Digestive Diseases and Sciences

, Volume 55, Issue 7, pp 1886–1895

Adsorptive Depletion of α4 Integrinhi- and CX3CR1hi-Expressing Proinflammatory Monocytes in Patients with Ulcerative Colitis

  • Shin-ichiro Takeda
  • Toru Sato
  • Tatsuro Katsuno
  • Tomoo Nakagawa
  • Yoshiko Noguchi
  • Osamu Yokosuka
  • Yasushi Saito
Original Article

Abstract

Background

Two main functionally distinct monocytes phenotypes are known: the CD14hiCD16 “classical” and the CD14+CD16+ “proinflammatory” phenotypes. The latter phenotype is elevated in patients with ulcerative colitis (UC) and is suspected to have a major role in the immunopathogenesis of UC.

Aim

To selectively deplete circulating proinflammatory CD14+CD16+ monocyte phenotype.

Methods

Seven corticosteroid-naïve patients with UC (clinical activity index = 8.7 ± 1.3) and seven healthy subjects were included. In patients with UC, granulocyte/monocyte adsorption (GMA) was done with an Adacolumn that selectively adsorbs leucocytes of the myeloid lineage. Blood from all subjects at baseline and from the patients immediately after the first GMA session was processed. Isolated monocytes were subjected to fluorescence-activated cell sorter analyses.

Results

The seven UC patients achieved remission (CAI ≤4) after 5–10 GMA sessions. GMA induced a strong fall in the ratio (%) of CD14+CD16+ to CD14hiCD16 monocytes, from 10.0 ± 1.4 to 3.0 ± 0.9. Further, expressions of α4 integrin (374.8 ± 26.1 mean fluorescence intensity, MFI) and CX3CR1 (49.5 ± 4.6 MFI) were significantly high on CD14+CD16+monocytes as compared with on CD14hiCD16 monocytes (169.2 ± 17.2 and 33.2 ± 3.6 MFI, respectively). Additionally, GMA significantly increased the ratio of the CD14hiCD16CCR2low “immature” monocytes from 3.74 ± 0.62 to 8.11 ± 0.56 MFI.

Conclusions

We found high expressions of α4 integrin and CX3CR1 on monocytes in patients with active UC, known to promote the extravasation of CD14+CD16+ monocytes into the mucosa. GMA effectively depletes CD14+CD16+ monocytes and concomitantly increases CD14hiCD16CCR2low “immature” monocytes; thus GMA was associated with the emergence of less inflammatory monocyte phenotype in circulation.

Keywords

Ulcerative colitis CD14+CD16+ monocytes CD14hiCD16CCR2low monocytes α4 Integrin CX3CR1 Adsorptive depletion of myeloid leucocytes 

References

  1. 1.
    Allison MC, Dhillon AP, Lewis WG, Pounder RE, eds. Inflammatory Bowel Disease. London: Mosby; 1998:15–95.Google Scholar
  2. 2.
    Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627–1640.CrossRefPubMedGoogle Scholar
  3. 3.
    Baumgart DC, Sandborn WJ. Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet. 2007;369:1641–1657.CrossRefPubMedGoogle Scholar
  4. 4.
    Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–434.CrossRefPubMedGoogle Scholar
  5. 5.
    Strober W, Fuss I, Mannon P. The fundamental basis of inflammatory bowel disease. J Clin Invest. 2007;117:514–521.CrossRefPubMedGoogle Scholar
  6. 6.
    Shih DQ, Targan SR. Immunopathogenesis of inflammatory bowel disease. World J Gastroenterol. 2008;14:390–400.CrossRefPubMedGoogle Scholar
  7. 7.
    Shimoyama T, Sawada K, Hiwatashi N, et al. Safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active ulcerative colitis: a multicenter study. J Clin Apher. 2001;16:1–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Yamamoto T, Umegae S, Kitagawa T, et al. Granulocyte and monocyte adsorptive apheresis in the treatment of active distal ulcerative colitis: a prospective, pilot study. Aliment Pharmacol Ther. 2004;20:783–792.CrossRefPubMedGoogle Scholar
  9. 9.
    Domenech E, Hinojosa J, Esteve-Comas M, et al. Granulocyteaphaeresis in steroid-dependent inflammatory bowel disease: a prospective, open, pilot study. Aliment Pharmacol Ther. 2004;20:1347–1352.CrossRefPubMedGoogle Scholar
  10. 10.
    Suzuki Y, Yoshimura N, Saniabadi AR, Saito Y. Selective granulocyte and monocyte adsorptive apheresis as a first-line treatment for steroid naive patients with active ulcerative colitis: a prospective uncontrolled study. Dig Dis Sci. 2004;49:565–571.CrossRefPubMedGoogle Scholar
  11. 11.
    Hanai H, Takeuchi K, Iida T, et al. Relationship between fecal calprotectin, intestinal inflammation, and peripheral blood neutrophils in patients with active ulcerative colitis. Dig Dis Sci. 2004;49:1438–1443.CrossRefPubMedGoogle Scholar
  12. 12.
    Kanke K, Nakano M, Hiraishi H, Terano A. Clinical evaluation of granulocyte/monocyte apheresis therapy for active ulcerative colitis. Dig Liver Dis. 2004;36:811–817.CrossRefPubMedGoogle Scholar
  13. 13.
    Naganuma M, Funakoshi S, Sakuraba A, et al. Granulocytapheresis is useful as an alternative therapy in patients with steroid-refractory or -dependent ulcerative colitis. Inflamm Bowel Dis. 2004;10:251–257.CrossRefPubMedGoogle Scholar
  14. 14.
    Andoh A, Tsujikawa T, Inatomi O, et al. Suppression of inflammatory cytokine secretion by granulocyte/monocyte adsorptive apheresis in active ulcerative colitis. Ther Apher Dial. 2005;9:123–127.CrossRefPubMedGoogle Scholar
  15. 15.
    Cuadrado E, Alonso M, de Juan M, Echaniz P, Arenas J. Regulatory T cells in patients with inflammatory bowel diseases treated with adacolumn granulocytapheresis. World J Gastroenterol. 2008;14:1521–1527.CrossRefPubMedGoogle Scholar
  16. 16.
    Takeda Y, Shiobara N, Saniabadi AR, Adachi M, Hiraishi K. Adhesion dependent release of hepatocyte growth factor and interleukin-1 receptor antagonist from human blood granulocytes and monocytes: evidence for the involvement of plasma IgG, complement C3 and beta2 integrin. Inflamm Res. 2004;53:277–283.CrossRefPubMedGoogle Scholar
  17. 17.
    Waitz G, Petermann S, Liebe S, Emmrich J, Ramlow W. Reduction of dendritic cells by granulocyte and monocyte adsorption apheresis in patients with ulcerative colitis. Dig Dis Sci. 2008;53:2507–2515.CrossRefPubMedGoogle Scholar
  18. 18.
    Takeda H, Suzuki Y, Takeda Y, et al. A multi center study of granulocyte and monocyte adsorption apheresis therapy for ulcerative colitis—clinical efficacy and production of interleukin-1 receptor antagonist. J Clin Apher. 2008;23:105–110.CrossRefPubMedGoogle Scholar
  19. 19.
    Sakimura K, Omori T, Iwashita E, et al. Clinical response is associated with elevated plasma interleukin-1 receptor antagonist during selective granulocyte and monocyte apheresis in patients with ulcerative colitis. Dig Dis Sci. 2006;51:1525–1531.CrossRefPubMedGoogle Scholar
  20. 20.
    Hanai H, Watanabe F, Yamada M, et al. Correlation of serum soluble TNF-alpha receptors I and II levels with disease activity in patients with ulcerative colitis. Am J Gastroenterol. 2004;99:1532–1538.CrossRefPubMedGoogle Scholar
  21. 21.
    Hanai H, Iida T, Yamada M, et al. Effects of adacolumn selective leukocytapheresis on plasma cytokines during active disease in patients with active ulcerative colitis. World J Gastroenterol. 2006;12:3393–3399.PubMedGoogle Scholar
  22. 22.
    Kashiwagi N, Sugimura K, Koiwai H, et al. Immunomodulatory effects of granulocyte and monocyte adsorption apheresis as a treatment for patients with ulcerative colitis. Dig Dis Sci. 2002;47:1334–1341.CrossRefPubMedGoogle Scholar
  23. 23.
    Aoki H, Nakamura K, Yoshimatsu Y, et al. Adacolumn selective leukocyte adsorption apheresis in patients with active ulcerative colitis: clinical efficacy, effects on plasma IL-8, and expression of Toll-like receptor 2 on granulocytes. Dig Dis Sci. 2007;52:1427–1433.CrossRefPubMedGoogle Scholar
  24. 24.
    Yokoyama Y, Fukunaga K, Fukuda Y, et al. Demonstration of low-regulatory CD25High+CD4+ and high-pro-inflammatory CD28CD4+ T-Cell subsets in patients with ulcerative colitis: modified by selective granulocyte and monocyte adsorption apheresis. Dig Dis Sci. 2007;52:2725–2731.CrossRefPubMedGoogle Scholar
  25. 25.
    Passlick B, Flieger D, Ziegler-Heitbrock HW. Identification and characterization of a novel monocyte subpopulation in human peripheral blood. Blood. 1989;74:2527–2534.PubMedGoogle Scholar
  26. 26.
    Belge KU, Dayyani F, Horelt A, et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol. 2002;168:3536–3542.PubMedGoogle Scholar
  27. 27.
    Ziegler-Heitbrock L. The CD14+CD16+ blood monocytes: their role in infection and inflammation. J Leukoc Biol. 2007;81:584–592.CrossRefPubMedGoogle Scholar
  28. 28.
    Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71–82.CrossRefPubMedGoogle Scholar
  29. 29.
    Strauss-Ayali D, Conrad SM, Mosser DM. Monocyte subpopulations and their differentiation patterns during infection. J Leukoc Biol. 2007;82:244–252.CrossRefPubMedGoogle Scholar
  30. 30.
    Gordon S, Taylor P. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–964.CrossRefPubMedGoogle Scholar
  31. 31.
    Hanai H, Iida T, Takeuchi K, et al. Adsorptive depletion of elevated proinflammatory CD14+CD16+DR++ monocytes in patients with inflammatory bowel disease. Am J Gastroenterol. 2008;103:1210–1216.CrossRefPubMedGoogle Scholar
  32. 32.
    Lichtiger S, Present DH, Kornbluth A, et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med. 1994;330:1841–1845.CrossRefPubMedGoogle Scholar
  33. 33.
    Tsou CL, Peters W, Si Y, et al. Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest. 2007;117:902–909.CrossRefPubMedGoogle Scholar
  34. 34.
    Serbina NV, Pamer EG. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nat Immunol. 2006;7:311–317.CrossRefPubMedGoogle Scholar
  35. 35.
    Saniabadi AR, Hanai H, Takeuchi K, et al. Adacolumn, an adsorptive carrier based granulocyte and monocyte apheresis device for the treatment of inflammatory and refractory diseases associated with leukocytes. Ther Apher Dial. 2003;7:48–59.CrossRefPubMedGoogle Scholar
  36. 36.
    Saniabadi AR, Hanai H, Suzuki Y, et al. Adacolumn for selective leukocytapheresis as a non-pharmacological treatment for patients with disorders of the immune system: an adjunct or an alternative to drug therapy? J Clin Apher. 2005;20:171–184.CrossRefPubMedGoogle Scholar
  37. 37.
    Saniabadi AR, Hanai H, Fukunaga K, et al. Therapeutic leukocytapheresis for inflammatory bowel disease. Transfus Apher Sci. 2007;37:191–200.CrossRefPubMedGoogle Scholar
  38. 38.
    Grage-Griebenow E, Zawatzky R, Kahlert H, Brade L, Flad H, Ernst M. Identification of a novel dendritic cell-like subset of CD64+/CD16+ blood monocytes. Eur J Immunol. 2001;31:48–56.CrossRefPubMedGoogle Scholar
  39. 39.
    Grage-Griebenow E, Flad HD, Ernst M, Bzowska M, Skrzeczynska J, Pryjma J. Human MO subsets as defined by expression of CD64 and CD16 differ in phagocytic activity and generation of oxygen intermediates. Immunobiology. 2000;202:42–50.PubMedGoogle Scholar
  40. 40.
    Serbina NV, Jia T, Hohl TM, Pamer EG. Monocyte-mediated defense against microbial pathogens. Annu Rev Immunol. 2008;26:421–452.CrossRefPubMedGoogle Scholar
  41. 41.
    Ancuta P, Rao R, Moses A, et al. Fractalkine preferentially mediates arrest and migration of CD16+ monocytes. J Exp Med. 2003;197:1701–1707.CrossRefPubMedGoogle Scholar
  42. 42.
    Stievano L, Piovan E, Amadori A. C and CX3C chemokines: cell sources and physiopathological implications. Crit Rev Immunol. 2004;24:205–228.CrossRefPubMedGoogle Scholar
  43. 43.
    Sans M, Danese S, de la Motte C, et al. Enhanced recruitment of CX3CR1+ T cells by mucosal endothelial cell-derived fractalkine in inflammatory bowel disease. Gastroenterology. 2007;132:139–153.CrossRefPubMedGoogle Scholar
  44. 44.
    Podolsky D, Lobb R, King N, et al. Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonal antibody. J Clin Invest. 1993;92:372–380.CrossRefPubMedGoogle Scholar
  45. 45.
    Hanai H, Watanabe F, Yamada M, et al. Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis. Digestion. 2004;70:36–44.CrossRefPubMedGoogle Scholar
  46. 46.
    Giampaolo B, Giuseppe P, Michele B, Alessandro M, Fabrizio S, Alfonso C. Treatment of active steroid-refractory inflammatory bowel diseases with granulocytapheresis: our experience with a prospective study. World J Gastroenterol. 2006;12:2201–2204.PubMedGoogle Scholar
  47. 47.
    Kruis W, Dignass A, Steinhagen-Thiessen E, et al. Open label trial of granulocyte apheresis suggests therapeutic efficacy in chronically active steroid refractory ulcerative colitis. World J Gastroenterol. 2005;11:7001–7006.PubMedGoogle Scholar
  48. 48.
    Bresci G, Parisi G, Mazzoni A, Scatena F, Capria A. Treatment of patients with acute ulcerative colitis: conventional corticosteroid therapy (MP) versus granulocytapheresis (GMA): a pilot study. Dig Liver Dis. 2007;39:430–434.CrossRefPubMedGoogle Scholar
  49. 49.
    Muratov V, Lundahl J, Ulfgren AK, et al. Down-regulation of interferon-gamma parallels clinical response to selective leukocyte apheresis in patients with inflammatory bowel disease: a 12 month follow-up study. Int J Colorectal Dis. 2006;21:493–504.CrossRefPubMedGoogle Scholar
  50. 50.
    Maiden L, Takeuchi K, Baur R, et al. Selective white cell apheresis reduces relapse rates in patients with IBD at significant risk of clinical relapse. Inflamm Bowel Dis. 2008;14:1413–1418.CrossRefPubMedGoogle Scholar
  51. 51.
    Cohen RD. Treating ulcerative colitis without medications—”look mom, no drugs!”. Gastroenterology. 2005;128:235–236.CrossRefPubMedGoogle Scholar
  52. 52.
    Schwartz D, Ferguson JR. Current pharmacologic treatment paradigms for inflammatory bowel disease and the potential role of granulocyte/monocyte apheresis. Curr Med Res Opin. 2007;23:2715–2728.CrossRefPubMedGoogle Scholar
  53. 53.
    Abreu MT, Plevy S, Sands BE, Weinstein R. Selective leukocyte apheresis for the treatment of inflammatory bowel disease. J Clin Gastroenterol. 2007;41:874–888.CrossRefPubMedGoogle Scholar
  54. 54.
    Sands BE, Sandborn WJ, Feagan B, et al. A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Gastroenterology. 2008;135:400–409.CrossRefPubMedGoogle Scholar
  55. 55.
    Suzuki Y, Yoshimura N, Fukuda K, Shirai K, Saito Y, Saniabadi AR. A retrospective search for predictors of clinical response to selective granulocyte and monocyte apheresis in patients with ulcerative colitis. Dig Dis Sci. 2006;51:2031–2038.CrossRefPubMedGoogle Scholar
  56. 56.
    Hanai H, Watanabe F, Takeuchi K, et al. Leukocyte adsorptive apheresis for the treatment of active ulcerative colitis: a prospective, uncontrolled, pilot study. Clin Gastroenterol Hepatol. 2003;1:28–35.CrossRefPubMedGoogle Scholar
  57. 57.
    Tanaka T, Okanobu H, Yoshimi S, et al. In patients with ulcerative colitis, adsorptive depletion of granulocytes and monocytes impacts mucosal level of neutrophils and clinically is most effective in steroid naive patients. Dig Liver Dis. 2008;40:731–736.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Shin-ichiro Takeda
    • 1
  • Toru Sato
    • 1
  • Tatsuro Katsuno
    • 1
  • Tomoo Nakagawa
    • 1
  • Yoshiko Noguchi
    • 1
  • Osamu Yokosuka
    • 2
  • Yasushi Saito
    • 1
  1. 1.Department of Clinical Cell Biology (F5), Graduate School of MedicineChiba UniversityChiba-shiJapan
  2. 2.Department of Medicine and Clinical Oncology (K1), Graduate School of MedicineChiba UniversityChiba-shiJapan

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