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Drug Insight: novel small molecules and drugs for immunosuppression

Nature Clinical Practice Gastroenterology & Hepatology volume 3, pages 633–644 (2006)Cite this article

Abstract

Gastrointestinal diseases can result from the inadequate or excessive response of the immune system to self or innocuous antigens. Moreover, the physiologic activation of the immune system against non-self antigens is a major clinical problem in liver organ transplantation. At present, many drugs are available that suppress the activation of the immune system, although most of the currently used immunosuppressive drugs lack specificity in terms of their molecular targets and, therefore, have the potential to generate numerous side effects. The advances that have been made in understanding the molecular events that underlie the activation of the immune system have led to the development of a new generation of 'small molecules' that are endowed with immunosuppressive properties and can serve as immunomodulatory agents. Among these new small molecules, inhibitors of Janus kinase 3, p21-Rac1 and p38 mitogen-activated protein kinase represent the most innovative approach to immunosuppression, and could be a promising alternative to current immunosuppressive therapies. Here, we report on the progress that has been made in the development of small molecules in the field of gastroenterology.

Key Points

  • Current immunosuppressive drugs have a wide range of effects, most of them undesirable

  • The discovery of intracellular pathways involved in immune system activation (e.g. JAK–STAT and p38–NFκB pathways) has provided potential new targets for immunosuppression

  • The ability to produce numerous, new, small molecules offers the possibility to obtain new specific inhibitors of key molecules involved in immune system activation

  • The discovery of new compounds that specifically target key molecules involved in immune system activation will provide new classes of immunosuppressive agents endowed with low toxicity and reduced side effects

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Figure 1: A schematic model of the mechanism of action of ciclosporin and tacrolimus.
Figure 2: The mechanism of action of JAK3 inhibitors.
Figure 3: Small GTPases (Ras-Grb, Rac, Raf, and Cdc42) activate the MAPK signaling pathways in immune cells and result in gene transcription in the nucleus.
Figure 4: Thio-GTP mediated induction of T-cell apoptosis.

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References

  1. Neurath MF et al. (2002) The role of TH1/TH2 polarization in mucosal immunity. Nat Med 8: 567–573

    Article  CAS  PubMed  Google Scholar 

  2. Hanauer SB and Present DH (2003) The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord 3: 81–92

    PubMed  Google Scholar 

  3. Hong JC and Kahan BD (2000) Immunosuppressive agents in organ transplantation: past, present, and future. Semin Nephrol 20: 108–125

    CAS  PubMed  Google Scholar 

  4. Kino T et al. (1987) FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 40: 1256–1265

    Article  CAS  Google Scholar 

  5. Tanaka H et al. (1987) Physicochemical properties of FK-506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transplant Proc 19: 11–16

    CAS  PubMed  Google Scholar 

  6. Harding MW et al. (1989) A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 341: 758–760

    Article  CAS  PubMed  Google Scholar 

  7. Shaw JP et al. (1988) Identification of a putative regulator of early T cell activation genes. Science 241: 202–205

    Article  CAS  PubMed  Google Scholar 

  8. Crabtree GR (1989) Contingent genetic regulatory events in T lymphocyte activation. Science 243: 355–361

    Article  CAS  PubMed  Google Scholar 

  9. Lichtiger S et al. (1994) Cyclosporine in severe ulcerative colitis refractory to steroid therapy. N Engl J Med 330: 1841–1845

    Article  CAS  PubMed  Google Scholar 

  10. Svanoni F et al. (1998) Effectiveness of cyclosporine A (CsA) in the treatment of active refractory ulcerative colitis (UC) [abstract]. Gastroenterology 114: A1096

    Article  Google Scholar 

  11. Van Assche G et al. (2003) Randomized, double-blind comparison of 4 mg/kg versus 2 mg/g intravenous cyclosporine in severe ulcerative colitis. Gastroenterology 125: 1025–1031

    Article  CAS  PubMed  Google Scholar 

  12. McDonald JW et al. (2005) Cyclosporine for induction of remission in Crohn's disease. The Cochrane Database of Systematic Reviews, Art. No CD000297

    Google Scholar 

  13. Hogenauer C et al. (2003) Effect of oral tacrolimus (FK 506) on steroid-refractory moderate/severe ulcerative colitis. Aliment Pharmacol Ther 18: 415–423

    Article  CAS  PubMed  Google Scholar 

  14. Baumgart DC, et al. (2003) Rescue therapy with tacrolimus is effective in patients with severe and refractory inflammatory bowel disease. Aliment Pharmacol Ther 17: 1273–1281

    Article  CAS  PubMed  Google Scholar 

  15. Lucey MR et al. (2005) A comparison of tacrolimus and cyclosporine in liver transplantation: effects on renal function and cardiovascular risk status. Am J Transplant 5: 1111–1119

    Article  CAS  PubMed  Google Scholar 

  16. Dumont FJ (2004) ISAtx-247 (Isotechnika/Roche). Curr Opin Investig Drugs 5: 542–550

    CAS  PubMed  Google Scholar 

  17. Corral LG and Kaplan G (1999) Immunomodulation by thalidomide and thalidomide analogs. Ann Rheum Dis 58 (Suppl 1): I107–I113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Corral LG et al. (1996) Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med 2: 506–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Corral LG et al. (1999) Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-α. J Immunol 163: 380–386

    CAS  PubMed  Google Scholar 

  20. Geitz H et al. (1996) Thalidomide selectively modulates the density of cell surface molecules involved in the adhesion cascade. Immunopharmacology 31: 213–221

    Article  CAS  PubMed  Google Scholar 

  21. Bauditz J et al. (2002) Thalidomide reduces tumour necrosis factor alpha and interleukin 12 production in patients with chronic active Crohn's disease. Gut 50: 196–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Abraham RT (1998) Mammalian target of rapamycin: immunosuppressive drugs uncover a novel pathway of cytokine receptor signaling. Curr Opin Immunol 10: 330–336

    Article  CAS  PubMed  Google Scholar 

  23. Calne RY et al. (1989) Rapamycin for immunosuppression in organ allografting. Lancet 2: 227

    Article  CAS  PubMed  Google Scholar 

  24. Kahan BD (1992) Cyclosporin A, FK506, rapamycin: the use of a quantitative analytic tool to discriminate immunosuppressive drug interactions. J Am Soc Nephrol 2 (Suppl): S222–S227

    CAS  PubMed  Google Scholar 

  25. Sanchez EQ et al. (2005) Sirolimus conversion after liver transplantation: improvement in measured glomerular filtration rate after 2 years. Transplant Proc 37: 4416–4423

    Article  CAS  PubMed  Google Scholar 

  26. Farkas S et al. (2006) Rapamycin decreases leukocyte migration in vivo and effectively reduces experimentally induced chronic colitis. Int J Colorectal Dis [doi:10.1007/s00384-005-0793-7]

  27. Lee SK and Surh CD (2005) Role of interleukin-7 in bone and T-cell homeostasis. Immunol Rev 208: 169–180

    Article  CAS  PubMed  Google Scholar 

  28. Sandrini S (2005) Use of IL-2 receptor antagonists to reduce delayed graft function following renal transplantation: a review. Clin Transplant 19: 705–710

    Article  PubMed  Google Scholar 

  29. Becker C et al. (2005) Stepwise regulation of TH1 responses in autoimmunity: IL-12-related cytokines and their receptors. Inflamm Bowel Dis 11: 755–764

    Article  PubMed  Google Scholar 

  30. Leonard WJ et al. (1994) Sharing of a common gamma chain, gamma c, by the IL-2, IL-4, and IL-7 receptors: implications for X-linked severe combined immunodeficiency (XSCID). Adv Exp Med Biol 365: 225–232

    Article  CAS  PubMed  Google Scholar 

  31. Asao H et al. (2001) Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex. J Immunol 167: 1–5

    Article  CAS  PubMed  Google Scholar 

  32. Leonard WJ and O'Shea JJ (1998) JAKs and STATs: biological implications. Annu Rev Immunol 16: 293–322

    Article  CAS  PubMed  Google Scholar 

  33. Cetkovic-Cvrlje M et al. (2001) Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice. Blood 98: 1607–1613

    Article  CAS  PubMed  Google Scholar 

  34. Sudbeck EA et al. (1999) Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. Clin Cancer Res 5: 1569–1582

    CAS  PubMed  Google Scholar 

  35. Uckun FM et al. (2002) Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-versus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model. Blood 99: 4192–4199

    Article  CAS  PubMed  Google Scholar 

  36. Cetkovic-Cvrlje M et al. (2003) Targeting JAK3 with JANEX-1 for prevention of autoimmune type 1 diabetes in NOD mice. Clin Immunol 106: 213–225

    Article  CAS  PubMed  Google Scholar 

  37. Linwong W et al. (2005) Inhibition of the antigen-induced activation of rodent mast cells by putative Janus kinase 3 inhibitors WHI-P131 and WHI-P154 in a Janus kinase 3-independent manner. Br J Pharmacol 145: 818–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Malavija R et al. (2001) In vivo pharmacokinetics and anti-anaphylactic activity of the novel mast cell inhibitor 4-(4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline (WHI-P131). Am J Ther 8: 35–39

    Article  CAS  PubMed  Google Scholar 

  39. Meydan N et al. (1996) Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379: 645–648

    Article  CAS  PubMed  Google Scholar 

  40. Kirken RA et al. (1999) Tyrphostin AG-490 inhibits cytokine-mediated JAK3/STAT5a/b signal transduction and cellular proliferation of antigen-activated human T cells. J Leukoc Biol 65: 891–899

    Article  CAS  PubMed  Google Scholar 

  41. Wang LH et al. (1999) JAK3, STAT, and MAPK signaling pathways as novel molecular targets for the tyrphostin AG-490 regulation of IL-2-mediated T cell response. J Immunol 162: 3897–3904

    CAS  PubMed  Google Scholar 

  42. Behbod F et al. (2001) Concomitant inhibition of Janus kinase 3 and calcineurin-dependent signaling pathways synergistically prolongs the survival of rat heart allografts. J Immunol 166: 3724–3732

    Article  CAS  PubMed  Google Scholar 

  43. Stepkowski SM et al. (2005) The Mannich base NC1153 promotes long-term allograft survival and spares the recipient from multiple toxicities. J Immunol 175: 4236–4246

    Article  CAS  PubMed  Google Scholar 

  44. Changelian PS et al. (2003) Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 302: 875–878

    Article  CAS  PubMed  Google Scholar 

  45. Borie DC et al. (2005) Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation 79: 791–801

    Article  CAS  PubMed  Google Scholar 

  46. Paniagua R et al. (2005) Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. Transplantation 80: 1283–1292

    Article  CAS  PubMed  Google Scholar 

  47. Kudlacz E et al. (2004) The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 4: 51–57

    Article  CAS  PubMed  Google Scholar 

  48. Mortellaro A et al. (1999) New immunosuppressive drug PNU156804 blocks IL-2-dependent proliferation and NF-κB and AP-1 activation. J Immunol 162: 7102–7109

    CAS  PubMed  Google Scholar 

  49. Stepkowski SM et al. (2001) PNU156804 inhibits Jak3 tyrosine kinase and rat heart allograft rejection. Transplant Proc 33: 3272–3273

    Article  CAS  PubMed  Google Scholar 

  50. Stepkowski SM et al. (2002) Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin. Blood 99: 680–689

    Article  CAS  PubMed  Google Scholar 

  51. Prajapati DN et al. (2003) Leflunomide treatment of Crohn's disease patients intolerant to standard immunomodulator therapy. J Clin Gastroenterol 37: 125–128

    Article  CAS  PubMed  Google Scholar 

  52. Siemasko K et al. (1998) Inhibition of JAK3 and STAT6 tyrosine phosphorylation by the immunosuppressive drug leflunomide leads to a block in IgG1 production. J Immunol 160: 1581–1588

    CAS  PubMed  Google Scholar 

  53. Brown GR et al. (2000) Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorg Med Chem Lett 10: 575–579

    Article  CAS  PubMed  Google Scholar 

  54. Tak PP and Firestein GS (2001) NF-κB: a key role in inflammatory diseases. J Clin Invest 107: 7–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Lee JC et al. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372: 739–746

    Article  CAS  PubMed  Google Scholar 

  56. Kyriakis JM and Avruch J (2001) Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev 81: 807–869

    Article  CAS  PubMed  Google Scholar 

  57. Pearson G et al. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22: 153–183

    CAS  PubMed  Google Scholar 

  58. Raingeaud J et al. (1996) MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell Biol 16: 1247–1255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lee JC et al. (1999) p38 mitogen-activated protein kinase inhibitors—mechanisms and therapeutic potentials. Pharmacol Ther 82: 389–397

    Article  CAS  PubMed  Google Scholar 

  60. Kaminska B (2005) MAPK signaling pathways as molecular targets for anti-inflammatory therapy—from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta 1754: 253–262

    Article  CAS  PubMed  Google Scholar 

  61. Waetzig GH et al. (2002) p38 mitogen-activated protein kinase is activated and linked to TNF-α signaling in inflammatory bowel disease. J Immunol 168: 5342–5351

    Article  CAS  PubMed  Google Scholar 

  62. Hollenbach E et al. (2004) Inhibition of p38 MAP kinase- and RICK/NF-κB-signaling suppresses inflammatory bowel disease. FASEB J 18: 1550–1552

    Article  CAS  PubMed  Google Scholar 

  63. Badger AM et al. (1996) Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther 279: 1453–1461

    CAS  PubMed  Google Scholar 

  64. Bianchi M et al. (1995) An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality. Mol Med 1: 254–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bianchi M et al. (1996) Suppression of proinflammatory cytokines in monocytes by a tetravalent guanylhydrazone. J Exp Med 183: 927–936

    Article  CAS  PubMed  Google Scholar 

  66. Hommes D et al. (2002) Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease. Gastroenterology 122: 7–14

    Article  CAS  PubMed  Google Scholar 

  67. Regan J et al. (2003) Structure-activity relationships of the p38α MAP kinase inhibitor 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796). J Med Chem 46: 4676–4686

    Article  CAS  PubMed  Google Scholar 

  68. Branger J et al. (2002) Anti-inflammatory effects of a p38 mitogen-activated protein kinase inhibitor during human endotoxemia. J Immunol 168: 4070–4047

    Article  CAS  PubMed  Google Scholar 

  69. Brahn E et al. (2002) Inhibition of collagen-induced arthritis with an inhibitor of p38 MAP kinase [abstract]. Arthritis Rheum 46 (Suppl): S566

    Google Scholar 

  70. Haddad JJ (2001) VX-745. Vertex Pharmaceuticals. Curr Opin Investig Drugs 2: 1070–1076

    CAS  PubMed  Google Scholar 

  71. Anselmo DM et al. (2002) FTY720 pretreatment reduces warm hepatic ischemia reperfusion injury through inhibition of T-lymphocyte infiltration. Am J Transplant 2: 843–849

    Article  CAS  PubMed  Google Scholar 

  72. Poppe D et al. (2006) Azathioprine suppresses ezrin-radixin-moesin-dependent T cell-APC conjugation through inhibition of Vav guanosine exchange activity on Rac proteins. J Immunol 176: 640–651

    Article  CAS  PubMed  Google Scholar 

  73. Tiede I et al. (2003) CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 111: 1133–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Gorelik L et al. (2000) Cutting edge: TGF-β inhibits TH type 2 development through inhibition of GATA-3 expression. J Immunol 165: 4773–4777

    Article  CAS  PubMed  Google Scholar 

  75. Gorelik L et al. (2002) Mechanism of transforming growth factor beta-induced inhibition of T helper type 1 differentiation. J Exp Med 195: 1499–1505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fantini MC et al. (2004) Cutting edge: TGF-β induces a regulatory phenotype in CD4+CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172: 5149–5153

    Article  CAS  PubMed  Google Scholar 

  77. Fantini MC et al. (2005) Transforming growth factor beta-induced Foxp3+ regulatory T cells suppress TH1-mediated experimental colitis. Gut 55: 671–680

    Article  PubMed  CAS  Google Scholar 

  78. Monteleone G et al. (2001) Blocking Smad7 restores TGF-β1 signaling in chronic inflammatory bowel disease. J Clin Invest 108: 601–609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Peschon JJ et al. (1994) Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J Exp Med 180: 1955–1960

    Article  CAS  PubMed  Google Scholar 

  80. Puel A et al. (1998) Defective IL7R expression in T−B+NK+ severe combined immunodeficiency. Nat Genet 20: 394–397

    Article  CAS  PubMed  Google Scholar 

  81. Becker TC et al. (2002) Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med 195: 1541–1548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Schluns KS et al. (2002) Cutting edge: requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol 168: 4827–4831

    Article  CAS  PubMed  Google Scholar 

  83. Kennedy MK et al. (2000) Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 191: 771–780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cooper MA et al. (2002) In vivo evidence for a dependence on interleukin 15 for survival of natural killer cells. Blood 100: 3633–3638

    Article  CAS  PubMed  Google Scholar 

  85. Zeng R et al. (2005) Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J Exp Med 201: 139–148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ma HL et al. (2003) IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN-γ. J Immunol 171: 608–615

    Article  CAS  PubMed  Google Scholar 

  87. Ozaki K et al. (2002) A critical role for IL-21 in regulating immunoglobulin production. Science 298: 1630–1634

    Article  CAS  PubMed  Google Scholar 

  88. Schorle H et al. (1991) Development and function of T cells in mice rendered interleukin-2-deficient by gene targeting. Nature 352: 621–624

    Article  CAS  PubMed  Google Scholar 

  89. Malek TR (2003) The main function of IL-2 is to promote the development of T regulatory cells. J Leukoc Biol 74: 961–965

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. University of Rome “Tor Vergata”, Rome, Italy

    Massimo C Fantini

  2. The University of Mainz “Johannes Gutenberg”,

    Massimo C Fantini

  3. Postdoctoral Fellow, The University of Mainz “Johannes Gutenberg”, Mainz, Germany

    Christoph Becker

  4. Fellow, The University of Mainz “Johannes Gutenberg”, Mainz, Germany

    Ralf Kiesslich

  5. Professor at the The University of Mainz “Johannes Gutenberg”, Mainz, Germany

    Markus F Neurath

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Correspondence to Markus F Neurath.

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Fantini, M., Becker, C., Kiesslich, R. et al. Drug Insight: novel small molecules and drugs for immunosuppression. Nat Rev Gastroenterol Hepatol 3, 633–644 (2006). https://doi.org/10.1038/ncpgasthep0611

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