Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Graft-versus-host Disease

Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target?

Bone Marrow Transplantation volume 48, pages 284–293 (2013)Cite this article

Subjects

Abstract

GVHD is a major complication after allo-SCT. In GVHD, some tissues like liver, intestine and skin are infiltrated by donor T cells while others like muscle are not. The mechanism underlying targeted tropism of donor T cells is not fully understood. In the present study, we aim to explore differences in gene expression profile among target versus non-target tissues in a mouse model of GVHD based on chemotherapy conditioning. Expression levels of JAK–signal transducers and activators of transcription (STAT), CXCL1, ICAM1 and STAT3 were increased in the liver and remained unchanged (or decreased) in the muscle and kidney after conditioning. At the start of GVHD the expression levels of CXCL9, ITGb2, SAA3, MARCO, TLR and VCAM1 were significantly higher in the liver or kidney compared with the muscle of GVHD animals. Moreover, biological processes of inflammatory reactions, leukocyte migration, response to bacterium and chemotaxis followed the same pattern. Our data show that both chemotherapy and allogenicity exclusively induce expression of inflammatory genes in target tissues. Moreover, gene expression profile and histopathological findings in the kidney are similar to those observed in the liver of GVHD mice.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Copelan EA . Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354: 1813–1826.

    Article  CAS  PubMed  Google Scholar 

  2. Mielcarek M, Martin PJ, Leisenring W, Flowers ME, Maloney DG, Sandmaier BM et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102: 756–762.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Hill GR, Ferrara JL . The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 2000; 95: 2754–2759.

    CAS  PubMed  Google Scholar 

  5. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman 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 

  6. Teshima T, Ferrara JL . Understanding the alloresponse: new approaches to graft-versus-host disease prevention. Semin Hematol 2002; 39: 15–22.

    Article  PubMed  Google Scholar 

  7. Kataoka Y, Iwasaki T, Kuroiwa T, Seto Y, Iwata N, Hashimoto N et al. The role of donor T cells for target organ injuries in acute and chronic graft-versus-host disease. Immunology 2001; 103: 310–318.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Kimura S, Horie A, Hiki Y, Yamamoto C, Suzuki S, Kuroda J et al. Nephrotic syndrome with crescent formation and massive IgA deposition following allogeneic bone marrow transplantation for natural killer cell leukemia/lymphoma. Blood 2003; 101: 4219–4221.

    Article  CAS  PubMed  Google Scholar 

  9. Homma CI, Kami M, Masuo S, Sakiyama M, Kojima R, Hori A et al. Graft-versus-host disease of the kidney after rapid tapering of cyclosporin following reduced intensity hematopoietic stem cell transplantation. Bone Marrow Transplant 2005; 35: 929–930.

    Article  CAS  PubMed  Google Scholar 

  10. Holler E, Kolb HJ, Mittermuller J, Kaul M, Ledderose G, Duell T et al. Modulation of acute graft-versus-host-disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNF alpha) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF alpha (MAK 195F). Blood 1995; 86: 890–899.

    CAS  PubMed  Google Scholar 

  11. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL . Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 1997; 90: 3204–3213.

    CAS  PubMed  Google Scholar 

  12. Ebert LM, Schaerli P, Moser B . Chemokine-mediated control of T cell traffic in lymphoid and peripheral tissues. Mol Immunol 2005; 42: 799–809.

    Article  CAS  PubMed  Google Scholar 

  13. New JY, Li B, Koh WP, Ng HK, Tan SY, Yap EH et al. T cell infiltration and chemokine expression: relevance to the disease localization in murine graft-versus-host disease. Bone Marrow Transplant 2002; 29: 979–986.

    Article  CAS  PubMed  Google Scholar 

  14. Mapara MY, Leng C, Kim YM, Bronson R, Lokshin A, Luster A et al. Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR. Biol Blood Marrow Transplant 2006; 12: 623–634.

    Article  CAS  PubMed  Google Scholar 

  15. Ma HH, Ziegler J, Li C, Sepulveda A, Bedeir A, Grandis J et al. Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3. Cell Immunol 2011; 268: 37–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Halloran PF, Autenried P, Ramassar V, Urmson J, Cockfield S . Local T cell responses induce widespread MHC expression. Evidence that IFN-gamma induces its own expression in remote sites. J Immunol 1992; 148: 3837–3846.

    CAS  PubMed  Google Scholar 

  17. Sadeghi B, Aghdami N, Hassan Z, Forouzanfar M, Rozell B, Abedi-Valugerdi M et al. GVHD after chemotherapy conditioning in allogeneic transplanted mice. Bone Marrow Transplant 2008; 42: 807–818.

    Article  CAS  PubMed  Google Scholar 

  18. Sadeghi B, Al-Hashmi S, Hassan Z, Rozell B, Concha H, Lundmark C et al. Expansion and activation kinetics of immune cells during early phase of GVHD in mouse model based on chemotherapy conditioning. Clin Dev Immunol 2010; 2010: 142943.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Perez-Simon JA, Diez-Campelo M, Martino R, Brunet S, Urbano A, Caballero MD et al. Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation. Br J Haematol 2005; 130: 394–403.

    Article  PubMed  Google Scholar 

  20. Ferrara JL, Cooke KR, Teshima T . The pathophysiology of acute graft-versus-host disease. Int J Hematol 2003; 78: 181–187.

    Article  CAS  PubMed  Google Scholar 

  21. Beilhack A, Schulz S, Baker J, Beilhack GF, Wieland CB, Herman EI et al. In vivo analyses of early events in acute graft-versus-host disease reveal sequential infiltration of T-cell subsets. Blood 2005; 106: 1113–1122.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Moore TA, Newstead MW, Strieter RM, Mehrad B, Beaman BL, Standiford TJ . Bacterial clearance and survival are dependent on CXC chemokine receptor-2 ligands in a murine model of pulmonary Nocardia asteroides infection. J Immunol 2000; 164: 908–915.

    Article  CAS  PubMed  Google Scholar 

  23. Eisele NA, Lee-Lewis H, Besch-Williford C, Brown CR, Anderson DM . Chemokine receptor CXCR2 mediates bacterial clearance rather than neutrophil recruitment in a murine model of pneumonic plague. Am J Pathol 2011; 178: 1190–1200.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Hotchkiss RS, Nicholson DW . Apoptosis and caspases regulate death and inflammation in sepsis. Nat Rev Immunol 2006; 6: 813–822.

    Article  CAS  PubMed  Google Scholar 

  25. Levy DE, Darnell JE . Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 2002; 3: 651–662.

    Article  CAS  PubMed  Google Scholar 

  26. Ihle JN . The Stat family in cytokine signaling. Curr Opin Cell Biol 2001; 13: 211–217.

    Article  CAS  PubMed  Google Scholar 

  27. Hassan M, Ehrsson H . Metabolism of 14C-busulfan in isolated perfused rat liver. Eur J Drug Metab Pharmacokinet 1987; 12: 71–76.

    Article  CAS  PubMed  Google Scholar 

  28. de Jonge ME, Huitema AD, Rodenhuis S, Beijnen JH . Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 2005; 44: 1135–1164.

    Article  CAS  PubMed  Google Scholar 

  29. Sadeghi B, Jansson M, Hassan Z, Mints M, Hagglund H, Abedi-Valugerdi M et al. The effect of administration order of BU and CY on engraftment and toxicity in HSCT mouse model. Bone Marrow Transplant 2008; 41: 895–904.

    Article  CAS  PubMed  Google Scholar 

  30. DeLeve LD, Wang X . Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes. Pharmacology 2000; 60: 143–154.

    Article  CAS  PubMed  Google Scholar 

  31. Rosenbeck LL, Kiel PJ, Kalsekar I, Vargo C, Baute J, Sullivan CK et al. Prophylaxis with sirolimus and tacrolimus +/- antithymocyte globulin reduces the risk of acute graft-versus-host disease without an overall survival benefit following allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2011; 17: 916–922.

    Article  CAS  PubMed  Google Scholar 

  32. Yang YG, Wang H, Asavaroengchai W, Dey BR . Role of Interferon-gamma in GVHD and GVL. Cell Mol Immunol 2005; 2: 323–329.

    CAS  PubMed  Google Scholar 

  33. Deeg HJ . Cytokines in graft-versus-host disease and the graft-versus-leukemia reaction. Int J Hematol 2001; 74: 26–32.

    Article  CAS  PubMed  Google Scholar 

  34. Symington FW, Symington BE, Liu PY, Viguet H, Santhanam U, Sehgal PB . The relationship of serum IL-6 levels to acute graft-versus-host disease and hepatorenal disease after human bone marrow transplantation. Transplantation 1992; 54: 457–462.

    Article  CAS  PubMed  Google Scholar 

  35. Hill GR, Cooke KR, Brinson YS, Bungard D, Ferrara JL . Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation. Transplantation 1999; 67: 1478–1480.

    Article  CAS  PubMed  Google Scholar 

  36. Ichiba T, Teshima T, Kuick R, Misek DE, Liu C, Takada Y et al. Early changes in gene expression profiles of hepatic GVHD uncovered by oligonucleotide microarrays. Blood 2003; 102: 763–771.

    Article  CAS  PubMed  Google Scholar 

  37. Ferrara JL, Reddy P . Pathophysiology of graft-versus-host disease. Semin Hematol 2006; 43: 3–10.

    Article  CAS  PubMed  Google Scholar 

  38. Mason DW, Dallman M, Barclay AN . Graft-versus-host disease induces expression of Ia antigen in rat epidermal cells and gut epithelium. Nature 1981; 293: 150–151.

    Article  CAS  PubMed  Google Scholar 

  39. Schiltz PM, Gomez GG, Read SB, Kulprathipanja NV, Kruse CA . Effects of IFN-gamma and interleukin-1beta on major histocompatibility complex antigen and intercellular adhesion molecule-1 expression by 9L gliosarcoma: relevance to its cytolysis by alloreactive cytotoxic T lymphocytes. J Interferon Cytokine Res 2002; 22: 1209–1216.

    Article  CAS  PubMed  Google Scholar 

  40. Collins T, Korman AJ, Wake CT, Boss JM, Kappes DJ, Fiers W et al. Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelial cells and dermal fibroblasts. Proc Natl Acad Sci USA 1984; 81: 4917–4921.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Faure-Andre G, Vargas P, Yuseff MI, Heuze M, Diaz J, Lankar D et al. Regulation of dendritic cell migration by CD74, the MHC class II-associated invariant chain. Science 2008; 322: 1705–1710.

    Article  CAS  PubMed  Google Scholar 

  42. Rahmsdorf HJ, Harth N, Eades AM, Litfin M, Steinmetz M, Forni L et al. Interferon-gamma, mitomycin C, and cycloheximide as regulatory agents of MHC class II-associated invariant chain expression. J Immunol 1986; 136: 2293–2299.

    CAS  PubMed  Google Scholar 

  43. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999; 285: 412–415.

    Article  CAS  PubMed  Google Scholar 

  44. Orito H, Fujimoto M, Ishiura N, Yanaba K, Matsushita T, Hasegawa M et al. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 cooperatively contribute to the cutaneous Arthus reaction. J Leukoc Biol 2007; 81: 1197–1204.

    Article  CAS  PubMed  Google Scholar 

  45. Ebnet K, Kaldjian EP, Anderson AO, Shaw S . Orchestrated information transfer underlying leukocyte endothelial interactions. Annu Rev Immunol 1996; 14: 155–177.

    Article  CAS  PubMed  Google Scholar 

  46. Norton J, Sloane JP, al-Saffar N, Haskard DO . Expression of adhesion molecules in human intestinal graft-versus-host disease. Clin Exp Immunol 1992; 87: 231–236.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Itoh S, Matsuzaki Y, Kimura T, Unno R, Ikegami T, Shoda J et al. Suppression of hepatic lesions in a murine graft-versus-host reaction by antibodies against adhesion molecules. J Hepatol 2000; 32: 587–595.

    Article  CAS  PubMed  Google Scholar 

  48. Bouazzaoui A, Spacenko E, Mueller G, Miklos S, Huber E, Holler E et al. Chemokine and chemokine receptor expression analysis in target organs of acute graft-versus-host disease. Genes Immun 2009; 10: 687–701.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to express their gratitude to Jennifer Usterud for reading the paper and writing assistance. The study was supported by grants from Swedish Cancer Foundation (Cancerfonden) and The Swedish Childhood Cancer Foundation (Barncancerfonden).

Author information

Authors and Affiliations

  1. Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden

    B Sadeghi, H Al-Chaqmaqchi, S Al-Hashmi, Z Hassan & M Hassan

  2. Bioinformatics and Expression Analysis core facility, Karolinska Institute, Stockholm, Sweden

    D Brodin

  3. Clinical Research Centre (KFC, Novum), Karolinska University Hospital-Huddinge, Stockholm, Sweden

    Z Hassan & M Hassan

  4. Department of Biochemistry and Biophysics, Arrhenius Laboratories for the Natural Sciences, Stockholm University, Stockholm, Sweden

    M Abedi-Valugerdi

  5. Department of Oncology and Pathology, Cancer Center Karolinska (CCK), Karolinska Hospital and Institute, Stockholm, Sweden

    A Moshfegh

Authors
  1. B Sadeghi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Al-Chaqmaqchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Al-Hashmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D Brodin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Z Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Abedi-Valugerdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A Moshfegh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B Sadeghi.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sadeghi, B., Al-Chaqmaqchi, H., Al-Hashmi, S. et al. Early-phase GVHD gene expression profile in target versus non-target tissues: kidney, a possible target?. Bone Marrow Transplant 48, 284–293 (2013). https://doi.org/10.1038/bmt.2012.120

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2012.120

Keywords

This article is cited by

Search

Advanced search

Quick links