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Immune Suppression

Zinc in pharmacological doses suppresses allogeneic reaction without affecting the antigenic response

Bone Marrow Transplantation volume 33, pages 1241–1246 (2004)Cite this article

Summary:

Zinc is an essential trace element for the immune system. Previously it was shown that zinc inhibits alloreactivity. In our present in vitro experiments, it is shown that zinc maintains the antigenic potency of the host while blocking the allogeneic response. These results were observed in experiments using tetanus toxoid as a well-established recall antigen and the mixed lymphocyte culture as an in vitro model for allogeneic reaction. To prove the in vivo relevance, an ex vivo experimental setup was established. This involved participants taking zinc orally for 1 week. Here it is shown that in vivo zinc application induced the same effect of blocking the mixed lymphocyte culture without influencing tetanus toxoid stimulation. So far, no clinical application studies have been performed, but the observed selective suppression of allogeneic reaction by zinc is the first step towards a new generation of immunosuppressants.

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References

  1. Danzer SG, Rink L . Cytokines in mixed lymphocyte culture as a prospective parameter for transplantation. Med Klin 1996; 91: 494–500.

    CAS  Google Scholar 

  2. Hayry P, Andersson LC, Nordling S et al. Allograft response in vitro. Transplant Rev 1972; 12: 91–140.

    CAS  PubMed  Google Scholar 

  3. Klein J, Chiang CL . Ability of H-2 regions to induce graft-vs-host disease. J Immunol 1976; 117: 736–740.

    CAS  PubMed  Google Scholar 

  4. Danzer SG, aCampo A, Kunze B et al. Identification of HLA-DRB1 and HLA-DQB1 identical individuals by a cytokine-based mixed lymphocyte culture. Lymphokine Cytokine Res 1994; 13: 303–308.

    CAS  PubMed  Google Scholar 

  5. Acha OH, Held W, Scarpellino L et al. Mls: a link between immunology and retrovirology. Int Rev Immunol 1992; 8: 327–336.

    Article  Google Scholar 

  6. Dickinson AM, Sviland L, Hamilton PJ et al. Cytokine involvement in predicting clinical graft-versus-host disease in allogeneic bone marrow transplant recipients. Bone Marrow Transplant 1994; 13: 65–70.

    CAS  Google Scholar 

  7. Danzer SG, aCampo C, Rink L . Interferon-gamma plays a key role in the human mixed lymphocyte culture. Bone Marrow Transplant 1996; 18: 991–996.

    CAS  PubMed  Google Scholar 

  8. Mihatsch MJ, Kyo M, Morozumi K et al. The side-effects of cyclosporine-A and tacrolimus. Clin Nephrol 1998; 49: 356–363.

    CAS  Google Scholar 

  9. Wellinghausen N, Kirchner H, Rink L . The immunobiology of zinc. Immunol Today 1997; 18: 519–520.

    Article  CAS  Google Scholar 

  10. Wellinghausen N, Rink L . The significance of zinc for leukocyte biology. J Leukoc Biol 1998; 64: 571–577.

    Article  CAS  Google Scholar 

  11. Rink L, Gabriel P . Zinc and the immune system. Proc Nutr Soc 2000; 59: 541–552.

    Article  CAS  Google Scholar 

  12. Allen JL, Perri RT, McClain CJ et al. Alterations in human natural killer cell activity and monocyte cytotoxicity induced by zinc deficiency. J Lab Clin Med 1983; 102: 577–589.

    CAS  PubMed  Google Scholar 

  13. Keen CL, Gershwin ME . Zinc deficiency and immune function. Ann Rev Nutr 1990; 10: 415–431.

    Article  CAS  Google Scholar 

  14. Fraker PJ, King LE, Laakko T et al. The dynamic link between the integrity of the immune system and zinc status. J Nutr 2000; 130 (Suppl. 5S): 1399S–1406S.

    Article  CAS  Google Scholar 

  15. Prasad AS . Zinc and immunity. Mol Chem Biochem 1998; 188: 63–69.

    Article  CAS  Google Scholar 

  16. Depasquale-Jardieu P, Fraker PJ . Interference in the development of a secondary immune response in mice by zinc deprivation: persistence of effects. J Nutr 1984; 114: 1762–1769.

    Article  CAS  Google Scholar 

  17. Minigari MC, Morretta A, Moretta L . Regulation of KIR expression in human T cells: a safety mechanism that repairs protective T cell responses. Immunol Today 1998; 19: 153–157.

    Article  Google Scholar 

  18. Chandra RK . Effect of vitamin and trace-element supplementation on immune responses and infection in the elderly. Lancet 1992; 340: 1124–1137.

    Article  CAS  Google Scholar 

  19. Wellinghausen N, Martin M, Rink L . Zinc inhibits interleukin-1-dependent T cell stimulation. Eur J Immunol 1997; 27: 2529–2535.

    Article  CAS  Google Scholar 

  20. aCampo C, Wellinghausen N, Faber C et al. Zinc inhibits the mixed lymphocyte culture. Biol Trace Elem Res 2001; 79: 15–22.

    Article  Google Scholar 

  21. Driessen C, Hirv K, Rink L et al. Induction of cytokines by zinc ions in human peripheral blood mononuclear cells and separated monocytes. Lymphokine Cytokine Res 1994; 13: 15–20.

    CAS  PubMed  Google Scholar 

  22. Prasad AS, Fitzgerald JT, Bao B et al. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000; 133: 245–252.

    Article  CAS  Google Scholar 

  23. Danzer SG, Kirchner H, Rink L . Cytokine interactions in human mixed lymphocyte culture. Transplantation 1994; 57: 1638–1642.

    Article  CAS  Google Scholar 

  24. Bonham M, O'Connor JM, Alexander HD et al. Zinc supplementation has no effect on circulating levels of peripheral blood leucocytes and lymphocyte subsets in healthy adult men. Br J Nutr 2003; 89: 695–703.

    Article  CAS  Google Scholar 

  25. Woo J, Sewell HF, Thomson AW . The influence of FK-506 and low-concentration cyclosporin on human lymphocyte activation antigen expression and blastogenesis: a flow cytometric analysis. Scand. J Immunol 1990; 31: 297–304.

    Article  CAS  Google Scholar 

  26. Fishman JA, Rubin RH . Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741–1751.

    Article  CAS  Google Scholar 

  27. Wang W, Gulden PH, Pierce RA et al. A naturally processed peptide presented by HLA-A*0201 is expressed at low abundance and recognized by an alloreactive CD8+ cytotoxic T cell with apparent high affinity. J Immunol 1997; 158: 5707–5804.

    Google Scholar 

  28. Bevan MJ . High determinant density may explain the phenomenon of alloreactivity. Immunol Today 1984; 5: 128–130.

    Article  CAS  Google Scholar 

  29. Obst R, Netuschil N, Klopfer K et al. The role of peptides in T cell alloreactivity is determined by self-major histocompatibility complex molecules. J Exp Med 2000; 191: 805–812.

    Article  CAS  Google Scholar 

  30. Fraser JD, Urban RG, Strominger JL et al. Zinc regulates the function of two superantigens. Proc Natl Acad Sci USA 1992; 89: 5507–5511.

    Article  CAS  Google Scholar 

  31. Liu KD, Gaffen SL, Goldsmith MA . JAK/STAT signaling by cytokine receptors. Curr Opin Immunol 1998; 10: 271–278.

    Article  CAS  Google Scholar 

  32. Welte T, Leitenberg L, Dittel BN et al. STAT5 interaction with the T cell receptor complex and stimulation of T cell proliferation. Science 1999; 283: 222–225.

    Article  CAS  Google Scholar 

  33. Gerwien J, Nielsen M, Labuda T et al. Cutting edge: TCR stimulation by antibody and bacterial superantigen induces STAT3 activation in human T cells. J Immunol 1999; 163: 1742–1745.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Romney Haylett for critical reading of the manuscript.

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Authors and Affiliations

  1. Institute of Immunology and Transfusion Medicine, University of Lübeck School of Medicine, Lübeck, Germany

    C Faber & P Gabriel

  2. Institute of Immunology, University Hospital, Rhine-Westfalia-Technical University of Aachen, Aachen, Germany

    K-H Ibs & L Rink

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  1. C Faber
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  2. P Gabriel
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  3. K-H Ibs
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  4. L Rink
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Correspondence to L Rink.

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Faber, C., Gabriel, P., Ibs, KH. et al. Zinc in pharmacological doses suppresses allogeneic reaction without affecting the antigenic response. Bone Marrow Transplant 33, 1241–1246 (2004). https://doi.org/10.1038/sj.bmt.1704509

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