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. 1998 Nov 1;102(9):1742–1748. doi: 10.1172/JCI3906

Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice.

W J Murphy 1, L A Welniak 1, D D Taub 1, R H Wiltrout 1, P A Taylor 1, D A Vallera 1, M Kopf 1, H Young 1, D L Longo 1, B R Blazar 1
PMCID: PMC509122  PMID: 9802888

Abstract

Graft-versus-host disease (GVHD), in which immunocompetent donor cells attack the host, remains a major cause of morbidity after allogeneic bone marrow transplantation (BMT). To understand the role of cytokines in the pathobiology of GVHD, we used cytokine knockout (KO) mice as a source of donor T cells. Two different MHC-disparate strain combinations were examined: BALB/c (H2(d)) donors into lethally irradiated C57BL/6 (H2(b)) recipients or C57BL/6 (H2(b)) donors into B10.BR (H2(k)) recipients. Donor cells were from mice in which either the interferon-gamma (IFN-gamma) or the IL-4 gene was selectively disrupted to understand the role of these cytokines in acute GVHD. In both strain combinations the same pattern was noted with regard to GVHD onset and morbidity. All mice exhibited the classic signs of acute GVHD: weight loss with skin, gut, and liver pathology resulting in morbidity and mortality. Surprisingly, donor cells obtained from mice lacking IFN-gamma gave rise to accelerated morbidity from GVHD when compared with cells from wild-type control donors. Similar results were obtained using normal donors when neutralizing antibodies to IFN-gamma were administered immediately after the BMT. These results suggest that IFN-gamma plays a role in protection from acute GVHD. In marked contrast, cells obtained from IL-4 KO mice resulted in protection from GVHD compared with control donors. Splenocytes from IFN KO mice stimulated with a mitogen proliferated to a significantly greater extent and produced more IL-2 compared with splenocytes obtained from IL-4 KO or control mice. Additionally, there was increased IL-2 production in the spleens of mice undergoing GVHD using IFN-gamma KO donors. These results therefore indicate, with regard to the TH1/ TH2 cytokine paradigm, the absence of a TH1-type cytokine can be deleterious in acute GVHD, whereas absence of a TH2 cytokine can be protective.

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Selected References

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  1. Billiau A., Heremans H., Vandekerckhove F., Dijkmans R., Sobis H., Meulepas E., Carton H. Enhancement of experimental allergic encephalomyelitis in mice by antibodies against IFN-gamma. J Immunol. 1988 Mar 1;140(5):1506–1510. [PubMed] [Google Scholar]
  2. Blazar B. R., Taylor P. A., Panoskaltsis-Mortari A., Gray G. S., Vallera D. A. Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts. Blood. 1995 May 1;85(9):2607–2618. [PubMed] [Google Scholar]
  3. Blazar B. R., Taylor P. A., Smith S., Vallera D. A. Interleukin-10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts. Blood. 1995 Feb 1;85(3):842–851. [PubMed] [Google Scholar]
  4. Brok H. P., Heidt P. J., van der Meide P. H., Zurcher C., Vossen J. M. Interferon-gamma prevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol. 1993 Dec 1;151(11):6451–6459. [PubMed] [Google Scholar]
  5. Brok H. P., Vossen J. M., Heidt P. J. 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 Mar;19(6):601–606. doi: 10.1038/sj.bmt.1700707. [DOI] [PubMed] [Google Scholar]
  6. Bunjes D., Theobald M., Nierle T., Arnold R., Heimpel H. Presence of host-specific interleukin 2-secreting T helper cell precursors correlates closely with active primary and secondary chronic graft-versus-host disease. Bone Marrow Transplant. 1995 May;15(5):727–732. [PubMed] [Google Scholar]
  7. Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
  8. Ellison C. A., Fischer J. M., HayGlass K. T., Gartner J. G. Murine graft-versus-host disease in an F1-hybrid model using IFN-gamma gene knockout donors. J Immunol. 1998 Jul 15;161(2):631–640. [PubMed] [Google Scholar]
  9. Ferber I. A., Brocke S., Taylor-Edwards C., Ridgway W., Dinisco C., Steinman L., Dalton D., Fathman C. G. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol. 1996 Jan 1;156(1):5–7. [PubMed] [Google Scholar]
  10. Ferrara J. L., Cooke K. R., Pan L., Krenger W. The immunopathophysiology of acute graft-versus-host-disease. Stem Cells. 1996 Sep;14(5):473–489. doi: 10.1002/stem.140473. [DOI] [PubMed] [Google Scholar]
  11. Fowler D. H., Kurasawa K., Husebekk A., Cohen P. A., Gress R. E. Cells of Th2 cytokine phenotype prevent LPS-induced lethality during murine graft-versus-host reaction. Regulation of cytokines and CD8+ lymphoid engraftment. J Immunol. 1994 Feb 1;152(3):1004–1013. [PubMed] [Google Scholar]
  12. Hill G. R., Crawford J. M., Cooke K. R., Brinson Y. S., Pan L., Ferrara J. L. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood. 1997 Oct 15;90(8):3204–3213. [PubMed] [Google Scholar]
  13. Hogarth P. J., Folkard S. G., Taylor M. J., Bianco A. E. Accelerated clearance of Onchocerca microfilariae and resistance to reinfection in interleukin-4 gene knockout mice. Parasite Immunol. 1995 Dec;17(12):653–657. doi: 10.1111/j.1365-3024.1995.tb01011.x. [DOI] [PubMed] [Google Scholar]
  14. Kopf M., Le Gros G., Bachmann M., Lamers M. C., Bluethmann H., Köhler G. Disruption of the murine IL-4 gene blocks Th2 cytokine responses. Nature. 1993 Mar 18;362(6417):245–248. doi: 10.1038/362245a0. [DOI] [PubMed] [Google Scholar]
  15. Krenger W., Cooke K. R., Crawford J. M., Sonis S. T., Simmons R., Pan L., Delmonte J., Jr, Karandikar M., Ferrara J. L. Transplantation of polarized type 2 donor T cells reduces mortality caused by experimental graft-versus-host disease. Transplantation. 1996 Nov 15;62(9):1278–1285. doi: 10.1097/00007890-199611150-00018. [DOI] [PubMed] [Google Scholar]
  16. Krenger W., Falzarano G., Delmonte J., Jr, Snyder K. M., Byon J. C., Ferrara J. L. Interferon-gamma suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease. Blood. 1996 Aug 1;88(3):1113–1121. [PubMed] [Google Scholar]
  17. Krenger W., Ferrara J. L. Dysregulation of cytokines during graft-versus-host disease. J Hematother. 1996 Feb;5(1):3–14. doi: 10.1089/scd.1.1996.5.3. [DOI] [PubMed] [Google Scholar]
  18. Krenger W., Ferrara J. L. Graft-versus-host disease and the Th1/Th2 paradigm. Immunol Res. 1996;15(1):50–73. doi: 10.1007/BF02918284. [DOI] [PubMed] [Google Scholar]
  19. Krenger W., Snyder K. M., Byon J. C., Falzarano G., Ferrara J. L. Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease. J Immunol. 1995 Jul 15;155(2):585–593. [PubMed] [Google Scholar]
  20. Krenger W., Snyder K., Smith S., Ferrara J. L. Effects of exogenous interleukin-10 in a murine model of graft-versus-host disease to minor histocompatibility antigens. Transplantation. 1994 Dec 15;58(11):1251–1257. [PubMed] [Google Scholar]
  21. Murphy W. J., Longo D. L. The potential role of NK cells in the separation of graft-versus-tumor effects from graft-versus-host disease after allogeneic bone marrow transplantation. Immunol Rev. 1997 Jun;157:167–176. doi: 10.1111/j.1600-065x.1997.tb00981.x. [DOI] [PubMed] [Google Scholar]
  22. Reiner S. L., Locksley R. M. The regulation of immunity to Leishmania major. Annu Rev Immunol. 1995;13:151–177. doi: 10.1146/annurev.iy.13.040195.001055. [DOI] [PubMed] [Google Scholar]
  23. Räisänen-Sokolowski A., Mottram P. L., Glysing-Jensen T., Satoskar A., Russell M. E. Heart transplants in interferon-gamma, interleukin 4, and interleukin 10 knockout mice. Recipient environment alters graft rejection. J Clin Invest. 1997 Nov 15;100(10):2449–2456. doi: 10.1172/JCI119787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Segal B. M., Dwyer B. K., Shevach E. M. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J Exp Med. 1998 Feb 16;187(4):537–546. doi: 10.1084/jem.187.4.537. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Storb R. Bone marrow transplantation. Transplant Proc. 1995 Oct;27(5):2649–2652. [PubMed] [Google Scholar]
  26. Strom T. B., Roy-Chaudhury P., Manfro R., Zheng X. X., Nickerson P. W., Wood K., Bushell A. The Th1/Th2 paradigm and the allograft response. Curr Opin Immunol. 1996 Oct;8(5):688–693. doi: 10.1016/s0952-7915(96)80087-2. [DOI] [PubMed] [Google Scholar]
  27. Sykes M., Pearson D. A., Szot G. L. IL-2-induced GVHD protection is not inhibited by cyclosporine and is maximal when IL-2 is given over a 25 h period beginning on the day following bone marrow transplantation. Bone Marrow Transplant. 1995 Mar;15(3):395–399. [PubMed] [Google Scholar]
  28. Sykes M., Romick M. L., Sachs D. H. Interleukin 2 prevents graft-versus-host disease while preserving the graft-versus-leukemia effect of allogeneic T cells. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5633–5637. doi: 10.1073/pnas.87.15.5633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sykes M., Szot G. L., Nguyen P. L., Pearson D. A. Interleukin-12 inhibits murine graft-versus-host disease. Blood. 1995 Sep 15;86(6):2429–2438. [PubMed] [Google Scholar]
  30. Ushiyama C., Hirano T., Miyajima H., Okumura K., Ovary Z., Hashimoto H. Anti-IL-4 antibody prevents graft-versus-host disease in mice after bone marrow transplantation. The IgE allotype is an important marker of graft-versus-host disease. J Immunol. 1995 Mar 15;154(6):2687–2696. [PubMed] [Google Scholar]
  31. Wall D. A., Sheehan K. C. The role of tumor necrosis factor and interferon gamma in graft-versus-host disease and related immunodeficiency. Transplantation. 1994 Jan;57(2):273–279. doi: 10.1097/00007890-199401001-00021. [DOI] [PubMed] [Google Scholar]
  32. Williamson E., Garside P., Bradley J. A., More I. A., Mowat A. M. Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease. J Immunol. 1997 Aug 1;159(3):1208–1215. [PubMed] [Google Scholar]

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