorders (NIGDs). The great majority of CD4+ T-cell clones generated from the gut of patients with CD produced high levels of interferon-gamma (IFN-gamma) but low or undetectable amounts of interleukin-4 (IL-4), whereas substantial proportions of CD4+ T-cell clones derived from the gut of patients with either ulcerative colitis or NIGDs produced IL-4 in addition to IFN-gamma. The immunohistochemical analysis revealed high numbers of activated CD4+ T cells showing IFN-gamma but not IL-4 reactivity, as well as substantial proportions of IL-12-containing macrophages, in the intestinal lamina propria and muscularis propria of patients with CD, whereas these cells were very rare or undetectable in patients with NIGDs. Culturing T cells from gut biopsy specimens of a patient with CD in the presence of a neutralizing anti-IL-12 antibody down-regulated the development of IFN-gamma-producing CD4+ T cells. These findings suggest that a critical event in the initiation of bowel inflammatory lesions in CD may involve up-regulation of IL-12 production, resulting in conditions that maximally promote type 1 T-helper immune responses.

Full text

PDF
823

Images in this article

828Figure 2
on p.828

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Annunziato F., Manetti R., Tomasévic I., Guidizi M. G., Biagiotti R., Giannò V., Germano P., Mavilia C., Maggi E., Romagnani S. Expression and release of LAG-3-encoded protein by human CD4+ T cells are associated with IFN-gamma production . FASEB J. 1996 May;10(7):769–776. doi: 10.1096/fasebj.10.7.8635694. [DOI] [PubMed] [Google Scholar]
  2. Assenmacher M., Schmitz J., Radbruch A. Flow cytometric determination of cytokines in activated murine T helper lymphocytes: expression of interleukin-10 in interferon-gamma and in interleukin-4-expressing cells. Eur J Immunol. 1994 May;24(5):1097–1101. doi: 10.1002/eji.1830240513. [DOI] [PubMed] [Google Scholar]
  3. Beagley K. W., Elson C. O. Cells and cytokines in mucosal immunity and inflammation. Gastroenterol Clin North Am. 1992 Jun;21(2):347–366. [PubMed] [Google Scholar]
  4. Braegger C. P., Nicholls S., Murch S. H., Stephens S., MacDonald T. T. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet. 1992 Jan 11;339(8785):89–91. doi: 10.1016/0140-6736(92)90999-j. [DOI] [PubMed] [Google Scholar]
  5. Breese E. J., Michie C. A., Nicholls S. W., Murch S. H., Williams C. B., Domizio P., Walker-Smith J. A., MacDonald T. T. Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology. 1994 Jun;106(6):1455–1466. doi: 10.1016/0016-5085(94)90398-0. [DOI] [PubMed] [Google Scholar]
  6. Chehimi J., Trinchieri G. Interleukin-12: a bridge between innate resistance and adaptive immunity with a role in infection and acquired immunodeficiency. J Clin Immunol. 1994 May;14(3):149–161. doi: 10.1007/BF01533364. [DOI] [PubMed] [Google Scholar]
  7. Del Prete G. F., De Carli M., D'Elios M. M., Maestrelli P., Ricci M., Fabbri L., Romagnani S. Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. Eur J Immunol. 1993 Jul;23(7):1445–1449. doi: 10.1002/eji.1830230707. [DOI] [PubMed] [Google Scholar]
  8. Del Prete G. F., Tiri A., Mariotti S., Pinchera A., Ricci M., Romagnani S. Enhanced production of gamma-interferon by thyroid-derived T cell clones from patients with Hashimoto's thyroiditis. Clin Exp Immunol. 1987 Aug;69(2):323–331. [PMC free article] [PubMed] [Google Scholar]
  9. Del Prete G., De Carli M., Almerigogna F., Daniel C. K., D'Elios M. M., Zancuoghi G., Vinante F., Pizzolo G., Romagnani S. Preferential expression of CD30 by human CD4+ T cells producing Th2-type cytokines. FASEB J. 1995 Jan;9(1):81–86. [PubMed] [Google Scholar]
  10. Duchmann R., Schmitt E., Knolle P., Meyer zum Büschenfelde K. H., Neurath M. Tolerance towards resident intestinal flora in mice is abrogated in experimental colitis and restored by treatment with interleukin-10 or antibodies to interleukin-12. Eur J Immunol. 1996 Apr;26(4):934–938. doi: 10.1002/eji.1830260432. [DOI] [PubMed] [Google Scholar]
  11. Fuss I. J., Neurath M., Boirivant M., Klein J. S., de la Motte C., Strong S. A., Fiocchi C., Strober W. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996 Aug 1;157(3):1261–1270. [PubMed] [Google Scholar]
  12. Gross V., Andus T., Caesar I., Roth M., Schölmerich J. Evidence for continuous stimulation of interleukin-6 production in Crohn's disease. Gastroenterology. 1992 Feb;102(2):514–519. doi: 10.1016/0016-5085(92)90098-j. [DOI] [PubMed] [Google Scholar]
  13. Gulwani-Akolkar B., Akolkar P. N., Minassian A., Pergolizzi R., McKinley M., Mullin G., Fisher S., Silver J. Selective expansion of specific T cell receptors in the inflamed colon of Crohn's disease. J Clin Invest. 1996 Sep 15;98(6):1344–1354. doi: 10.1172/JCI118921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kirsner J. B., Shorter R. G. Recent developments in nonspecific inflammatory bowel disease (second of two parts). N Engl J Med. 1982 Apr 8;306(14):837–848. doi: 10.1056/NEJM198204083061404. [DOI] [PubMed] [Google Scholar]
  15. Kühn R., Löhler J., Rennick D., Rajewsky K., Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
  16. Ma X., Chow J. M., Gri G., Carra G., Gerosa F., Wolf S. F., Dzialo R., Trinchieri G. The interleukin 12 p40 gene promoter is primed by interferon gamma in monocytic cells. J Exp Med. 1996 Jan 1;183(1):147–157. doi: 10.1084/jem.183.1.147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Maggi E., Biswas P., Del Prete G., Parronchi P., Macchia D., Simonelli C., Emmi L., De Carli M., Tiri A., Ricci M. Accumulation of Th-2-like helper T cells in the conjunctiva of patients with vernal conjunctivitis. J Immunol. 1991 Feb 15;146(4):1169–1174. [PubMed] [Google Scholar]
  18. Maggi E., Giudizi M. G., Biagiotti R., Annunziato F., Manetti R., Piccinni M. P., Parronchi P., Sampognaro S., Giannarini L., Zuccati G. Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in human immunodeficiency virus type 1 infection. J Exp Med. 1994 Aug 1;180(2):489–495. doi: 10.1084/jem.180.2.489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Maggi E., Parronchi P., Manetti R., Simonelli C., Piccinni M. P., Rugiu F. S., De Carli M., Ricci M., Romagnani S. Reciprocal regulatory effects of IFN-gamma and IL-4 on the in vitro development of human Th1 and Th2 clones. J Immunol. 1992 Apr 1;148(7):2142–2147. [PubMed] [Google Scholar]
  20. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mazlam M. Z., Hodgson H. J. Interrelations between interleukin-6, interleukin-1 beta, plasma C-reactive protein values, and in vitro C-reactive protein generation in patients with inflammatory bowel disease. Gut. 1994 Jan;35(1):77–83. doi: 10.1136/gut.35.1.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Meuwissen S. G., Feltkamp-Vroom T. M., De La Rivière A. B., Von Dem Borne A. E., Tytgat G. N. Analysis of the lympho-plasmacytic infiltrate in Crohn's disease with special reference to identification of lymphocyte-subpopulations. Gut. 1976 Oct;17(10):770–780. doi: 10.1136/gut.17.10.770. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mitsuyama K., Toyonaga A., Sasaki E., Watanabe K., Tateishi H., Nishiyama T., Saiki T., Ikeda H., Tsuruta O., Tanikawa K. IL-8 as an important chemoattractant for neutrophils in ulcerative colitis and Crohn's disease. Clin Exp Immunol. 1994 Jun;96(3):432–436. doi: 10.1111/j.1365-2249.1994.tb06047.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  25. Mueller C., Knoflach P., Zielinski C. C. T-cell activation in Crohn's disease. Increased levels of soluble interleukin-2 receptor in serum and in supernatants of stimulated peripheral blood mononuclear cells. Gastroenterology. 1990 Mar;98(3):639–646. [PubMed] [Google Scholar]
  26. Mullin G. E., Lazenby A. J., Harris M. L., Bayless T. M., James S. P. Increased interleukin-2 messenger RNA in the intestinal mucosal lesions of Crohn's disease but not ulcerative colitis. Gastroenterology. 1992 May;102(5):1620–1627. doi: 10.1016/0016-5085(92)91722-g. [DOI] [PubMed] [Google Scholar]
  27. Neurath M. F., Fuss I., Kelsall B. L., Stüber E., Strober W. Antibodies to interleukin 12 abrogate established experimental colitis in mice. J Exp Med. 1995 Nov 1;182(5):1281–1290. doi: 10.1084/jem.182.5.1281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Niessner M., Volk B. A. Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reversed transcribed polymerase chain reaction (RT-PCR). Clin Exp Immunol. 1995 Sep;101(3):428–435. doi: 10.1111/j.1365-2249.1995.tb03130.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Parronchi P., Macchia D., Piccinni M. P., Biswas P., Simonelli C., Maggi E., Ricci M., Ansari A. A., Romagnani S. Allergen- and bacterial antigen-specific T-cell clones established from atopic donors show a different profile of cytokine production. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4538–4542. doi: 10.1073/pnas.88.10.4538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Powrie F., Correa-Oliveira R., Mauze S., Coffman R. L. Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity. J Exp Med. 1994 Feb 1;179(2):589–600. doi: 10.1084/jem.179.2.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Powrie F. T cells in inflammatory bowel disease: protective and pathogenic roles. Immunity. 1995 Aug;3(2):171–174. doi: 10.1016/1074-7613(95)90086-1. [DOI] [PubMed] [Google Scholar]
  32. Pupilli C., Gomez R. A., Tuttle J. B., Peach M. J., Carey R. M. Spatial association of renin-containing cells and nerve fibers in developing rat kidney. Pediatr Nephrol. 1991 Nov;5(6):690–695. doi: 10.1007/BF00857873. [DOI] [PubMed] [Google Scholar]
  33. Raab Y., Hällgren R., Gerdin B. Enhanced intestinal synthesis of interleukin-6 is related to the disease severity and activity in ulcerative colitis. Digestion. 1994;55(1):44–49. doi: 10.1159/000201122. [DOI] [PubMed] [Google Scholar]
  34. Romagnani S. Lymphokine production by human T cells in disease states. Annu Rev Immunol. 1994;12:227–257. doi: 10.1146/annurev.iy.12.040194.001303. [DOI] [PubMed] [Google Scholar]
  35. Sad S., Marcotte R., Mosmann T. R. Cytokine-induced differentiation of precursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. Immunity. 1995 Mar;2(3):271–279. doi: 10.1016/1074-7613(95)90051-9. [DOI] [PubMed] [Google Scholar]
  36. Strickland R. G., Husby G., Black W. C., Williams R. C., Jr Peripheral blood and intestinal lymphocyte sub-populations in Crohn's disease. Gut. 1975 Nov;16(11):847–853. doi: 10.1136/gut.16.11.847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. de Carli M., D'Elios M. M., Mariotti S., Marcocci C., Pinchera A., Ricci M., Romagnani S., del Prete G. Cytolytic T cells with Th1-like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves' ophthalmopathy. J Clin Endocrinol Metab. 1993 Nov;77(5):1120–1124. doi: 10.1210/jcem.77.5.8077301. [DOI] [PubMed] [Google Scholar]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

RESOURCES