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Novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses

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Abstract

Immune regulatory pathways involving the newly discovered T regulatory (Treg) and Th17 cells are amongst the principal targets of immunosuppressive agents employed in transplant recipients and key mediators of host inflammatory responses in fungal infections. These novel signaling pathways, in concert with or independent of Th1/Th2 responses, have potentially important implications for yielding valuable insights into the pathogenesis of immune reconstitution syndrome (IRS) in transplant recipients, for aiding the diagnosis of this entity, and for achieving a balance of immune responses that enhance host immunity while curbing unfettered inflammation in IRS.

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References

  1. Singh N, Perfect JR (2007) Immune reconstitution syndrome associated with opportunistic mycoses. Lancet Infect Dis 7:395–401

    Article  PubMed  Google Scholar 

  2. Lortholary O, Fontanet A, Memain N et al (2005) Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 19:1043–1049

    Article  PubMed  Google Scholar 

  3. Shelburne SA, Hamill RJ, Rodriguez-Barradas MC et al (2002) Immune reconstitution inflammatory syndrome, emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 81:213–227

    Article  PubMed  Google Scholar 

  4. Casadevall A, Pirofski LA (2003) The damage-response framework of microbial pathogenesis. Nat Rev Microbiol 1:17–24

    Article  PubMed  CAS  Google Scholar 

  5. Shelburne SA, Darcourt J, White C Jr et al (2005) The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 40:1045–1052

    Article  Google Scholar 

  6. Hirsch HH, Kaufmann G, Sendi P et al (2004) Immune reconstitution in HIV-infected patients. Clin Infect Dis 38:1159–1166

    Article  PubMed  Google Scholar 

  7. Cheng VCC, Yuen KY, Wong SSY et al (2001) Immunorestitution disease in patients not infected with HIV. Eur J Clin Microbiol Infect Dis 20:402–406

    Article  PubMed  CAS  Google Scholar 

  8. Einsiedel L, Gordon DL, Dyer JR (2004) Paradoxical inflammatory reaction during treatment of Cryptococcus neoformans var. gattii meningitis in an HIV seronegative woman. Clin Infect Dis 39:e78–e82

    Article  PubMed  Google Scholar 

  9. Clemons KV, Stevens DA (2001) Overview of host defense mechanisms in systemic mycoses and the basis for immunotherapy. Semin Respir Infect 16:60–66

    Article  PubMed  CAS  Google Scholar 

  10. Romani L, Pucetti P (2007) Controlling pathogenic inflammation to fungi. Expert Rev Anti Infect Ther 5:1007–1017

    Article  PubMed  CAS  Google Scholar 

  11. Cenci E, Perito S, Enssle KH et al (1997) Th1 and Th2 cytokines in mice with invasive aspergillosis. Infect Immun 65:564–570

    PubMed  CAS  Google Scholar 

  12. Parkin J, Cohen B (2001) An overview of the immune system. Lancet 357:1777–1789

    Article  PubMed  CAS  Google Scholar 

  13. Goriely S, Goldman M (2007) The interleukin-12 family: new players in transplantation immunity? Am J Transplant 7:278–284

    Article  PubMed  CAS  Google Scholar 

  14. Nelms K, Keegan A, Zamorano J et al (1999) The IL-4 receptor: signaling mechanisms and biologic functions. Ann Rev Immunol 17:701–738

    Article  CAS  Google Scholar 

  15. Afzali B, Lombardi G, Lechler R, Lord G (2007) The role of T helper (TH17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 148:32–46

    Article  PubMed  CAS  Google Scholar 

  16. Mangan P, Harrington L, O’Quinn D et al (2006) Transforming growth factor-beta induces development of the T (H) 17 lineage. Nature 441:231–234

    Article  PubMed  CAS  Google Scholar 

  17. Cooke A (2006) Th17 cells in inflammatory conditions. Rev Diabetic Stud 372–375

  18. Bi Y, Guangwei L, Yang R (2007) Th17 cell induction and immune regulatory effects. J Cell Physiol 211:273–278

    Article  PubMed  CAS  Google Scholar 

  19. Schmidt-Weber C, Akdis M, Akdis C (2007) TH17 cells in the big picture of immunology. J Allergy Clin Immunol 120:247–254

    Article  PubMed  CAS  Google Scholar 

  20. Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 3:281–286

    Article  CAS  Google Scholar 

  21. Bettelli E, Carrier Y, Gao W et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  PubMed  CAS  Google Scholar 

  22. Veldhoen M, Hocking R, Atkins C et al (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de nova differentiation of IL-17-producing T cells. Immunity 24:179–189

    Article  PubMed  CAS  Google Scholar 

  23. Pyzik M, Piccirillo C (2007) TGF-beta 1 modulates FoxP3 expression and regulatory activity in distinct CD4+ T cell subsets. J Leukov Biol 82:335–346

    Article  CAS  Google Scholar 

  24. Chen W, Jin W, Hardegen N et al (2003) Conversion of peripheral TGF-beta CD4+CD5-naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 1875–1886

  25. Yagi H, Normura T, Nakamura K et al (2004) Crucial role of FoxP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol 11:1643–1656

    Article  CAS  Google Scholar 

  26. Sakaguchi S (2005) Naturally arising FoxP3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immun 6:345–354

    Article  PubMed  CAS  Google Scholar 

  27. Fontenot J, Gavin M, Rudensky A (2003) FoxP3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immun 4:330–336

    Article  PubMed  CAS  Google Scholar 

  28. Waldmann H, Graca L, Cobbold S et al (2004) Regulatory T cells and organ transplantation. Semin Immunol 16:119–126

    Article  PubMed  CAS  Google Scholar 

  29. de Kleer I, Wedderburn L, Taams L et al (2004) CD4+CD25bright regulatory T cells activity regulate inflammation in the joints of patients with the remitting form of juvenile idiopathic arthritis. J Immunol 10:6423–6435

    Google Scholar 

  30. Matthys P, Vermeire K, Mitera T et al (1998) Anti-IL-12 antibody prevents the development and progression of collagen-induced arthritis in IFN-gamma receptor-deficient mice. Eur J Immunol 28:2143–2151

    Article  PubMed  CAS  Google Scholar 

  31. Tang Q, Henriksen K, Bi M et al (2004) In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199:1455–1465

    Article  PubMed  CAS  Google Scholar 

  32. Long E, Wood K (2007) Understanding FOXP3: progress towards achieving transplantation tolerance. Transplantation 84:459–461

    Article  PubMed  CAS  Google Scholar 

  33. Gras J, Cornet A, Latinne D et al (2004) Evidence that Th1/Th2 immune deviation impacts on early graft acceptance after pediatric liver transplantation: results of immunological monitoring in 40 children. Am J Transplant 4:444

    Article  Google Scholar 

  34. Saggi B, Fisher R, Naar J et al (1999) Intragraft cytokine expression in tolerant rat renal allografts with rapamycin and cyclosporin immunosuppression. Clin Transplant 13:90–97

    Article  PubMed  CAS  Google Scholar 

  35. Salama A, Najafian N, Clarkson M et al (2003) Regulatory CD25+ T cells in human kidney transplant recipients. J Am Soc Nephrol 6:1643–1651

    Article  Google Scholar 

  36. Graca L, Cobbold S, Waldmann H (2002) Identification of regulatory T cells in tolerated allografts. J Exp Med 195:1641

    Article  PubMed  CAS  Google Scholar 

  37. Bloom DD, Brahmbhatt R, Knechtle S (2007) Flow cytometric characterization regulatory T lymphocyte populations in renal transplant patients treated with Campath and tacrolimus. Presented at the American Transplant Congress, May 5–7, San Francisco, CA

  38. Lopez M, Clarkson M, Sayegh A et al (2006) A novel mechanism of action for anti-thymocyte globulin induction of CD4+CD25+FoxP3+ regulatory T cells. J Am Soc Nephrol 10:2644–2646

    Google Scholar 

  39. Watanabe T, Masuyama J, Sohma Y et al (2006) CD52 is a novel costimulatory molecule for induction of CD4+ regulatory T cells. Clin Immunol 3:247–259

    Article  CAS  Google Scholar 

  40. Karagiannidis C, Akdis M, Holopainen P et al (2004) Glucocorticoids up-regulate CAP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol 114:1425–1433

    Article  PubMed  CAS  Google Scholar 

  41. Segundo D, Ruiz J, Izquierdo M et al (2006) Calcineurin inhibitors, but no rapamycin, reduce percentages of CD4+CD25+FoxP3+ Regulatory T cells in renal transplant recipients. Transplantation 82:550–557

    Article  PubMed  CAS  Google Scholar 

  42. Baan C, van der Mast B, Klepper M et al (2005) Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin of the induction of FoxP3 in human T Cells. Transplantation 80:110–117

    Article  PubMed  CAS  Google Scholar 

  43. Bensinger S, Walsh P, Zhang J (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+regulatory T cells. J Immunol 172:5287

    PubMed  CAS  Google Scholar 

  44. Fontenot J, Rasmussen J, Gavin M et al (2005) A function for interleukin 2 in FoxP3-expressing regulatory T cells. Nat Immunol 6:1142

    Article  PubMed  CAS  Google Scholar 

  45. Battaglia M, Stabilini A, Roncarolo M (2005) Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105:4743–4748

    Article  PubMed  CAS  Google Scholar 

  46. Nagai H, Guo J, Choi H et al (1995) Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis. J Infect Dis 172:1554–1560

    PubMed  CAS  Google Scholar 

  47. Kawakami K (2004) Regulation by innate immune T lymphocytes in the host defense against pulmonary infection with Cryptococcus neoformans. Jpn J Infect Dis 57:137–145

    PubMed  CAS  Google Scholar 

  48. Decken K, Kohler G, Palmer-Lehmann K et al (1998) Interleukin-12 is essential for protective Th1 response in mice infected with Cryptococcus neoformans. Infect Immun 66:4994–5000

    PubMed  CAS  Google Scholar 

  49. Aguirre K, Havell EA, Gibson GW (1995) Role of tumor necrosis factor and gamma interferon in acquired resistance to Cryptococcus neoformans in the central nervous system of mice. Infect Immun 63:1725–1731

    PubMed  CAS  Google Scholar 

  50. Vecchiarelli A, Retini C, Monari C et al (1996) Purified capsular polysaccharide of Cryptococcus neoformans induces interleukin-10 secretion by human monocytes. Infect Immun 64:2846–2849

    PubMed  CAS  Google Scholar 

  51. Vecchiarelli A, Retini C, Pietrella D et al (1995) Downregulation by cryptococcal polysaccharide of tumor necrosis factor alpha and interleukin-1β secretion from human monocytes. Infect Immun 63:2919–2923

    PubMed  CAS  Google Scholar 

  52. Rudner X, Happel K, Young E et al (2007) Interleukin-23 (IL-23)-IL-17 cytokine axis in murine Pneumocystis carinii infection. Infect Immun 75:3055–3061

    Article  PubMed  CAS  Google Scholar 

  53. Zelante T, De Luca A, Bonifazi P et al (2007) IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance. Eur J Immunol 37:2695–2706

    Article  PubMed  CAS  Google Scholar 

  54. Rogers PD, Pearson MM, Cleary JD et al (2002) Differential expression of genes encoding immunomodulatory proteins in response to amphotericin B in human mononuclear cells identified by cDNA microarray analysis. J Antimicrob Chemotherap 50:811–817

    Article  CAS  Google Scholar 

  55. Razonable RR, Henault M, Lee LN et al (2005) Secretion of proinflammatory cytokines and chemokines during amphotericin B exposure is mediated by coactivation of toll-like receptors 1 and 2. Antimicrob Ag Chemother 4:1617–1621

    Article  CAS  Google Scholar 

  56. Shadkchan Y, Keisari Y, Segal E (2004) Cytokines in mice treated with amphotericin B-intralipid. Med Mycol 42:123–128

    Article  PubMed  CAS  Google Scholar 

  57. Hohl T, Feldmesser M, Perlin D et al (2007) Caspofungin modulates inflammatory responses to Aspergillus fumgiatus through stage-specific effects on fungal β-glucan exposure. Annual meeting of the Infectious Diseases Society of America, 4–7 October, San Diego, CA

  58. Wheeler RT, Fink GR (2006) A drug-sensitive genetic network masks fungi from the immune system. PLOS Pathogens 2:328–339

    Article  CAS  Google Scholar 

  59. Lortholary O, Sitbon K, Dromer F et al (2005) Evidence for HIV and Cryptococcus neoformans interactions on the pro- and antiinflammatory responses in blood during AIDS-associated cryptococcosis. Clin Microbiol Infect 11:296–300

    Article  PubMed  CAS  Google Scholar 

  60. Singh N, Lortholary O, Alexander BD et al (2005) An “immune reconstitution syndrome”-like entity associated with Cryptococcus neoformans infections in organ transplant recipients. Clin Infect Dis 40:1756–1761

    Article  PubMed  CAS  Google Scholar 

  61. Breton G, Adle-Biassette H, Therby A et al (2006) Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 20:119–121

    Article  PubMed  Google Scholar 

  62. Cheng VCC, Yuen KY, Chan WM et al (2000) Immunorestitution disease involving the innate and adaptive response. Clin Infect Dis 30:882–892

    Article  PubMed  CAS  Google Scholar 

  63. Miceli M, Maertens J, Buve K et al (2007) Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: proof of principle, description, and clinical and research implications. Cancer 110:112–120

    Article  PubMed  Google Scholar 

  64. Tang Q, Bluestone J (2006) Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev 212:217–237

    Article  PubMed  CAS  Google Scholar 

  65. Tarbell K, Petit L, Zuo X et al (2007) Dendritic cell-expanded, islet-specific CD4+CD25+CD62L+regulatory T cells restore normoglycemia in diabetic NOD mice. J Exp Med 204:191–201

    Article  PubMed  CAS  Google Scholar 

  66. Tarbell K, Yamazaki S, Olson K et al (2004) CD25+CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 199:1467–1477

    Article  PubMed  CAS  Google Scholar 

  67. Ingram P, Howman R, Leahy M et al (2007) Cryptococcal immune reconstitution inflammatory syndrome following alemtuzumab therapy. Clin Infect Dis 12:115–117

    Article  Google Scholar 

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Acknowledgements

This work is supported by NIH/NIAID grant R01 AI 054719-01.

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  1. Infectious Diseases Section, VA Medical Center, University Drive C, Pittsburgh, PA, 15240, USA

    N. Singh

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Singh, N. Novel immune regulatory pathways and their role in immune reconstitution syndrome in organ transplant recipients with invasive mycoses. Eur J Clin Microbiol Infect Dis 27, 403–408 (2008). https://doi.org/10.1007/s10096-008-0461-2

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