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Effect of Palifermin in a Murine Model of Graft-Versus-Host Disease (GVHD) Associated with Th2 Cytokine Production, Autoantibody Production, and Glomerulonephritis

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Palifermin (recombinant human keratinocyte growth factor) prevents the development of acute, lethal graft-versus-host disease (GVHD). It does so, at least in part, by protecting cells from injury. Another property of Palifermin is immune regulation. How the latter influences the evolution of GVHD remains uncertain. We explored the effect of Palifermin on GVHD in the DBA/2 → ((DBA/2)×(C57BL/6))F1-hybrid strain combination, a model associated with autoantibody production and glomerulonephritis. Untreated recipients survived until at least day 150 post-induction. Palifermin-treated recipients succumbed between days 50 and 90 with levels of proteinuria of up to 20 g/L, ascites, and rapidly progressive, crescentic glomerulonephritis that was most severe in mice with the greatest levels of proteinuria. Kidney sections from both Palifermin-treated and untreated recipients showed the presence of granular deposits of IgG, IgM, IgA, and C3 in the mesangium and the glomerular basement membrane. Electron microscopy confirmed the extensive glomerular immune complex deposition. Antinuclear and anti-dsDNA antibodies were present in sera from both treated and untreated recipients; however, those in the latter were only detectable if the serum was kept at 37°C, indicating that they were cryoglobulins. IL-4 was detectable only in cultures from Palifermin-treated recipients and the levels of IL-5 and IL-13 were significantly higher in the Palifermin-treated group than in untreated GVHD mice. IFN-γ was only detectable in untreated GVHD mice. These data suggest that although Palifermin can protect mice with acute GVHD, it exacerbates GVHD in a model associated with autoantibody production and a preponderance of Th2 cytokines.

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ACKNOWLEDGMENTS

We thank Amgen Inc. for providing us with the Palifermin for the study and Dr. Robert Colvin for his advice with regard to cryoglobulins. We also thank Jacqie Fischer and Bill Stefura for their excellent technical assistance. This project was supported by grants to JGG and CAE from the Canadian Institute of Health Research, the Manitoba Regional Partnership Program (Medical Research Council of Canada and the Manitoba Health Research Council), and the Manitoba Institute of Child Health.

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Authors and Affiliations

  1. Department of Pathology, University of Manitoba, Winnipeg, Canada

    CYNTHIA A. ELLISON, IAN W. GIBSON & JOHN G. GARTNER

  2. Manitoba Blood and Marrow Transplant Program, Cancer Care Manitoba, Winnipeg, Canada

    CYNTHIA A. ELLISON

  3. Department of Immunology, University of Manitoba, Winnipeg, Canada

    KENT T. HAYGLASS & JOHN G. GARTNER

  4. Department of Pathology, University of Manitoba, 401J Brodie Center, 727 McDermot Avenue, Winnipeg, Manitoba, Canada, R3E 3P5

    CYNTHIA A. ELLISON

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  1. CYNTHIA A. ELLISON
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Correspondence to CYNTHIA A. ELLISON.

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ELLISON, C., GIBSON, I., HAYGLASS, K. et al. Effect of Palifermin in a Murine Model of Graft-Versus-Host Disease (GVHD) Associated with Th2 Cytokine Production, Autoantibody Production, and Glomerulonephritis. J Clin Immunol 26, 485–494 (2006). https://doi.org/10.1007/s10875-006-9039-x

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