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Environmental conditions are important for establishing and evaluating pre-clinical models of GVHD

Bone Marrow Transplantation volume 47, pages 607–609 (2012)Cite this article

GVHD remains the major complication of allo-HSCT. Murine models are the primary system used to understand GVHD, and to develop potential therapies. Several factors are critical for GVHD in these models; including histocompatibility, conditioning regimen, and T-cell number. We serendipitously found that environmental factors such as the caging system and bedding also significantly impact the kinetics of GVHD in these models. This is important because such factors may influence the experimental conditions required to cause GVHD and how mice respond to various treatments. Consequently, this is likely to alter interpretation of results between research groups, and the perceived effectiveness of experimental therapies.

Our laboratory routinely used a major histocompatibility-mismatched murine model of HSCT (UBI-GFP/BL6 → BALB/c) that developed rapid and severe GVHD.1 We combined clinically relevant doses of myeloablative chemotherapy (CY 60 mg/kg on days −3 and −2) and radiation (1000 cGy, split dose on day −1) before administering 1 × 107 BM cells and 1 × 107 splenocytes (SP) to conditioned recipients on the day of transplant (day 0). Recipient mice were then housed in traditional filter top cages (Techniplast) with sawdust bedding in a PC2 facility. These mice reliably developed lethal GVHD within 7–11 days (n=60–100 mice per year). Recently, our animal housing was upgraded to micro-environmental comfort, isolation, containment, enrichment (MICE) cages (Australian Animal Care Systems, Dromana, Victoria, Australia) with an enclosed airflow system and absorbent newspaper pellet bedding. Changes in occupational health and safety requirements also obliged us to change the cages daily for 5 days after the last CY injection. Under these conditions control mice developed lethal GVHD between 7 and 25 days, or not at all, prompting us to investigate whether our upgraded animal facility caused the later onset of the disease.

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References

  1. Turner BE, Kambouris ME, Sinfield L, Lange J, Burns AM, Lourie R et al. Reduced intensity conditioning for allogeneic hematopoietic stem-cell transplant determines the kinetics of acute graft-versus-host disease. Transplantation 2008; 8: 968–976.

    Article  Google Scholar 

  2. Jones TD, Snyder WS, Auxier JA . Absorbed dose, dose equivalent and LET distributions in cylindrical phantoms irradiated by a collimated beam of monoenergetic neutrons. Health Phys 1971; 21: 253–272.

    Article  CAS  PubMed  Google Scholar 

  3. van Bekkum DW, Knaan S . Role of bacterial microflora in development of intestinal lesions from graft-versus-host reaction. J Natl Cancer Inst 1977; 58: 787–790.

    Article  CAS  PubMed  Google Scholar 

  4. van Bekkum DW, Roodenburg J, Heidt PJ, van der Waaij D . Mitigation of secondary disease of allogeneic mouse radiation chimeras by modification of the intestinal microflora. J Natl Cancer Inst 1974; 52: 401–404.

    Article  CAS  PubMed  Google Scholar 

  5. Storb R, Prentice RL, Buckner CD, Clift RA, Appelbaum F, Deeg J et al. Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. N Engl J Med 1983; 308: 302–307.

    Article  CAS  PubMed  Google Scholar 

  6. Beelen DW, Elmaagacli A, Muller KD, Hirche H, Schaefer UW . Influence of intestinal bacterial decontamination using metronidazole and ciprofloxacin or ciprofloxacin alone on the development of acute graft-versus-host disease after marrow transplantation in patients with hematologic malignancies: final results and long-term follow-up of an open-label prospective randomized trial. Blood 1999; 93: 3267–3275.

    CAS  PubMed  Google Scholar 

  7. Sudres M, Norol F, Trenado A, Gregoire S, Charlotte F, Levacher B et al. Bone marrow mesenchymal stem cells suppress lymphocyte proliferation in vitro but fail to prevent graft-versus-host disease in mice. J Immunol 2006; 176: 7761–7767.

    Article  CAS  PubMed  Google Scholar 

  8. Markey KA, MacDonald KP, Hill GR . Recipient plasmacytoid DCs are not required to prime allogeneic T-cell responses after BMT. Blood 2009; 113: 6038–6039.

    Article  CAS  PubMed  Google Scholar 

  9. Christensen ME, Turner BE, Sinfield LJ, Kollar K, Cullup H, Waterhouse NJ et al. Mesenchymal stromal cells transiently alter the inflammatory milieu post-transplant to delay graft-versus-host disease. Haematologica 2010; 95: 2102–2110.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I 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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was funded by the National Health & Medical Research Council, Australia (AMR 434507 and NJW 566706), the Australian Research Council (FT0991446) and an Australian Postgraduate Award (MC). HC is Jose Carreras International Leukaemia Foundation Fellow. AMR is a Queensland Government Smart Futures Fellow.

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Authors and Affiliations

  1. Bone Marrow Transplant Team, Mater Medical Research Institute, South Brisbane, Queensland, Australia

    M E Christensen, L J Sinfield, H Cullup & A M Rice

  2. Apoptosis and Cytotoxicity Laboratory, Mater Medical Research Institute, South Brisbane, Queensland, Australia

    M E Christensen & N J Waterhouse

  3. Adult Stem Cell Team, Mater Medical Research Institute, South Brisbane, Queensland, Australia

    K Atkinson

  4. University of Queensland, Brisbane, Queensland, Australia

    M E Christensen, H Cullup, N J Waterhouse, K Atkinson & A M Rice

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  1. M E Christensen
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Correspondence to A M Rice.

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Christensen, M., Sinfield, L., Cullup, H. et al. Environmental conditions are important for establishing and evaluating pre-clinical models of GVHD. Bone Marrow Transplant 47, 607–609 (2012). https://doi.org/10.1038/bmt.2011.128

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