Advertisement

Dipeptidylpeptidase IV (DPIV) and Alanyl-Aminopeptidases (AAPs) as a New Target Complex for Treatment of Autoimmune and Inflammatory Diseases—Proof of Concept in a Mouse Model of Colitis

  • Ute Bank
  • Janine Tadje
  • Martin Helmuth
  • Sofia Stefin
  • Michael Täger
  • Carmen Wolke
  • Anke Wischeropp
  • Annelore Ittenson
  • Dirk Reinhold
  • Siegfried Ansorge
  • Uwe Lendeckel
Part of the Advances in Experimental Medicine and Biology book series (volume 575)

4. Conclusions

In summary these results strongly support the idea that AAPs and DPIV represent a promising target complex for the pharmacological therapy of T cell-mediated diseases by preserving and enhancing endogenous immunosuppressive mechanisms. Whereas inhibitors of AAPs appear to preferentially act on CD4+CD25+ regulatory T cells by preserving their immunosuppressive activity via enhanced expression of immunosuppressive cytokines and FOXP3, inhibition of DPIV leads to increased production/release of TGF-β1 and inhibition of cellular proliferation of predominantly activated effector T cells. Thus, specific inhibition of DPIV and AAPs via small molecular compounds provides a new approach for the pharmacological treatment of autoimmune and inflammatory diseases that simultaneously interferes with two major axis of T cell function.

Keywords

Dextran Sulphate Sodium Suppressive Activity FOXP3 Expression Immunosuppressive Cytokine Target Complex 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ansorge S, Reinhold D, Lendeckel U, 2003, Propolis and some of its constituents down-regulate DNA synthesis and inflammatory cytokine production but induce TGF-beta1 production of human immune cells. Z Naturforsch. 58: 580–589.Google Scholar
  2. Baecher-Allan C, Brown JA, Freeman GJ, and Hafler DA, 2003, CD4+CD25+ regulatory cells from human peripheral blood express very high levels of CD25 ex vivo. Novartis Found Symp. 252: 67–88; discussion 88–91, 106–114.PubMedGoogle Scholar
  3. Bukowska A, Tadje J, Arndt M, Wolke C, Kähne T, Bartsch J, Faust J, Neubert K, Hashimoto Y, and Lendeckel U, 2003, Transcriptional regulation of cytosol and membrane alanyl-aminopeptidase in human T cell subsets. Biol Chem. 384: 657–665.CrossRefPubMedGoogle Scholar
  4. Hori S, Nomura T, and Sakaguchi S, 2003, Control of regulatory T cell development by the transcription factor Foxp3. Science. 299: 1057–1061.CrossRefPubMedGoogle Scholar
  5. Itoh M, Takahashi T, Sakaguchi N, Kuniyasu Y, Shimizu J, Otsuka F, Sakaguchi S, 1999, Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol. 162: 5317–5326.PubMedGoogle Scholar
  6. Kähne T, Lendeckel U, Wrenger S, Neubert K, Ansorge S, Reinhold D, 1999, Dipeptidyl peptidase IV: a cell surface peptidase involved in regulating T cell growth (review). Int J Mol Med. 4: 3–15.PubMedGoogle Scholar
  7. Khattri R, Cox T, Yasayko SA, and Ramsdell F, 2003, An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 4: 337–342.CrossRefPubMedGoogle Scholar
  8. Lendeckel U, Bukowska A, Lättig JH, and Brandt W, 2004, Alanyl-aminopeptidases in human T cells. Structures and functions. In Aminopeptidases. N.M. Hooper and U. Lendeckel, editors. Kluwer Academic/Plenum Publishers, New York, Boston, Dordrecht, London, Moscow.Google Scholar
  9. Lendeckel U, Arndt M, Frank K, Wex T, and Ansorge S, 1999, Role of alanyl aminopeptidase in growth and function of human T cells (review). Int J Mol Med. 4: 17–27.PubMedGoogle Scholar
  10. Lendeckel U, Arndt M, Bukowska A, Tadje J, Wolke C, Kähne T, Neubert K, Faust J, Ittenson A, Ansorge S, and Reinhold D, 2003, Synergistic action of DPIV and APN in the regulation of T cell function. Adv Exp Med Biol. 524: 123–131.PubMedCrossRefGoogle Scholar
  11. O’Garra A and Vieira P, 2004, Regulatory T cells and mechanisms of immune system control. Nat Med. 10: 801–805.CrossRefPubMedGoogle Scholar
  12. Sakaguchi S, 2003, The origin of FOXP3-expressing CD4+ regulatory T cells: thymus or periphery. J Clin Invest. 112: 1310–1312.CrossRefPubMedGoogle Scholar
  13. Thornton AM and Shevach EM, 1998, CD4+4CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 188: 287–296.CrossRefPubMedGoogle Scholar
  14. Walker MR, Kasprowicz DJ, Gersuk VH, Benard A, Van Landeghen M, Buckner JH, and Ziegler SF, 2003, Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25− T cells. J Clin Invest. 112: 1437–1443.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Ute Bank
    • 1
  • Janine Tadje
    • 2
  • Martin Helmuth
    • 1
  • Sofia Stefin
    • 1
  • Michael Täger
    • 1
  • Carmen Wolke
    • 2
  • Anke Wischeropp
    • 2
  • Annelore Ittenson
    • 3
  • Dirk Reinhold
    • 3
  • Siegfried Ansorge
    • 1
  • Uwe Lendeckel
    • 2
  1. 1.IMTMOtto-von-Guericke-University MagdeburgMagdeburgGermany
  2. 2.Institute of Experimental Internal MedicineOtto-von-Guericke-University MagdeburgMagdeburgGermany
  3. 3.Institute of ImmunologyOtto-von-Guericke-University MagdeburgMagdeburgGermany

Personalised recommendations