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Distinctive Pattern of Cytokine Production and Adhesion Molecule Expression in Peripheral Blood Memory CD4+ T Cells from Patients with Active Crohn’s Disease

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An expansion of both circulating and intestinal lamina propria CD4+CD45RO+ T cells has been described in patients with Crohn’s disease. We studied both the cytokine profile and the expression of adhesion molecules on this T-cell subset. Peripheral blood CD4+CD45RO+ T cells from patients with Crohn’s disease (n=45) were assessed by flow cytometry and RT-PCR methods. The cytokine profile was also measured in intestinal lamina propria from seven patients. They were classified according to the CDAI and the results were compared with those of patients with ulcerative colitis (n=21) and noninflammatory intestinal conditions (n=15), and healthy controls (n=39). The mean percentage of circulating CD4+CD45RO+ T cells producing intracellular TNF was higher in active than in inactive Crohn’s disease patients (p < 0.001), active (p = 0.49) and inactive ulcerative colitis (p = 0.019), and healthy controls (p =0. 017). TNF expression correlated with CDAI (p < 0.001). An increased expression of intracellular IL-2, IL-6, and IL-10 in active Crohn’s disease patients was also found. CD62L was downregulated in active Crohn’s disease patients while no differences were observed in CD49d and CD11a expression. Lamina propria CD4+CD45RO+ T cells from active Crohn’s disease lesions showed an increased intracellular staining of TNF, IFN-γ, and IL-10. Both peripheral and intestinal mucosa CD4+CD45RO+ T cells from active Crohn’s disease patients show an increased production of TNF. In addition, the circulating CD4+CD45RO+ T-cell subset expresses a pattern of adhesion molecules that promotes homing to extranodal lymphoid tissues. This T-cell subset may play a relevant role in the immunopathogenesis of Crohn’s disease.

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Abbreviations

5-AS:

5-aminosalicylate

APC:

allophycocyanine

CD:

Crohn’s disease

CDAI:

Crohn’s Disease Activity Index

FITC:

fluorescein isothiocyanate

IBD:

inflammatory bowel disease

MACS:

magnetic cell separation system

PBMC:

peripheral blood mononuclear cells

PE:

phycoerythrin

PMA:

phorbol myristate acetate

SEM:

standard error of the mean

Th:

T helper

UC:

ulcerative colitis.

REFERENCES

  1. Fiocchi C: Inflammatory bowel disease: Etiology and pathogenesis. Gastroenterology 115:182–205, 1998

    Article  PubMed  CAS  Google Scholar 

  2. Elson CO: The immunology of inflammatory bowel disease. In Inflammatory Bowel Disease, Kirsner JB (ed). New York, Raven, 2000, pp 208–239

    Google Scholar 

  3. Podolsky DK: Inflammatory bowel disease. N Engl J Med 347:417–429, 2002

    Article  PubMed  CAS  Google Scholar 

  4. Papadakis KA, Targan RS: Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 51:289–298, 2000

    Article  PubMed  CAS  Google Scholar 

  5. Sprent J, Surh CD: T cell memory. Annu Rev Immunol 20:551–579, 2002

    Article  PubMed  CAS  Google Scholar 

  6. Ley K, Kansas GS: Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation. Nat Rev Immunol 4:325–335, 2004

    Article  PubMed  CAS  Google Scholar 

  7. Pribila JT, Quale AC, Mueller KL, Shimizu Y: Integrins and T cell mediated immunity. Annu Rev Immunol 22:157–180, 2004

    Article  PubMed  CAS  Google Scholar 

  8. Roman LI, Manzano L, De La Hera A, Abreu L, Rossi I, Alvarez-Mon M: Expanded CD4+CD45RO+ phenotype and defective proliferative response in T lymphocytes from patients with Crohn’s disease. Gastroenterology110:1008–1019, 1996

    Article  PubMed  CAS  Google Scholar 

  9. Mariani P, Bachetoni A, D’Alessandro M, Lomanto D, Mazzocchi P, Speranza V: Effector Th-1 cells with cytotoxic function in the intestinal lamina propria of patients with Crohn’s disease. Dig Dis Sci 45:2029–2035, 2000

    Article  PubMed  CAS  Google Scholar 

  10. Garcia de Tena J, Manzano L, Leal JC, Antonio ES, Sualdea V, Alvarez-Mon A: Active Crohn’s disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells. J Clin Immunol 24:185–196, 2004

    Article  PubMed  CAS  Google Scholar 

  11. Lennard-Jones JE: Classification of inflammatory bowel disease. Scand J Gastroenterol 170(24 Suppl):2–6, 1989

    Article  CAS  Google Scholar 

  12. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study. Gastroenterology 70:439–444, 1976

    PubMed  CAS  Google Scholar 

  13. Truelove SC, Witts LJ: Cortisone in ulcerative colitis: Final report on a therapeutic trial. BMJ 2:1041–1048, 1955

    Article  CAS  PubMed  Google Scholar 

  14. Garcia-Suarez J, Prieto A, Reyes E, Manzano L, Merino JL, Alvarez-Mon M: Severe chronic autoimmune thrombocytopenic purpura is associated with an expansion of CD56+ CD3- natural killer cells subset. Blood 82:1538–1545, 1993

    PubMed  CAS  Google Scholar 

  15. Prieto A, Reyes E, Garcia-Suarez J, Carrion F, Hernandez MP, Chafer J, Alvarez-Mon M: A low blood lymphocyte count is associated with an expansion of activated cytotoxic T lymphocytes in patients with B cell chronic lymphocytic leukemia. Eur J Haematol 59:89–99, 1997

    Google Scholar 

  16. Prieto A, Reyes E, Diaz D, Hernandez-Fuentes MP, Monserrat J, Perucha E, Muñoz L, Vangioni R, de La Hera A, Orfao A, Alvarez-Mon M: A new method for the simultaneous analysis of growth and death of immunophenotypically defined cells in culture. Cytometry 39:56–66, 2000

    Article  PubMed  CAS  Google Scholar 

  17. Papadakis KA, Targan SR: Tumor necrosis factor: Biology and therapeutic inhibitors. Gastroenterology 119:1148–1157, 2000

    Article  PubMed  CAS  Google Scholar 

  18. Reinecker HC, Steffen M, Witthoeft T, Pflueger I, Schreiber S, MacDermott RP, Raedler A: Enhanced secretion of tumour necrosis factor-alpha, IL-6, and IL-1 beta by isolated lamina propria mononuclear cells from patients with ulcerative colitis and Crohn’s disease. Clin Exp Immunol 94:174–81, 1993

    Article  PubMed  CAS  Google Scholar 

  19. Breese EJ, Michie CA, Nicholls SW, Murch SH, Williams CB, Domizio P, Walker-Smith JA, MacDonald TT: Tumor necrosis factor alpha-producing cells in the intestinal mucosa of children with inflammatory bowel disease. Gastroenterology 106:1455–1466, 1994

    PubMed  CAS  Google Scholar 

  20. Braegger CP, Nicholls S, Murch SH, Stephens S, MacDonald TT: Tumour necrosis factor alpha in stool as a marker of intestinal inflammation. Lancet 339:89–91, 1992

    Article  PubMed  CAS  Google Scholar 

  21. Lilja I, Gustafson-Svard C, Franzen L, Sjodhal R: Tumor necrosis factor-alpha in ileal mast cells in patients with Crohn’s disease. Digestion 61:68–76, 2000

    Article  PubMed  CAS  Google Scholar 

  22. Bouma G, Oudkerk Pool M, Scharenberg JG, Kolkman JJ, von Blomberg BM, Scheper RJ, Meuwissen SG, Pena AS: Differences in the intrinsic capacity of peripheral blood mononuclear cells to produce tumor necrosis factor alpha and beta in patients with inflammatory bowel disease and healthy controls. Scand J Gastroenterol 30:1095–1100, 1995

    Article  PubMed  CAS  Google Scholar 

  23. Niederau C, Backmerhoff F, Schumacher B, Niederau C: Inflammatory mediators and acute phase proteins in patients with Crohn’s disease and ulcerative colitis. Hepatogastroenterology 44:90–107, 1997

    PubMed  CAS  Google Scholar 

  24. Kucharzik T, Lugering N, Weigelt H, Adolf M, Domschke W, Stoll R: Immunoregulatory properties of IL-13 in patients with inflammatory bowel disease; Comparison with IL-4 and IL-10. Clin Exp Immunol 104:483–490, 1996

    Article  PubMed  CAS  Google Scholar 

  25. Cappello M, Keshav S, Prince C, Jewell DP, Gordon S: Detection of mRNAs for macrophage products in inflammatory bowel disease by in situ hybridisation. Gut 33:1214–1219, 1992

    Article  PubMed  CAS  Google Scholar 

  26. Ito H, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A, Matsumoto T, Yamamura T, Azuma J, Nishimoto N, Yoshizaki K, Shimoyama T, Kishimoto T: A pilot randomized of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn’s disease. Gastroenterology 126:989–996, 2004

    Article  PubMed  CAS  Google Scholar 

  27. Fais S, Capobianchi MR, Pallone F, Di Marco P, Boirivant M, Dianzani F, Torsoli A: Spontaneous release of interferon γ by intestinal lamina propria lymphocytes in Crohn’s disease. Kinetics of in vitro response to interferon γ inducers. Gut 32:403–407, 1991

    Article  PubMed  CAS  Google Scholar 

  28. Breese E, Braegger CP, Corrigan CJ, Walker-Smith JA, MacDonald TT: Interleukin-2- and interferon-γ-secreting T cells in normal and diseased human intestinal mucosa. Immunology 78:127–131, 1993

    PubMed  CAS  Google Scholar 

  29. Parronchi P, Romagnani P, Annunziato F, Sampognaro S, Becchio A, Giannarini L: Type 1 T-helper cell predominance and interleukin-12 expression in the gut of patients with Crohn’s disease. Am J Pathol 150:823–832, 1997

    PubMed  CAS  Google Scholar 

  30. Nakamura M, Saito H, Kasanuki J, Tamura Y, Yoshida S: Cytokine production in patients with inflammatory bowel disease. Gut 33:933–937, 1992

    Article  PubMed  CAS  Google Scholar 

  31. Elsasser-Beile U, von Kleist S, Gerlach S, Gallati H, Monting JS: Cytokine production in whole blood cell cultures of patients with Crohn’s disease and ulcerative colitis. J Clin Lab Anal 8:447–451, 1994

    Article  PubMed  CAS  Google Scholar 

  32. Mutchnick MG, Lee HH, Hollander DI, Haynes GD, Chua DC: Defective in vitro gamma interferon production and elevated serum immunoreactive thymosin beta 4 levels in patients with inflammatory bowel disease. Clin Immunol Immunopathol 47:84–92, 1988

    Article  PubMed  CAS  Google Scholar 

  33. Cohavy O, Zhou J, Granger SW, Ware CF, Targan SR: LIGHT expression by mucosal T cells may regulate IFN-gamma expression in the intestine. J Immunol 173:251–258, 2004

    PubMed  CAS  Google Scholar 

  34. Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM: The dual role of IL-10. Trends Immunol 24:36–43, 2003

    Article  PubMed  CAS  Google Scholar 

  35. Tilg H, van Montfrans C, van den Ende A, Kaser A, van Deventer SJ, Schreiber S, Gregor M, Ludwiczek O, Rutgeerts P, Gasche C, Koningsberger JC, Abreu L, Kuhn I, Cohard M, LeBeaut A, Grint P, Weiss G: Treatment of Crohn’s disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon gamma. Gut 50:191–195, 2002

    Article  PubMed  CAS  Google Scholar 

  36. Garcia de Tena J, Espinosa LM, Alvarez-Mon M: N Engl J Med 347:1982–1984, 2002

    Article  PubMed  Google Scholar 

  37. Cominelli F: Cytokine-based therapies for Crohn’s disease. N Engl J Med 351:2045–2048, 2004

    Article  PubMed  CAS  Google Scholar 

  38. Ghosh S, Goldin E, Gordon FH, Malchow HA, Rask-Madsen J, Rutgeerts P, Vyhnalek P, Zadorova Z, Palmer T, Donoghue S: Natalizumab for active Crohn’s disease. N Engl J Med 348:24–32, 2003

    Article  PubMed  CAS  Google Scholar 

  39. Ellis CN, Krueger GG: Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 345:248–255, 2001

    Article  PubMed  CAS  Google Scholar 

  40. Kraan MC, van Kuijk AW, Dinant HJ, Goedkoop AY, Smeets TJ, de Rie MA, Dijkmans BA, Vaishnaw AK, Bos JD, Tak PP: Alefacept treatment in psoriatic arthritis: Reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum 46:2776–2784, 2002

    Article  PubMed  CAS  Google Scholar 

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ACKNOWLEDGMENTS

This work was partially supported by Red Nacional de Hígado y Gastroenterología from Instituto de Salud Carlos III (PI021801). Dr. J. García de Tena received a grant from Instituto de Salud Carlos III n° 4345/99. We are indebted to Alfredo Prieto for study design and Jorge Montserrat for skillful technical assistance.

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Authors and Affiliations

  1. Laboratorio de Inmunología Clínica y Oncología, Unidad asociada I+D del Consejo Superior de Investigaciones Científicas, Departamento de Medicina, Universidad de Alcalá, Alcalá de Henares, Spain

    Jaime García De Tena, Luis Manzano, Juan Carlos Leal, Esther San Antonio, Verónica Sualdea & Melchor Álvarez-Mon

  2. Servicio de Urgencias, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain

    Jaime García De Tena

  3. Servicio de Medicina Interna, Hospital Universitario Ramón y Cajal, Madrid, Alcalá de Henares, Spain

    Luis Manzano

  4. Servicio de Aparato Digestivo, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain

    Juan Carlos Leal

  5. Servicio de Enfermedades del Sistema Inmune y Oncología, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Spain

    Melchor Álvarez-Mon

  6. Departamento de Medicina, Universidad de Alcalá, Carretera Madrid-Barcelona, Km 33,600, 28871, Alcalá de Henares, Madrid, Spain

    Luis Manzano & Melchor Álvarez-Mon

Authors
  1. Jaime García De Tena
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  2. Luis Manzano
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  3. Juan Carlos Leal
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  4. Esther San Antonio
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  5. Verónica Sualdea
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  6. Melchor Álvarez-Mon
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Corresponding author

Correspondence to Luis Manzano.

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Dr. García de Tena and Dr. Manzano are joint first authors

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Tena, J.G.D., Manzano, L., Leal, J.C. et al. Distinctive Pattern of Cytokine Production and Adhesion Molecule Expression in Peripheral Blood Memory CD4+ T Cells from Patients with Active Crohn’s Disease. J Clin Immunol 26, 233–242 (2006). https://doi.org/10.1007/s10875-006-9016-4

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  • DOI: https://doi.org/10.1007/s10875-006-9016-4

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