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Graft-Versus-Host Disease

Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD

Abstract

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation. Pretransplant conditioning regimes cause release of proinflammatory cytokines that stimulate alloreactive donor T cells to attack recipient tissues. IL-10 has been shown to directly downregulate CD4+ T cells by suppressing IL-2 secretion and a critical role played by regulatory T cells has been demonstrated in animal models. One defining cytokine profile for regulatory T cells is the production of IL-10. Release of specific cytokines (IL-10, IL-4 and IFN-γ) was detected using ELISPOT technology, following stimulation of donor peripheral blood mononuclear cells by recipient (human leukocyte antigen-matched sibling) alloantigen or by mitogen. Correlation between the frequency of cytokine-releasing cells and the development of acute GVHD was investigated. A high frequency of donor cells producing IL-10 in response to recipient alloantigen stimulation correlated with absence of acute GVHD after bone marrow transplant (BMT), while low frequency was strongly associated with severe GVHD. This study presents strong evidence that estimating the frequency of donor alloreactive cells producing IL-10 in response to recipient antigens will provide valuable information prior to BMT regarding potential transplant outcome.

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References

  1. Antin JH, Ferrara JLM . Cytokine dysregulation and acute graft-versus-host disease. Blood 1992; 80: 2964–2968.

    CAS  PubMed  Google Scholar 

  2. Krenger W, Hill GE, Ferrara JL . Cytokine cascades in acute-graft-versus-host disease. Transplantation 1997; 64: 553–558.

    Article  CAS  PubMed  Google Scholar 

  3. Holler E, Roncarolo MG, Hintermeier-Knabe R, Eissner G, Ertl B, Schultz U et al. Prognostic significance of increased IL-10 production in patients prior to allogeneic bone marrow transplantation. Bone Marrow Transplant 2000; 25: 237–241.

    Article  CAS  PubMed  Google Scholar 

  4. De Waal Malefyt R, Yssel H, Roncarolo M-G, Spits H, de Vries JE . Interleukin-10. Curr Opin Immunol 1992; 4: 314–320.

    Article  CAS  PubMed  Google Scholar 

  5. Willems F, Marchant R, Delville JP . Interleukin 10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes. Eur J Immunogenet 1994; 24: 1007–1009.

    Article  CAS  Google Scholar 

  6. Taga K, Mostowski H, Tosato G . Human interleukin-10 can directly inhibit T-cell growth. Blood 1993; 81: 2964–2971.

    CAS  PubMed  Google Scholar 

  7. Groux H, Bigler M, de Vries JE, Roncarolo M-G . Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells. J Exp Med 1996; 184: 19–29.

    Article  CAS  PubMed  Google Scholar 

  8. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S . Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002; 196: 389–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH . Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001; 193: 1285–1294.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997; 389: 737–742.

    Article  CAS  PubMed  Google Scholar 

  11. Glucksberg H, Storb R, Fefer A, Buckner CD, Neimann PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  12. Czerkinsky C, Andersson G, Ekre HP, Nilsson LA, Klareskog L, Ouchterlony O . Reverse ELISPOT assay for clonal analysis of cytokine production. I. Enumeration of gamma-interferon-secreting cells. J Immunol Methods 1988; 110: 29–36.

    Article  CAS  PubMed  Google Scholar 

  13. Weston LE, Geczy AF, Farrell C . Donor helper T-cell frequencies as predictors of acute graft-versus-host disease in bone marrow transplantation between HLA-identical siblings. Transplantation 1997; 64: 836–841.

    Article  CAS  PubMed  Google Scholar 

  14. Taga K, Tosato G . IL-10 inhibits human T cell proliferation and IL-2 production. J Immunol 1992; 148: 1143–1148.

    CAS  PubMed  Google Scholar 

  15. Bacchetta R, Bigler M, Touraine J-L, Parkman R, Tovo P-A, Abrams J et al. High levels of interleukin-10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hematopoietic stem cells. J Exp Med 1994; 179: 493–502.

    Article  CAS  PubMed  Google Scholar 

  16. Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Narula SK, Smith S, Roncarolo M-G et al. Interleukin-10 dose-dependent regulation of CD4+ and CD8+ T cell-mediated graft-versus-host disease. Transplantation 1998; 66: 1220–1229.

    Article  CAS  PubMed  Google Scholar 

  17. Chen ZM, O'Shaughnessy MJ, Gramaglia I, Panoskaltsis-Mortari A, Murphy WJ, Narula S et al. IL-10 and TGF-beta induce alloreactive CD4+CD25- T cells to acquire regulatory cell function. Blood 2003; 101: 5076–5083.

    Article  CAS  PubMed  Google Scholar 

  18. Rafiq K, Charitidou L, Bullens DMA, Kasran A, Lorre K, Ceuppens J et al. Regulation of the IL-10 production by human T cells. Scand J Immunol 2001; 53: 139–147.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to L E Weston.

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Weston, L., Geczy, A. & Briscoe, H. Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD. Bone Marrow Transplant 37, 207–212 (2006). https://doi.org/10.1038/sj.bmt.1705218

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