Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-Versus-Host Disease

Induction of oral tolerance in bone marrow transplantation recipients suppresses graft-versus-host disease in a semiallogeneic mouse model

Bone Marrow Transplantation volume 32, pages 363–369 (2003)Cite this article

Summary:

Graft-versus-host disease (GVHD) is the major obstacle for successful allogeneic stem cell transplantation (SCT). Morbidity and mortality are high, and novel therapeutic strategies are required. Current therapy, which is based mainly on immunosuppression, is associated with a high degree of complications. Immune hyporesponsiveness induced by oral antigen administration has recently been shown to prevent the development of chronic GVHD (cGVHD) in a murine model. The aim of the present study was to evaluate whether it is possible to induce tolerance and to alleviate GVHD in a semiallogeneic transplantation model in mice. GVHD was generated by infusing 2 × 107 splenocytes from C57BL/6 donor mice into (C57BL/6 × Balb/c)F1 recipient mice, which received 7 Gy 60Co total body irradiation (TBI) prior to transplantation. Oral tolerance was induced by feeding recipient F1 mice with five oral doses of proteins, 50 μg/mouse, extracted from C57BL/6 splenocytes on alternate days following transplantation. In vitro mixed lymphocyte reaction (MLR) from tolerized and nontolerized mice was performed. Recipient mice were followed for chimerism, and for clinical and histological parameters of GVHD. Induction of tolerance was documented by a significant reduction in MLR response of tolerated vs nontolerated splenocytes. A significant alleviation of the clinical and pathological manifestation of GVHD was observed in the liver, small bowel, and skin. Tolerance induction did not jeopardize engraftment. These results may constitute a step towards reducing the frequency of GVHD via manipulation of the immune system.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Ferrara JLM, Deeg HJ . Graft versus host disease. N Engl J Med 1991; 324: 667–672.

    Article  CAS  Google Scholar 

  2. Vogelsang GB . Graft versus host disease: implications from basic immunology for prophylaxis and treatment. Cancer Treat Res 1997; 77: 87–97.

    Article  CAS  Google Scholar 

  3. Weiner HL . Oral tolerance: immune mechanisms and treatment of autoimmune diseases. Immunol Today 1997; 18: 335–343.

    Article  CAS  Google Scholar 

  4. Strobel S, Mowat AM . Immune response to dietary antigens: oral tolerance. Immunol Today 1998; 4: 173–181.

    Article  Google Scholar 

  5. Nagler A, Pines M, Abadi U et al. Oral tolerization ameliorates liver disorders associated with chronic graft versus host disease in mice. Hepatology 2000; 31: 641–648.

    Article  CAS  Google Scholar 

  6. Massi D, Franchi A, Pimpinelli N et al. A reappraisal of the histopathologic criteria for the diagnosis of cutaneous allogeneic acute graft-vs-host disease. Am J Clin Pathol 1999; 112: 791–800.

    Article  CAS  Google Scholar 

  7. Howell CD, Yoder TY, Vierlinng JM . Suppressor function of liver mononuclear cells isolated during chronic graft versus host disease. Cell Immunol 1992; 140: 54–66.

    Article  CAS  Google Scholar 

  8. Ilan Y, Gotsman I, Pines M et al. Induction of oral tolerance in splenocyte recipients towards pre transplant antigens ameliorates chronic graft versus host disease in a murine model. Blood 2000; 95: 3613–3619.

    CAS  PubMed  Google Scholar 

  9. Ilan Y, Weksler-Zangen S, Ben-Horin S et al. Treatment of experimental colitis by oral tolerance induction: a central role for suppressor lymphocytes. Am J of Gastroenterol 2000; 95: 966–973.

    Article  CAS  Google Scholar 

  10. Ilan Y, Prakash R, Davidson A et al. Tolerization to adenoviral antigens permits long term gene expression using recombinant adenoviral vectors. J Clin Invest 1997; 99: 1098–1106.

    Article  CAS  Google Scholar 

  11. Gotsman I, Beinart R, Alper R et al. Induction of oral tolerance towards hepatitis B envelope antigens in a murine model. Antiviral Res 2000; 48: 17–26.

    Article  CAS  Google Scholar 

  12. Ghobrial RR, Hamashima T, Wang ME et al. Induction of transplantation tolerance by chimeric donor/recipient class I RT1.A molecules. Transplantation 1996; 62: 1002–1010.

    Article  CAS  Google Scholar 

  13. Howell CD, De Victor D, Li J et al. Liver T cell subsets and adhesion molecules in murine graft versus host disease. Bone Marrow Transplant 1995; 16: 139–145.

    CAS  PubMed  Google Scholar 

  14. Pines M, Knopov V, Genina O et al. Halofuginone, a specific inhibitor of collagen type I synthesis, prevents dimethylnitrosamine-induced liver cirrhosis. J Hepatol 1997; 27: 391–398.

    Article  CAS  Google Scholar 

  15. Woodruff IM, Hansen JA, Good RA et al. The pathology of graft versus host reaction in adults receiving bone marrow transplants. Trans Proc 1976; 8: 675–684.

    CAS  Google Scholar 

  16. Ferrara JL . Cytokine inhibitors and graft versus host disease. Ann NY Acad Sci 1995; 770: 227–236.

    Article  CAS  Google Scholar 

  17. Hancock W, Polansli M, Zhang J et al. Suppression of insulitis in NOD mice by oral insulin administration is associated with selective expression of IL-4-10, TGF-β and prostaglandin E. Am J Pathol 1995; 147: 1193–1197.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Neurath M, Kelasall BL, Presky DH et al. Experimental Granulomatous Colitis in Mice is Abrogated by Induction of TGFβ-mediated Oral Tolerance. J Exp Med 1996; 183: 2605–2616.

    Article  CAS  Google Scholar 

  19. Ilan Y, Sauter B, Roy Chowdhury N et al. Oral tolerization to adenoviral proteins permits repeated adenovirus-mediated gene therapy in rats with pre-existing immunity to adenovirus. Hepatology 1998; 27: 1368–1376.

    Article  CAS  Google Scholar 

  20. Gotsman I, Shlomai A, Alper R et al. Amelioration of immune-mediated experimental colitis: tolerance induction in the presence of pre-existing immunity and surrogate antigen bystander effect. J Pharmacol Exp Ther 2001; 297: 926–932.

    CAS  PubMed  Google Scholar 

  21. Shlomai A, Trop A, Gotsman I et al. Immunemodulation of experimental colitis: the role of NK1.1+ liver lymphocytes and surrogate antigen-bystander effect. J Pathol 2001; 195: 498–507.

    Article  CAS  Google Scholar 

  22. Nagler A, Barak V, Slavin S . Role of cytokines in graft versus host reaction and rejection following allogeneic bone marrow transplantation. In: Aggarwal BB and Puri RK (eds). Human Cytokines: their Role in Disease and Therapy, Vol. 35. Blackwell Science UK, 1995, pp 153–161.

    Google Scholar 

  23. Krenger W, Hill GR, Ferrara JLM . Cytokine cascades in graft versus host disease. Transplantation 1997; 64: 553–558.

    Article  CAS  Google Scholar 

  24. Krenger W, Ferrara JLM . Graft versus host disease and the Th1/Th2 paradigm. Immunol Res 1996; 15: 50–73.

    Article  CAS  Google Scholar 

  25. Barak V, Levi-Schaffer F, Nisman B et al. Cytokine dysregulation in chronic graft versus host disease. Leuk Lymphoma 1995; 17: 169–173.

    Article  CAS  Google Scholar 

  26. Nagler A, Or R, Kalickman I et al. Elevated inflammatory cytokine levels in bone marrow graft rejection. Transplantation 1995; 60: 943–948.

    Article  CAS  Google Scholar 

  27. Tabbara IA, Zimmerman K, Morgan C, Nahleh Z . Allogeneic hematopoietic stem cell transplantation: complications and results. Arch Intern Med 2002; 162: 1558–1566.

    Article  Google Scholar 

  28. Cavazzana-Calvo M, Andre-Schmutz I, Hacein-Bey-Abina S et al. Improving immune reconstitution while preventing graft-versus-host disease in allogeneic stem cell transplantation. Semin Hematol 2002; 39: 32–40.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the following grants: The Roaman-Epstein Liver Research Foundation; Israel Cancer Research Fund; Israel Cancer Association Research Grant. A grant from ENZO Biochem.

Author information

Authors and Affiliations

  1. Department of Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Israel

    A Nagler & M Ohana

  2. Department of Medicine, Liver Unit, Hadassah University Hospital, Jerusalem, Israel

    M Ohana, R Alper & Y Ilan

  3. Department of Pathology, Hadassah University Hospital, Jerusalem, Israel

    V Doviner & Y Sherman

  4. ENZO Biochem Inc, New York, USA

    E Rabbani & D Engelhardt

Authors
  1. A Nagler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Ohana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Alper
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. V Doviner
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Y Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E Rabbani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. D Engelhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Y Ilan
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagler, A., Ohana, M., Alper, R. et al. Induction of oral tolerance in bone marrow transplantation recipients suppresses graft-versus-host disease in a semiallogeneic mouse model. Bone Marrow Transplant 32, 363–369 (2003). https://doi.org/10.1038/sj.bmt.1704145

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1704145

Keywords

This article is cited by

Search

Advanced search

Quick links