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Journal of Clinical Immunology

Published in:

01-09-2008

Palifermin Mediates Immunoregulatory Effects in Addition to its Cytoprotective Effects in Mice with Acute Graft-Versus-Host Disease

Authors: Cynthia A. Ellison, Bryce M. Makar, Jacqie M. M. Wiseman, Ionela Gheorghiu, Masaru Taniguchi, John G. Gartner

Published in: Journal of Clinical Immunology | Issue 5/2008

Abstract

Introduction

Treating recipient mice with palifermin (recombinant human keratinocyte growth factor) prevents the development of acute, lethal, graft-versus-host disease (GVHD). This is due, at least in part, to the ability of palifermin to protect epithelial cells from injury. Using the C57BL/6→(C57BL/6 × DBA/2)F₁-hybrid model, we previously showed that the protective effect of palifermin was also associated with redirection of the cytokine profile from Th1 to Th2.

Discussion

To study this immunoregulatory effect more directly, we induced acute GVH reactions in which we treated the donors rather than the recipients with palifermin. The recipient mice were protected from GVHD-associated morbidity, and their cytokine profile was predominantly Th2. The palifermin-treated donor mice alone showed a similar Th2 cytokine profile, and we observed elevated levels of thymic stromal lymphopoietin mRNA in the thymus. We further demonstrated that treating the donor mice with palifermin protects against GVHD-associated morbidity, even if the donors are deficient in Vα14i natural killer T cells. Our findings clearly show that palifermin mediates immunoregulatory effects in addition to its cytoprotective effects and that both are likely to be involved in the mechanism through which palifermin provides protection from acute murine GVHD.

Martin PJ, Hansen JA, Buckner CD, Sanders JE, Deeg HJ, Stewart P, et al. Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood 1985;66:664–72.PubMed

Papa G, Arcese W, Mauro FR, Bianchi A, Alimena G, De Felice L, et al. Standard conditioning regimen and T-depleted donor bone marrow for transplantation in chronic myeloid leukemia. Leuk Res. 1986;10:1469–75.PubMedCrossRef

Woodruff JM, Eltringham JR, Casey HW. Early secondary disease in the Rhesus monkey I. A. comparative histopathologic study. Lab Invest. 1969;20:499–511.PubMed

Nestel FP, Price KS, Seemayer TA, Lapp WS. Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med. 1992;175:405–13.PubMedCrossRef

Stuber E, Buschenfeld A, von Freier A, Arendt T, Folsch UR. Intestinal crypt cell apoptosis in murine acute graft versus host disease is mediated by tumour necrosis factor alpha and not by the FasL–Fas interaction: effect of pentoxifylline on the development of mucosal atrophy. Gut 1999;45:229–35.PubMedCrossRef

Garside P, Hutton AK, Severn A, Liew FY, Mowat AM. Nitric oxide mediates intestinal pathology in graft-vs.-host disease. Eur J Immunol. 1992;22:2141–5.PubMedCrossRef

Finch PW, Rubin JS, Miki T, Ron D, Aaronson SA. Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. Science 1989;245:752–5.PubMedCrossRef

Rubin JS, Osada H, Finch PW, Taylor WG, Rudikoff S, Aaronson SA. Purification and characterization of a newly identified growth factor specific for epithelial cells. Proc Natl Acad Sci U S A. 1989;86:802–6.PubMedCrossRef

Boismenu R, Havran WL. Modulation of epithelial cell growth by intraepithelial gamma delta T cells. Science 1994;266:1253–5.PubMedCrossRef

10.

Yi ES, Shabaik AS, Lacey DL, Bedoya AA, Yin S, Housley RM, et al. Keratinocyte growth factor causes proliferation of urothelium in vivo. J Urol. 1995;154:1566–70.PubMedCrossRef

11.

Staiano-Coico L, Krueger JG, Rubin JS, D, Limi S, Vallat VP, Valentino L, et al. Human keratinocyte growth factor effects in a porcine model of epidermal wound healing. J Exp Med. 1993;178:865–78.PubMedCrossRef

12.

Bottaro DP, Rubin JS, Ron D, Finch PW, Florio C, Aaronson SA. Characterization of the receptor for keratinocyte growth factor. Evidence for multiple fibroblast growth factor receptors. J Biol Chem. 1990;265:12767–70.PubMed

13.

Housley RM, Morris CF, Boyle W, Ring B, Biltz R, Tarpley JE, et al. Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract. J Clin Invest. 1994;94:1764–77.PubMedCrossRef

14.

Ulich TR, Yi ES, Cardiff R, Yin S, Bikhazi N, Biltz R, et al. Keratinocyte growth factor is a growth factor for mammary epithelium in vivo. The mammary epithelium of lactating rats is resistant to the proliferative action of keratinocyte growth factor. Am J Pathol. 1994;144:862–8.PubMed

15.

Parrott JA, Kim G, Mosher R, Skinner MK. Expression and action of keratinocyte growth factor (KGF) in normal ovarian surface epithelium and ovarian cancer. Mol Cell Endocrinol. 2000;167:77–87.PubMedCrossRef

16.

Pierce GF, Yanagihara D, Klopchin K, Danilenko DM, Hsu E, Kenney WC, et al. Stimulation of all epithelial elements during skin regeneration by keratinocyte growth factor. J Exp Med. 1994;179:831–40.PubMedCrossRef

17.

Panos RJ, Rubin JS, Csaky KG, Aaronson SA, Mason RJ. Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium. J Clin Invest. 1993;92:969–77.PubMedCrossRef

18.

Yi ES, Williams ST, Lee H, Malicki DM, Chin EM, Yin S, et al. Keratinocyte growth factor ameliorates radiation- and bleomycin-induced lung injury and mortality. Am J Pathol. 1996;149:1963–70.PubMed

19.

Ulich TR, Whitcomb L, Tang W, O, Conner Tressel P, Tarpley J, Yi ES, et al. Keratinocyte growth factor ameliorates cyclophosphamide-induced ulcerative hemorrhagic cystitis. Cancer Res. 1997;57:472–5.PubMed

20.

Farrell CL, Bready JV, Rex KL, Chen JN, DiPalma CR, Whitcomb KL, et al. Keratinocyte growth factor protects mice from chemotherapy and radiation-induced gastrointestinal injury and mortality. Cancer Res. 1998;58:933–9.PubMed

21.

Frank S, Munz B, Werner S. The human homologue of a bovine non-selenium glutathione peroxidase is a novel keratinocyte growth factor-regulated gene. Oncogene 1997;14:915–21.PubMedCrossRef

22.

Takeoka M, Ward WF, Pollack H, Kamp DW, Panos RJ. KGF facilitates repair of radiation-induced DNA damage in alveolar epithelial cells. Am J Physiol. 1997;272:L1174–80.PubMed

23.

Panoskaltsis-Mortari A, Lacey DL, Vallera DA, Blazar BR. Keratinocyte growth factor administered before conditioning ameliorates graft-versus-host disease after allogeneic bone marrow transplantation in mice. Blood 1998;92:3960–7.PubMed

24.

Krijanovski OI, Hill GR, Cooke KR, Teshima T, Crawford JM, Brinson YS, et al. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood 1999;94:825–31.PubMed

25.

Ellison CA, Natuik SA, Fischer JM, McIntosh AR, Scully SA, Bow EJ, et al. Effect of recombinant human keratinocyte growth factor (rHuKGF) on the immunopathogenesis of intestinal graft-vs.-host disease induced without a preconditioning regimen. J Clin Immunol. 2004;24:197–211.PubMedCrossRef

26.

Panoskaltsis-Mortari A, Taylor PA, Rubin JS, Uren A, Welniak LA, Murphy WJ, et al. Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning-induced tissue injury. Blood 2000;96:4350–6.PubMed

27.

Ellison CA, Gibson IW, Hayglass KT, Gartner JG. 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. 2006;26:485–94.PubMedCrossRef

28.

Gartner JG, Merry AC, Smith CI. An analysis of pulmonary natural killer cell activity in F1-hybrid mice with acute graft-versus-host reactions. Transplantation 1988;46:879–86.PubMedCrossRef

29.

Ellison CA, Taniguchi M, Fischer JM, Hayglass KT, Gartner JG. Graft-versus-host disease in recipients of grafts from natural killer T cell-deficient (Ja281^−/−) donors. Immunology 2006;119:338–47.PubMedCrossRef

30.

Ellison CA, Fischer JM, HayGlass KT, Gartner JG. Murine graft-versus-host disease in an F1-hybrid model using IFN-gamma gene knockout donors. J Immunol. 1998;161:631–40.PubMed

31.

Rus V, Svetic A, Nguyen P, Gause WC, Via CS. Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murine graft-versus-host disease. Regulatory role of donor CD8+T cells. J Immunol. 1995;155:2396–406.PubMed

32.

Ellison CA, HayGlass KT, Fischer JM, Rector ES, MacDonald GC, Gartner JG. Depletion of natural killer cells from the graft reduces interferon-gamma levels and lipopolysaccharide-induced tumor necrosis factor-alpha release in F1 hybrid mice with acute graft-versus-host disease. Transplantation 1998;66:284–94.PubMedCrossRef

33.

Yang X, Gieni RS, Mosmann TR, HayGlass KT. Chemically modified antigen preferentially elicits induction of Th1-like cytokine synthesis patterns in vivo. J Exp Med. 1993;178:349–53.PubMedCrossRef

34.

MacDonald GC, Gartner JG. Natural killer (NK) cell activity in mice with acute graft-versus-host reactions: characterization of a Thy-1+NK-like cell with a broadened spectrum of lytic activity in the spleen and lymph nodes. Scand J Immunol. 1991;33:553–65.PubMedCrossRef

35.

Pross HF, Baines MG, Rubin P, Shragge P, Patterson MS. Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity. J Clin Immunol. 1981;1:51–63.PubMedCrossRef

36.

Ellison CA, Natuik SA, McIntosh AR, Scully SA, Danilenko DM, Gartner JG. The role of interferon-gamma, nitric oxide and lipopolysaccharide in intestinal graft-versus-host disease developing in F1-hybrid mice. Immunology 2003;109:440–9.PubMedCrossRef

37.

Piguet PF, Grau GE, Allet B, Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med. 1987;166:1280–9.PubMedCrossRef

38.

MacDonald GC, Gartner JG. The host/donor origin of cells mediating NK and NK-like cytotoxic activity in F1 hybrid mice with acute graft-versus-host reactions. Transplantation 1991;52:141–3.PubMedCrossRef

39.

Ellison CA, MacDonald GC, Rector ES, Gartner JG. Gamma delta T cells in the pathobiology of murine acute graft-versus-host disease. Evidence that gamma delta T cells mediate natural killer-like cytotoxicity in the host and that elimination of these cells from donors significantly reduces mortality. J Immunol. 1995;155:4189–98.PubMed

40.

Erickson M, Morkowski S, Lehar S, Gillard G, Beers C, Dooley J, et al. Regulation of thymic epithelium by keratinocyte growth factor. Blood 2002;100:3269–78.PubMedCrossRef

41.

Liu YJ, Soumelis V, Watanabe N, Ito T, Wang YH, Malefyt Rde W, et al. TSLP: an epithelial cell cytokine that regulates T cell differentiation by conditioning dendritic cell maturation. Annu Rev Immunol. 2007;25:193–219.PubMedCrossRef

42.

Blazar BR, Weisdorf DJ, Defor T, Goldman A, Braun T, Silver S, et al. Phase 1/2 randomized, placebo-control trial of palifermin to prevent graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Blood 2006;108:3216–22.PubMedCrossRef

43.

Friend SL, Hosier S, Nelson A, Foxworthe D, Williams DE, Farr A. A thymic stromal cell line supports in vitro development of surface IgM+B cells and produces a novel growth factor affecting B and T lineage cells. Exp Hematol. 1994;22:321–8.PubMed

44.

Levin SD, Koelling RM, Friend SL, Isaksen DE, Ziegler SF, Perlmutter RM, et al. Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+B cells in vitro and signals via a novel mechanism. J Immunol. 1999;162:677–83.PubMed

45.

Ray RJ, Furlonger C, Williams DE, Paige CJ. Characterization of thymic stromal-derived lymphopoietin (TSLP) in murine B cell development in vitro. Eur J Immunol. 1996;26:10–6.PubMedCrossRef

46.

Al-Shami A, Spolski R, Kelly J, Fry T, Schwartzberg PL, Pandey A, et al. A role for thymic stromal lymphopoietin in CD4(+) T cell development. J Exp Med. 2004;200:159–68.PubMedCrossRef

47.

Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB, et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol. 2005;6:1047–53.PubMedCrossRef

48.

Confer DL, Miller JP. Optimal donor selection: Beyond HLA. Biol Blood Marrow Transplant. 2007;13:83–6.CrossRef

49.

Handgretinger R, Kurtzberg J, Egeler RM. Indications and donor selections for allogeneic stem cell transplantation in children with hematologic malignancies. Pediatr Clin North Am. 2008;55:71–6. x.PubMedCrossRef

50.

Remberger M, Watz E, Ringden O, Mattsson J, Shanwell A, Wikman A. Major ABO blood group mismatch increases the risk for graft failure after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13:675–82.PubMedCrossRef

Title: Palifermin Mediates Immunoregulatory Effects in Addition to its Cytoprotective Effects in Mice with Acute Graft-Versus-Host Disease
Authors: Cynthia A. Ellison
Bryce M. Makar
Jacqie M. M. Wiseman
Ionela Gheorghiu
Masaru Taniguchi
John G. Gartner
Publication date: 01-09-2008
Publisher: Springer US
Published in: Journal of Clinical Immunology / Issue 5/2008
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-008-9216-1

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Abstract

Introduction

Discussion

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