Biology of Blood and Marrow Transplantation
Volume 15, Issue 11 , Pages 1347-1353 , November 2009

Dichotomous Role of Interferon-γ in Allogeneic Bone Marrow Transplant

  • Ying Lu
  • ,
  • Edmund K. Waller

      Affiliations

    • Corresponding Author InformationCorrespondence and reprint requests: Edmund K. Waller, MD, PhD FACP, Emory University School of Medicine, Winship Cancer Institute, 1365C Clifton Road NE, Room C4002, Atlanta, GA 30322.

Received 6 May 2009 ,Accepted 16 July 2009.

References 

  1. Farrar MA, Schreiber RD. The molecular cell biology of interferon-gamma and its receptor. Annu Rev Immunol. 1993;11:571–611
  2. Schroder K, Hertzog PJ, Ravasi T, Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol. 2004;75:163–189
  3. Frucht DM, Fukao T, Bogdan C, Schindler H, O'Shea JJ, Koyasu S. IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol. 2001;22:556–560
  4. Flaishon L, Hershkoviz R, Lantner F, et al. Autocrine secretion of interferon gamma negatively regulates homing of immature B cells. J Exp Med. 2000;192:1381–1388
  5. Harris DP, Haynes L, Sayles PC, et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nat Immunol. 2000;1:475–482
  6. Baker J, Verneris MR, Ito M, Shizuru JA, Negrin RS. Expansion of cytolytic CD8(+) natural killer T cells with limited capacity for graft-versus-host disease induction due to interferon gamma production. Blood. 2001;97:2923–2931
  7. Asai O, Longo DL, Tian ZG, et al. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. J Clin Invest. 1998;101:1835–1842
  8. Trotta R, Col JD, Yu J, et al. TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J Immunol. 2008;181:3784–3792
  9. Munder M, Mallo M, Eichmann K, Modolell M. Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: a novel pathway of autocrine macrophage activation. J Exp Med. 1998;187:2103–2108
  10. Fukao T, Matsuda S, Koyasu S. Synergistic effects of IL-4 and IL-18 on IL-12-dependent IFN-gamma production by dendritic cells. J Immunol. 2000;164:64–71
  11. Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004;1024:138–146
  12. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol. 2006;24:99–146
  13. Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB. Interleukin-10 and related cytokines and receptors. Annu Rev Immunol. 2004;22:929–979
  14. Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, Stewart TA. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993;259:1739–1742
  15. Sun Y, Tawara I, Toubai T, Reddy P. Pathophysiology of acute graft-versus-host disease: recent advances. Transl Res. 2007;150:197–214
  16. Ferrara JL, Cooke KR, Teshima T. The pathophysiology of acute graft-versus-host disease. Int J Hematol. 2003;78:181–187
  17. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 2009;373:1550–1561
  18. Yang YG, Wang H, Asavaroengchai W, Dey BR. Role of interferon-gamma in GVHD and GVL. Cell Mol Immunol. 2005;2:323–329
  19. 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
  20. Takatsuka H, Yamada S, Okamoto T, et al. Predicting the severity of intestinal graft-versus-host disease from leukotriene B4 levels after bone marrow transplantation. Bone Marrow Transplant. 2000;26:1313–1316
  21. Mowat AM. Antibodies to IFN-gamma prevent immunologically mediated intestinal damage in murine graft-versus-host reaction. Immunology. 1989;68:18–23
  22. Yang YG, Qi J, Wang MG, Sykes M. Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood. 2002;99:4207–4215
  23. Tarrant TK, Silver PB, Wahlsten JL, et al. Interleukin 12 protects from a T helper type 1-mediated autoimmune disease, experimental autoimmune uveitis, through a mechanism involving interferon gamma, nitric oxide, and apoptosis. J Exp Med. 1999;189:219–230
  24. Brok HP, Vossen JM, Heidt PJ. IFN-gamma-mediated prevention of graft-versus-host disease: pharmacodynamic studies and influence on proliferative capacity of chimeric spleen cells. Bone Marrow Transplant. 1998;22:1005–1010
  25. Brok HP, Heidt PJ, van der Meide PH, Zurcher C, Vossen JM. Interferon-gamma prevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol. 1993;151:6451–6459
  26. Hidalgo LG, Halloran PF. Role of IFN-gamma in allograft rejection. Crit Rev Immunol. 2002;22:317–349
  27. Asavaroengchai W, Wang H, Wang S, et al. An essential role for IFN-gamma in regulation of alloreactive CD8 T cells following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2007;13:46–55
  28. Liu Y, Janeway CA. Interferon gamma plays a critical role in induced cell death of effector T cell: a possible third mechanism of self-tolerance. J Exp Med. 1990;172:1735–1739
  29. Frasca L, Nasso M, Spensieri F, et al. IFN-gamma arms human dendritic cells to perform multiple effector functions. J Immunol. 2008;180:1471–1481
  30. Munn DH, Sharma MD, Lee JR, et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science. 2002;297:1867–1870
  31. King NJ, Thomas SR. Molecules in focus: indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol. 2007;39:2167–2172
  32. Wood KJ, Sawitzki B. Interferon gamma: a crucial role in the function of induced regulatory T cells in vivo. Trends Immunol. 2006;27:183–187
  33. Wall DA, Hamberg SD, Reynolds DS, Burakoff SJ, Abbas AK, Ferrara JL. Immunodeficiency in graft-versus-host disease. I. Mechanism of immune suppression. J Immunol. 1988;140:2970–2976
  34. Brok HP, Vossen JM, Heidt PJ. Interferon-gamma-mediated prevention of graft-versus-host disease: development of immune competent and allo-tolerant T cells in chimeric mice. Bone Marrow Transplant. 1997;19:601–606
  35. Szebeni J, Wang MG, Pearson DA, Szot GL, Sykes M. IL-2 inhibits early increases in serum gamma interferon levels associated with graft-versus-host-disease. Transplantation. 1994;58:1385–1393
  36. Butturini A, Gale RP. T cell depletion in bone marrow transplantation for leukemia: current results and future directions. Bone Marrow Transplant. 1988;3:185–192
  37. Li JM, Giver CR, Waller EK. Graft engineering using ex vivo methods to limit GVHD: fludarabine treatment generates superior GVL effects in allogeneic BMT. Exp Hematol. 2006;34:895–904
  38. Li JM, Gorechlad J, Larsen CP, Waller EK. Apoptotic donor leukocytes limit mixed-chimerism induced by CD40-CD154 blockade in allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2006;12:1239–1249
  39. Waller EK, Giver CR, Rosenthal H, et al. Facilitating T-cell immune reconstitution after haploidentical transplantation in adults. Blood Cells Mol Dis. 2004;33:233–237
  40. Hossain MS, Roback JD, Pollack BP, Jaye DL, Langston A, Waller EK. Chronic GvHD decreases antiviral immune responses in allogeneic BMT. Blood. 2007;109:4548–4556
  41. Hossain MS, Roback JD, Wang F, Waller EK. Host and donor immune responses contribute to antiviral effects of amotosalen-treated donor lymphocytes following early posttransplant cytomegalovirus infection. J Immunol. 2008;180:6892–6902
  42. Giver CR, Montes RO, Mittelstaedt S, et al. Ex vivo fludarabine exposure inhibits graft-versus-host activity of allogeneic T cells while preserving graft-versus-leukemia effects. Biol Blood Marrow Transplant. 2003;9:616–632
  43. Sykes M, Szot GL, Nguyen PL, Pearson DA. Interleukin-12 inhibits murine graft-versus-host disease. Blood. 1995;86:2429–2438
  44. Yang YG, Sergio JJ, Pearson DA, Szot GL, Shimizu A, Sykes M. Interleukin-12 preserves the graft-versus-leukemia effect of allogeneic CD8 T cells while inhibiting CD4-dependent graft-versus-host disease in mice. Blood. 1997;90:4651–4660
  45. Yang YG, Sykes M. The role of interleukin-12 in preserving the graft-versus-leukemia effect of allogeneic CD8 T cells independently of GVHD. Leuk Lymphoma. 1999;33:409–420
  46. Reddy P, Teshima T, Kukuruga M, et al. Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J Exp Med. 2001;194:1433–1440
  47. Reddy P, Ferrara JL. Role of interleukin-18 in acute graft-vs-host disease. J Lab Clin Med. 2003;141:365–371
  48. Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat Med. 2005;11:1299–1305
  49. Reddy P, Maeda Y, Liu C, Krijanovski OI, Korngold R, Ferrara JL. A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med. 2005;11:1244–1249
  50. Shlomchik WD, Couzens MS, Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science. 1999;285:412–415
  51. Lonial S, Torre C, David E, Harris W, Arellano M, Waller EK. Regulation of alloimmune responses by dendritic cell subsets. Exp Hematol. 2008;36:1309–1317
  52. Waller EK, Rosenthal H, Jones TW, et al. Larger numbers of CD4(bright) dendritic cells in donor bone marrow are associated with increased relapse after allogeneic bone marrow transplantation. Blood. 2001;97:2948–2956
  53. Li JM, Waller EK. Donor 1-presenting cells regulate T-cell expansion and antitumor activity after allogeneic bone marrow transplantation. Biol Blood Marrow Transplant. 2004;10:540–551
  54. Li JM, Waller EK. The yin and yang of adaptive immunity in allogeneic hematopoietic cell transplantation: donor antigen-presenting cells can either augment or inhibit donor T cell alloreactivity. Adv Exp Med Biol. 2007;590:69–87
  55. Li JM, Southerland L, Lu Y et al. Activation, immune polarization, and graft-versus-leukemia activity of donor T-cells are regulated by specific subsets of donor bone marrow antigen-presenting cells in allogeneic hematopoietic stem cell transplantation. J Immunol (in revision).
  56. Wang H, Asavaroengchai W, Yeap BY, et al. Paradoxical effects of IFN-gamma in graft-versus-host disease reflect promotion of lymphohematopoietic graft-versus-host reactions and inhibition of epithelial tissue injury. Blood. 2009;113:3612–3619
  57. Herberman RB, Nunn ME, Holden HT, Lavrin DH. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer. 1975;16:230–239
  58. Kiessling R, Petranyi G, Klein G, Wigzel H. Genetic variation of in vitro cytolytic activity and in vivo rejection potential of non-immunized semi-syngeneic mice against a mouse lymphoma line. Int J Cancer. 1975;15:933–940
  59. Mocikat R, Braumuller H, Gumy A, et al. Natural killer cells activated by MHC class I(low) targets prime dendritic cells to induce protective CD8 T cell responses. Immunity. 2003;19:561–569
  60. Adam C, King S, Allgeier T, et al. DC-NK cell cross talk as a novel CD4 + T-cell-independent pathway for antitumor CTL induction. Blood. 2005;106:338–344
  61. Gerosa F, Baldani-Guerra B, Nisii C, Marchesini V, Carra G, Trinchieri G. Reciprocal activating interaction between natural killer cells and dendritic cells. J Exp Med. 2002;195:327–333
  62. Fujii S. Application of natural killer T-cells to posttransplantation immunotherapy. Int J Hematol. 2005;81:1–5
  63. Ellison CA, Taniguchi M, Fischer JM, Hayglass KT, Gartner JG. Graft-versus-host disease in recipients of grafts from natural killer T cell-deficient (Jalpha281(−/−)) donors. Immunology. 2006;119:338–347
  64. Kim JH, Choi EY, Chung DH. Donor bone marrow type II (non-Valpha14Jalpha18 CD1d-restricted) NKT cells suppress graft-versus-host disease by producing IFN-gamma and IL-4. J Immunol. 2007;179:6579–6587
  65. Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ. IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med. 2005;201:1925–1935
  66. Sakaguchi S. Naturally arising Foxp3-expressing CD25 + CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6:345–352
  67. Edinger M, Hoffmann P, Ermann J, et al. CD4 + CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144–1150
  68. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet. 2008;371:1579–1586
  69. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363:1439–1441
  70. Uccelli A, Moretta L, Pistoia V. Immunoregulatory function of mesenchymal stem cells. Eur J Immunol. 2006;36:2566–2573
  71. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–1822
  72. Zhang B, Liu R, Shi D, et al. Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2-dependent regulatory dendritic cell population. Blood. 2009;113:46–57
  73. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2:141–150
  74. Krampera M, Cosmi L, Angeli R, et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells. 2006;24:386–398
  75. Polchert D, Sobinsky J, Douglas G, et al. IFN-gamma activation of mesenchymal stem cells for treatment and prevention of graft versus host disease. Eur J Immunol. 2008;38:1745–1755
  76. Ning H, Yang F, Jiang M, et al. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia. 2008;22:593–599
  77. Berner V, Liu H, Zhou Q, et al. IFN-gamma mediates CD4 + T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy. Nat Med. 2007;13:354–360
  78. Fluhr H, Krenzer S, Stein GM, et al. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis. J Cell Sci. 2007;120:4126–4133
  79. Shin EC, Ahn JM, Kim CH, et al. IFN-gamma induces cell death in human hepatoma cells through a TRAIL/death receptor-mediated apoptotic pathway. Int J Cancer. 2001;93:262–268
  80. Ichiba T, Teshima T, Kuick R, et al. Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays. Blood. 2003;102:763–771
  81. Puccetti P, Grohmann U. IDO and regulatory T cells: a role for reverse signalling and non-canonical NF-kappaB activation. Nat Rev Immunol. 2007;7:817–823
  82. Terness P, Bauer TM, Rose L, et al. Inhibition of allogeneic T cell proliferation by indoleamine 2,3-dioxygenase-expressing dendritic cells: mediation of suppression by tryptophan metabolites. J Exp Med. 2002;196:447–457
  83. Sharma MD, Hou DY, Liu Y, et al. Indoleamine 2,3-dioxygenase controls conversion of Foxp3 + Tregs to TH17-like cells in tumor-draining lymph nodes. Blood. 2009;113:6102–6111
  84. Mohib K, Guan Q, Diao H, Du C, Jevnikar AM. Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells. Am J Physiol Renal Physiol. 2007;293:F801–F812
  85. Jasperson LK, Bucher C, Panoskaltsis-Mortari A, et al. Indoleamine 2,3-dioxygenase is a critical regulator of acute graft-versus-host disease lethality. Blood. 2008;111:3257–3265
  86. Steckel NK, Kuhn U, Beelen DW, Elmaagacli AH. Indoleamine 2,3-dioxygenase expression in patients with acute graft-versus-host disease after allogeneic stem cell transplantation and in pregnant women: association with the induction of allogeneic immune tolerance?. Scand J Immunol. 2003;57:185–191

 Financial disclosure: See Acknowledgments on page 1351.

PII: S1083-8791(09)00345-0

doi: 10.1016/j.bbmt.2009.07.015

Biology of Blood and Marrow Transplantation
Volume 15, Issue 11 , Pages 1347-1353 , November 2009