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Graft-Versus-Host Disease

Selective elimination of alloreactivity in vitro and in vivo while sparing other T-cell-mediated immune responses

Bone Marrow Transplantation volume 47, pages 838–845 (2012)Cite this article

Abstract

Selective elimination of alloreactive cells was carried out in the set-up of T-cell-mediated immunotherapy in an effort to gain the benefits of hematopoietic allogeneic transplantation while reducing the risk of GVHD. Low MW chemical compounds were screened for their effect on T-cell-mediated immune responses of murine- and human-derived lymphocytes. Selected compounds were further tested in secondary MLR assays in which sensitization to alloantigens was carried out in vitro, in the presence or absence of a given compound, followed by exposure to related and unrelated alloantigens or T-cell mitogenic stimulation. At a low concentration of <1 μM, a quinazoline derivative named AO#349 [2-(3,4,5-trimethoxyphenyl)-N-p-tolylquinazolin-4-amine], was able to induce 78–90% inhibition of a selective allogeneic response while retaining >92% immune reactivity to unrelated alloantigens and mitogenic stimuli in vitro. Following allogeneic sensitization in the presence of AO#349, elimination of alloreactivity to the priming alloantigens was also proved in a murine model of GVHD: 10 out of 15 sub-lethally irradiated mice inoculated with these sensitized cells were GVHD-free for >200 days. AO#349 was efficient in induction of a selective elimination of alloreactivity and should be considered for clinical application in allogeneic cell-mediated immunotherapy.

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References

  1. Mitsuyasu RT, Champlin RE, Gale RP, Ho WG, Lenarsky C, Winston D et al. Treatment of donor bone marrow with monoclonal anti-T-cell antibody and complement for the prevention of graft-versus-host disease. A prospective, randomized, double-blind trial. Ann Intern Med 1986; 105: 20–26.

    Article  CAS  Google Scholar 

  2. Devetten MP, Vose JM . Graft-versus-host disease: how to translate new insights into new therapeutic strategies. Biol Blood Marrow Transplant 2004; 10: 815–825.

    Article  Google Scholar 

  3. Fowler DH . Shared biology of GVHD and GVT effects: potential methods of separation. Crit Rev Oncol Hematol 2006; 57: 225–244.

    Article  Google Scholar 

  4. Shlomchik WD . Graft-versus-host disease. Nat Rev Immunol 2007; 7: 340–352.

    Article  CAS  Google Scholar 

  5. Messina C, Faraci M, de Fazio V, Dini G, Calo MP, Calore E . Prevention and treatment of acute GvHD. Bone Marrow Transplant 2008; 41 (Suppl 2): S65–S70.

    Article  CAS  Google Scholar 

  6. Chao NJ . Are there effective new strategies for the treatment of acute and chronic GvHD? Best Pract Res Clin Haematol 2008; 21: 93–98.

    Article  CAS  Google Scholar 

  7. Panigrahi S, Morecki S, Yacovlev E, Gelfand Y, Kassir J, Slavin S . A novel approach for prevention of lethal GVHD by selective elimination of alloreactive donor lymphocytes prior to stem cell transplantation. Exp Hematol 2004; 32: 756–764.

    Article  CAS  Google Scholar 

  8. Prigozhina TB, Elkin G, Khitrin S, Slavin S . Depletion of donor-reactive cells as a new concept for improvement of mismatched bone marrow engraftment using reduced-intensity conditioning. Exp Hematol 2004; 32: 1110–1117.

    Article  Google Scholar 

  9. Prigozhina TB, Elkin G, Khitrin S, Slavin S . Prevention of acute graft-vs-host disease by a single low-dose cyclophosphamide injection following allogeneic bone marrow transplantation. Exp Hematol 2008; 36: 1750–1759.

    Article  CAS  Google Scholar 

  10. Morecki S, Slavin S, Ben-Sasson SA . Selective abrogation of alloreactivity via priming in the presence of aphidicolin, a specific inhibitor of DNA polymerase. J Immunol 1989; 143: 838–843.

    CAS  PubMed  Google Scholar 

  11. Godfrey WR, Krampf MR, Taylor PA, Blazar BR . Ex vivo depletion of alloreactive cells based on CFSE dye dilution, activation antigen selection, and dendritic cell stimulation. Blood 2004; 103: 1158–1165.

    Article  CAS  Google Scholar 

  12. Mielke S, Solomon SR, Barrett AJ . Selective depletion strategies in allogeneic stem cell transplantation. Cytotherapy 2005; 7: 109–115.

    Article  CAS  Google Scholar 

  13. Aviner S, Yao X, Krauthgamer R, Gan Y, Goren-Arbel R, Klein T et al. Large-scale preparation of human anti-third-party veto cytotoxic T lymphocytes depleted of graft-versus-host reactivity: a new source for graft facilitating cells in bone marrow transplantation. Hum Immunol 2005; 66: 644–652.

    Article  CAS  Google Scholar 

  14. Barrett AJ, Le Blanc K . Prophylaxis of acute GVHD: manipulate the graft or the environment? Best Pract Res Clin Haematol 2008; 21: 165–176.

    Article  CAS  Google Scholar 

  15. Chen BJ, Cui X, Liu C, Chao NJ . Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process. Blood 2002; 99: 3083–3088.

    Article  CAS  Google Scholar 

  16. Boumedine RS, Roy DC . Elimination of alloreactive T cells using photodynamic therapy. Cytotherapy 2005; 7: 134–143.

    Article  CAS  Google Scholar 

  17. Harris DT, Sakiestewa D, Lyons C, Kreitman RJ, Pastan I . Prevention of graft-versus-host disease (GVHD) by elimination of recipient-reactive donor T cells with recombinant toxins that target the interleukin 2 (IL-2) receptor. Bone Marrow Transplant 1999; 23: 137–144.

    Article  CAS  Google Scholar 

  18. André-Schmutz I, Le Deist F, Hacein-Bey-Abina S, Vitetta E, Schindler J, Chedeville G et al. Immune reconstitution without graft-versus-host disease after haemopoietic stem-cell transplantation: a phase 1/2 study. Lancet 2002; 360: 130–137.

    Article  Google Scholar 

  19. Amrolia PJ, Muccioli-Casadei G, Yvon E, Huls H, Sili U, Wieder ED et al. Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. Blood 2003; 102: 2292–2299.

    Article  CAS  Google Scholar 

  20. Fehse B, Frerk O, Goldmann M, Bulduk M, Zander AR . Efficient depletion of alloreactive donor T lymphocytes based on expression of two activation-induced antigens (CD25 and CD69). Br J Haematol 2000; 109: 644–651.

    Article  CAS  Google Scholar 

  21. Koh MB, Prentice HG, Lowdell MW . Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis. Bone Marrow Transplant 1999; 23: 1071–1079.

    Article  CAS  Google Scholar 

  22. Prigozhina TB, Gurevitch O, Elkin G, Morecki S, Yakovlev E, Slavin S . CD40 ligand-specific antibodies synergize with cyclophosphamide to promote long-term transplantation tolerance across MHC barriers but inhibit graft-vs-leukemia effects of transplanted cells. Exp Hematol 2003; 31: 81–88.

    Article  CAS  Google Scholar 

  23. Ge X, Brown J, Sykes M, Boussiotis VA . CD134-allodepletion allows selective elimination of alloreactive human T cells without loss of virus-specific and leukemia-specific effectors. Biol Blood Marrow Transplant 2008; 14: 518–530.

    Article  CAS  Google Scholar 

  24. Wehler TC, Nonn M, Brandt B, Britten CM, Gröne M, Todorova M et al. Targeting the activation-induced antigen CD137 can selectively deplete alloreactive T cells from antileukemic and antitumor donor T-cell lines. Blood 2007; 109: 365–373.

    Article  CAS  Google Scholar 

  25. Hartwig UF, Robbers M, Wickenhauser C, Huber C . Murine acute graft-versus-host disease can be prevented by depletion of alloreactive T lymphocytes using activation-induced cell death. Blood 2002; 99: 3041–3049.

    Article  CAS  Google Scholar 

  26. Hartwig UF, Nonn M, Khan S, Link I, Huber C, Herr W . Depletion of alloreactive donor T lymphocytes by CD95-mediated activation-induced cell death retains antileukemic, antiviral, and immunoregulatory T cell immunity. Biol Blood Marrow Transplant 2008; 14: 99–109.

    Article  CAS  Google Scholar 

  27. Morecki S, Gelfand Y, Yacovlev E, Eizik O, Shabat Y, Slavin S . CpG-induced myeloid CD11b+Gr-1+ cells efficiently suppress T cell-mediated immunoreactivity and graft-versus-host disease in a murine model of allogeneic cell therapy. Biol Blood Marrow Transplant 2008; 14: 973–984.

    Article  CAS  Google Scholar 

  28. Morecki S, Panigrahi S, Pizov G, Yacovlev E, Gelfand Y, Eizik O et al. Effect of KRN7000 on induced graft-vs-host disease. Exp Hematol 2004; 32: 630–637.

    Article  CAS  Google Scholar 

  29. Morecki S, Yacovlev E, Gelfand Y, Uzi I, Slavin S . Cell therapy with preimmunized effector cells mismatched for minor histocompatible antigens in the treatment of a murine mammary carcinoma. J Immunother 2001; 24: 114–121.

    Article  CAS  Google Scholar 

  30. Kaplan E . Non-parametric estimation from incomplete observation. Am Stat 1958; 53: 457–481.

    Article  Google Scholar 

  31. Mantel N . Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966; 50: 163–170.

    CAS  PubMed  Google Scholar 

  32. Gazit A, Yaish P, Gilon C, Levitzki A . Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors. J Med Chem 1989; 32: 2344–2352.

    Article  CAS  Google Scholar 

  33. Säemann MD, Böhmig GA, Osterreicher CH, Staffler G, Diakos C, Krieger PM et al. Suppression of primary T-cell responses and induction of alloantigen-specific hyporesponsiveness in vitro by the janus kinase inhibitor tyrphostin AG490. Transplantation 2000; 70: 1215–1225.

    Article  Google Scholar 

  34. Baeuerle PA, Baichwal VR . NF-kappa B as a frequent target for immunosuppressive and anti-inflammatory molecules. Adv Immunol 1997; 65: 111–137.

    Article  CAS  Google Scholar 

  35. Ghosh S, May MJ, Kopp EB . NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol 1998; 16: 225–260.

    Article  CAS  Google Scholar 

  36. Karin M, Ben-Neriah Y . Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Annu Rev Immunol 2000; 18: 621–663.

    Article  CAS  Google Scholar 

  37. Sun K, Welniak LA, Panoskaltsis-Mortari A, O’Shaughnessy MJ, Liu H, Barao I et al. Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib. Proc Natl Acad Sci USA 2004; 101: 8120–8125.

    Article  CAS  Google Scholar 

  38. Vodanovic-Jankovic S, Hari P, Jacobs P, Komorowski R, Drobyski WR . NF-kappaB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145. Blood 2006; 107: 827–834.

    Article  CAS  Google Scholar 

  39. Zhou R, Zhang F, He PL, Zhou WL, Wu QL, Xu JY et al. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide analog mediates immunosuppressive effects in vitro and in vivo. Int Immunopharmacol 2005; 5: 1895–1903.

    Article  CAS  Google Scholar 

  40. Fu YF, Zhu YN, Ni J, Zhong XG, Tang W, Zhou R et al. (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative, prevents experimental autoimmune encephalomyelitis via inhibiting T cell activation. J Neuroimmunol 2006; 175: 142–151.

    Article  CAS  Google Scholar 

  41. Tang W, Zhou R, Yang Y, Li YC, Yang YF, Zuo JP . Suppression of (5R)-5-hydroxytriptolide (LLDT-8) on allograft rejection in full MHC-mismatched mouse cardiac transplantation. Transplantation 2006; 81: 927–933.

    Article  CAS  Google Scholar 

  42. Tang W, Yang Y, Zhang F, Li YC, Zhou R, Wang JX et al. Prevention of graft-versus-host disease by a novel immunosuppressant, (5R)-5-hydroxytriptolide (LLDT-8), through expansion of regulatory T cells. Int Immunopharmacol 2005; 5: 1904–1913.

    Article  CAS  Google Scholar 

  43. Saiga K, Toyoda E, Tokunaka K, Masuda A, Matsumoto S, Mashiba H et al. NK026680, a novel compound suppressive of dendritic cell function, ameliorates mortality in acute lethal graft-versus-host reaction in mice. Bone Marrow Transplant 2006; 37: 317–323.

    Article  CAS  Google Scholar 

  44. Cetkovic-Cvrlje M, Roers BA, Waurzyniak B, Liu XP, Uckun FM . Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice. Blood 2001; 98: 1607–1613.

    Article  CAS  Google Scholar 

  45. Sagiv-Barfi I, Weiss E, Levitzki A . Design, synthesis, and evaluation of quinazoline T cell proliferation inhibitors. Bioorg Med Chem 2010; 18: 6404–6413.

    Article  CAS  Google Scholar 

  46. Prigozhina TB, Gurevitch O, Morecki S, Yakovlev E, Elkin G, Slavin S . Nonmyeloablative allogeneic bone marrow transplantation as immunotherapy for hematologic malignancies and metastatic solid tumors in preclinical models. Exp Hematol 2002; 30: 89–96.

    Article  Google Scholar 

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Acknowledgements

The authors wish to thank Kirin Brewery Co. Ltd, Tokyo, Japan for its generous support of our research.

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Author notes

  1. S Slavin

    Present address: Current address: The International Center for Cell Therapy and Cancer Immunotherapy (CTCI), Tel-Aviv 64239, Israel,

Authors and Affiliations

  1. Department of Bone Marrow Transplantation and Cancer Immunotherapy, Cell Therapy and Transplantation Research Laboratory, Hadassah University Hospital, Jerusalem, Israel

    S Morecki, Y Gelfand, E Yacovlev, O Eizik, Y Shabat & S Slavin

  2. Department of Biological Chemistry The Hebrew University, Jerusalem, Israel

    I Sagiv

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Correspondence to S Morecki.

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Morecki, S., Gelfand, Y., Yacovlev, E. et al. Selective elimination of alloreactivity in vitro and in vivo while sparing other T-cell-mediated immune responses. Bone Marrow Transplant 47, 838–845 (2012). https://doi.org/10.1038/bmt.2011.198

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