Journal of Clinical Immunology

, Volume 30, Issue 2, pp 235–240

IL-17 Contributes to the Development of Chronic Rejection in a Murine Heart Transplant Model

  • Satoshi Itoh
  • Susumu Nakae
  • Robert C. Axtell
  • Jeffrey B. Velotta
  • Naoyuki Kimura
  • Naoki Kajiwara
  • Yoichiro Iwakura
  • Hirohisa Saito
  • Hideo Adachi
  • Lawrence Steinman
  • Robert C. Robbins
  • Michael P. Fischbein
Article

Abstract

Background

Although interleukin-17 (IL-17) has been reported to participate in the pathogenesis of infectious, autoimmune and allergic disorders, the precise role in allograft rejection remains uncertain. This study illustrates that IL-17 contributes to the pathogenesis of chronic allograft rejection.

Result

Utilizing a murine heterotopic heart transplant model system, IL-17-deficient recipient mice had decreased allograft inflammatory cell recruitment, decreased IL-6, MCP-1, and KC production, and reduced graft coronary artery disease (GCAD). Intragraft gamma delta (γδ) T cells appear to be the predominant source of IL-17 production.

Conclusion

Therefore, IL-17 neutralization may provide a potential target for novel therapeutic treatment for cardiac allograft rejection.

Keywords

IL-17 graft coronary artery disease γδ T cell 

References

  1. 1.
    Taylor DO, Edwards LB, Boucek MM, Trulock EP, Aurora P, Christie J, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult heart transplant report—2007. J Heart Lung Transplant. 2007;26:769–81.CrossRefPubMedGoogle Scholar
  2. 2.
    Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-17 family and IL-17 receptors. Cytokine Growth Factor Rev. 2003;14:155–74.CrossRefPubMedGoogle Scholar
  3. 3.
    Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity. 2004;21:467–76.CrossRefPubMedGoogle Scholar
  4. 4.
    Oboki K, Ohno T, Saito H, Nakae S. Th17 and allergy. Allergol Int. 2008;57:121–34.CrossRefPubMedGoogle Scholar
  5. 5.
    Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev. 2008;226:57–79.CrossRefPubMedGoogle Scholar
  6. 6.
    Van Kooten C, Boonstra JG, Paape ME, Fossiez F, Banchereau J, Lebecque S, et al. Interleukin-17 activates human renal epithelial cells in vitro and is expressed during renal allograft rejection. J Am Soc Nephrol. 1998;9:1526–34.PubMedGoogle Scholar
  7. 7.
    Loong CC, Hsieh HG, Lui WY, Chen A, Lin CY. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. J Pathol. 2002;197:322–32.CrossRefPubMedGoogle Scholar
  8. 8.
    Tesar BM, Du W, Shirali AC, Walker WE, Shen H, Goldstein DR. Aging augments IL-17 T-cell alloimmune responses. Am J Transplant. 2009;9:54–63.CrossRefPubMedGoogle Scholar
  9. 9.
    Antonysamy MA, Fanslow WC, Fu F, Li W, Qian S, Troutt AB, et al. Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors. J Immunol. 1999;162:577–84.PubMedGoogle Scholar
  10. 10.
    Li J, Simeoni E, Fleury S, Dudler J, Fiorini E, Kappenberger L, et al. Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model. Eur J Cardiothorac Surg. 2006;29:779–83.CrossRefPubMedGoogle Scholar
  11. 11.
    Tang JL, Subbotin VM, Antonysamy MA, Troutt AB, Rao AS, Thomson AW. Interleukin-17 antagonism inhibits acute but not chronic vascular rejection. Transplantation. 2001;72:348–50.CrossRefPubMedGoogle Scholar
  12. 12.
    Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu Rev Immunol. 2007;25:821–52.CrossRefPubMedGoogle Scholar
  13. 13.
    Rickel EA, Siegel LA, Yoon BR, Rottman JB, Kugler DG, Swart DA, et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol. 2008;181:4299–310.PubMedGoogle Scholar
  14. 14.
    Nakae S, Komiyama Y, Nambu A, Sudo K, Iwase M, Homma I, et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity. 2003;17:375–87.CrossRefGoogle Scholar
  15. 15.
    Fischbein MP, Ardehali A, Yun J, Schoenberger S, Laks H, Irie Y, et al. CD40 signaling replaces CD4+ lymphocytes and its blocking prevents chronic rejection of heart transplants. J Immunol. 2000;165:7316–22.PubMedGoogle Scholar
  16. 16.
    Tanaka M, Fedoseyeva EV, Robbins RC. Graft coronary artery disease in murine cardiac allografts: proposal to meet the need for standardized assessment. J Heart Lung Transplant. 2005;24:316–22.CrossRefPubMedGoogle Scholar
  17. 17.
    Yuan X, Paez-Cortez J, Schmitt-Knosalla I, D’Addio F, Mfarrej B, Donnarumma M, et al. A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med. 2008;205:3133–44.CrossRefPubMedGoogle Scholar
  18. 18.
    Glimcher LH, Townsend MJ, Sullivan BM, Lord GM. Lord. Recent developments in the transcriptional regulation of cytolytic effector cells. Nat Rev Immunol. 2004;4:900–11.CrossRefPubMedGoogle Scholar
  19. 19.
    Fujiwara M, Hirose K, Kagami S, Takatori H, Wakashin H, Tamachi T, et al. T-bet inhibits both TH2 cell-mediated eosinophil recruitment and TH17 cell-mediated neutrophil recruitment into the airways. J Allergy Clin Immunol. 2007;119:662–70.CrossRefPubMedGoogle Scholar
  20. 20.
    Fischbein MP, Yun J, Laks H, Irie Y, Oslund-Pinderski L, Fishbein MC, et al. Regulated interleukin-10 expression prevents chronic rejection of transplanted hearts. J Thorac Cardiovasc Surg. 2003;126:216–23.CrossRefPubMedGoogle Scholar
  21. 21.
    Fischbein MP, Yun J, Laks H, Irie Y, Fishbein MC, Espejo M, et al. CD8+ lymphocytes augment chronic rejection in a MHC class II mismatched model. Transplantation. 2001;71:1146–53.CrossRefPubMedGoogle Scholar
  22. 22.
    Salomon RN, Hughes CC, Schoen FJ, Payne DD, Pober JS, Libby P. Human coronary transplantation-associated arteriosclerosis. Evidence for a chronic immune reaction to activated graft endothelial cells. Am J Pathol. 1991;138:791–8.PubMedGoogle Scholar
  23. 23.
    Fossiez F, Djossou O, Chomarat P, Flores-Romo L, Ait-Yahia S, Maat C, et al. T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med. 1996;183:2593–603.CrossRefPubMedGoogle Scholar
  24. 24.
    Starnes T, Robertson M, Sledge G, Kelich S, Nakshatri H, Broxmeyer H, et al. Cutting edge: IL-17F, a novel cytokine selectively expressed in activated T cells and monocytes. Regulates angiogenesis and endothelial cell cytokine production. J Immunology. 2001;167:4137–40.Google Scholar
  25. 25.
    Eid R, Rao D, Zhou J, Lo S, Ranjbaran H, Gallo A, et al. Interleukin-17 and Inteferon-γ are produced concomitantly by human coronary artery-infiltrating T cells and act synergistically on vascular smooth muscle cells. Circulation. 2009;119:1424–32.CrossRefPubMedGoogle Scholar
  26. 26.
    Nagano H, Mitchell RN, Taylor MK, Hasegawa S, Tilney NL, Libby P. Interferon-gamma deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse hearts. J Clin Invest. 1997;100:550–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Tellides G, Tereb DA, Kirkiles-Smith NC, Kim RW, Wilson JH, Schechner JS, et al. Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature. 2000;403:207–11.CrossRefPubMedGoogle Scholar
  28. 28.
    Jensen KD, Su X, Shin S, Li L, Youssef S, Yamasaki S, et al. Thymic selection determines gammadelta T cell effector fate: antigen-naive cells make interleukin-17 and antigen-experienced cells make interferon gamma. Immunity. 2008;29:90–100.CrossRefPubMedGoogle Scholar
  29. 29.
    Shichita T, Sugiyama Y, Ooboshi H, Sugimori H, Nakagawa R, Takada I, et al. Pivotal role of cerebral interleukin-17-producing γδT cells in the delayed phase of ischemic brain injury. Nat Med. 2009;15:946–50.CrossRefPubMedGoogle Scholar
  30. 30.
    Ivanov II, Zhou L, Littman DR. Transcriptional regulation of Th17 cell differentiation. Semin Immunol. 2007;19:409–17.CrossRefPubMedGoogle Scholar
  31. 31.
    McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, McClanahan T, et al. TGF-ß and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat Immunol. 2007;8:1390–7.CrossRefPubMedGoogle Scholar
  32. 32.
    Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179–89.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Satoshi Itoh
    • 1
    • 7
  • Susumu Nakae
    • 2
    • 3
    • 4
  • Robert C. Axtell
    • 5
  • Jeffrey B. Velotta
    • 1
  • Naoyuki Kimura
    • 1
  • Naoki Kajiwara
    • 2
    • 3
  • Yoichiro Iwakura
    • 6
  • Hirohisa Saito
    • 2
    • 3
  • Hideo Adachi
    • 7
  • Lawrence Steinman
    • 5
  • Robert C. Robbins
    • 1
  • Michael P. Fischbein
    • 1
  1. 1.Department of Cardiothoracic SurgeryStanford University School of MedicineStanfordUSA
  2. 2.Department of Allergy and ImmunologyNational Research Institute for Child Health and DevelopmentTokyoJapan
  3. 3.Atopy Research CenterJuntendo UniversityTokyoJapan
  4. 4.Frontier Research Initiative, The Institute of Medical ScienceUniversity of TokyoTokyoJapan
  5. 5.Department of Neurology and Neurological SciencesStanford University School of MedicineStanfordUSA
  6. 6.Center for Experimental Medicine, The Institute of Medical ScienceUniversity of TokyoTokyoJapan
  7. 7.Department of Cardiovascular Surgery, Saitama Medical CenterJichi Medical UniversitySaitamaJapan

Personalised recommendations