Cutaneous Chronic Graft-Versus-Host Disease Does Not Have the Abnormal Endothelial Phenotype or Vascular Rarefaction Characteristic of Systemic Sclerosis

Background The clinical and histologic appearance of fibrosis in cutaneous lesions in chronic graft-versus -host disease (c-GVHD) resembles the appearance of fibrosis in scleroderma (SSc). Recent studies identified distinctive structural changes in the superficial dermal microvasculature and matrix of SSc skin. We compared the dermal microvasculature in human c-GVHD to SSc to determine if c-GVHD is a suitable model for SSc. Methodology/Principal Findings We analyzed skin biopsies of normal controls (n = 24), patients with SSc (n = 30) and c-GVHD with dermal fibrosis (n = 133)). Immunostaining was employed to identify vessels, vascular smooth muscle, dermal matrix, and cell proliferation. C-GVHD and SSc had similar dermal matrix composition and vascular smooth muscle pathology, including intimal hyperplasia. SSc, however, differed significantly from c-GVHD in three ways. First, there were significantly fewer (p = 0.00001) average vessels in SSc biopsies (9.8) when compared with c-GVHD (16.5). Second, in SSc, endothelial markers were decreased significantly (19/19 and 12/14 for VE cadherin and vWF (p = <0.0001 and <0.05), respectively). In contrast, 0/13 c-GVHD biopsies showed loss of staining with canonical endothelial markers. Third, c-GVHD contained areas of microvascular endothelial proliferation not present in the SSc biopsies. Conclusions/Significance The sclerosis associated with c-GVHD appears to resemble wound healing. Focal capillary proliferation occurs in early c-GVHD. In contrast, loss of canonical endothelial markers and dermal capillaries is seen in SSc, but not in c-GVHD. The loss of VE cadherin in SSc, in particular, may be related to microvascular rarefaction because VE cadherin is necessary for angiogenesis. C-GVHD is a suitable model for studying dermal fibrosis but may not be applicable for studying the microvascular alterations characteristic of SSc.

[1]  Marcella Q. Salomão,et al.  Corneal stroma PDGF blockade and myofibroblast development. , 2009, Experimental eye research.

[2]  P. Sandset,et al.  Differential impact of conventional‐dose and low‐dose postmenopausal hormone therapy, tibolone and raloxifene on C‐reactive protein and other inflammatory markers , 2008, Journal of thrombosis and haemostasis : JTH.

[3]  H. Matsubara,et al.  Circulating endothelial progenitor cells decreased in patients with sclerodermatous chronic graft-versus-host disease. , 2008, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[4]  Stephen M. Schwartz,et al.  Capillary Regeneration in Scleroderma: Stem Cell Therapy Reverses Phenotype? , 2008, PloS one.

[5]  J. Pober,et al.  Human Effector Memory CD4+ T Cells Directly Recognize Allogeneic Endothelial Cells In Vitro and In Vivo , 2007, The Journal of Immunology.

[6]  M. Mayes,et al.  High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study. , 2007, Blood.

[7]  S. Svegliati,et al.  Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. , 2007, Blood.

[8]  W. Shlomchik,et al.  Graft-versus-host disease , 2007, Nature Reviews Immunology.

[9]  P. Libby,et al.  Vascular remodeling in transplant vasculopathy. , 2007, Circulation research.

[10]  D. Judge,et al.  Angiotensin II type 1 receptor blockade attenuates TGF-β–induced failure of muscle regeneration in multiple myopathic states , 2007, Nature Medicine.

[11]  M. Turner,et al.  Cutaneous manifestations of chronic graft-versus-host disease. , 2006, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[12]  A. Gabrielli,et al.  Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. , 2006, The New England journal of medicine.

[13]  K. Sullivan,et al.  Allogeneic marrow transplantation in patients with severe systemic sclerosis: resolution of dermal fibrosis. , 2006, Arthritis and rheumatism.

[14]  P. Carmeliet,et al.  VE‐Cadherin‐Cre‐recombinase transgenic mouse: A tool for lineage analysis and gene deletion in endothelial cells , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[15]  P. Huber,et al.  Angiogenesis: the VE-cadherin switch. , 2006, Trends in cardiovascular medicine.

[16]  R. Sackstein.  A revision of Billingham's tenets: the central role of lymphocyte migration in acute graft-versus-host disease. , 2006, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[17]  M. Washington,et al.  Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. , 2006, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[18]  L. Hummers,et al.  Paclitaxel Modulates TGFβ Signaling in Scleroderma Skin Grafts in Immunodeficient Mice , 2005, PLoS medicine.

[19]  M. Turner,et al.  National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. , 2005, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[20]  Y. Kodera,et al.  Intestinal thrombotic microangiopathy after allogeneic bone marrow transplantation: a clinical imitator of acute enteric graft-versus-host disease , 2004, Bone Marrow Transplantation.

[21]  J. Varga,et al.  Animal models of scleroderma. , 2004, Methods in molecular medicine.

[22]  J. Mary,et al.  Prognostic value of apoptotic cells and infiltrating neutrophils in graft-versus-host disease of the gastrointestinal tract in humans: TNF and Fas expression. , 2004, Blood.

[23]  M. Becker,et al.  Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. , 2003, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[24]  G. Gabbiani,et al.  The myofibroblast in wound healing and fibrocontractive diseases , 2003, The Journal of pathology.

[25]  Shin-Seok Lee,et al.  Elevated vascular endothelial growth factor in systemic sclerosis. , 2003, The Journal of rheumatology.

[26]  S. Jimenez,et al.  Murine animal models of systemic sclerosis , 2002, Current opinion in rheumatology.

[27]  G. Taylor,et al.  P311 induces a TGF-beta1-independent, nonfibrogenic myofibroblast phenotype. , 2002, The Journal of clinical investigation.

[28]  Yunliang Chen,et al.  Dysregulation of transforming growth factor beta signaling in scleroderma: overexpression of endoglin in cutaneous scleroderma fibroblasts. , 2002 .

[29]  J. Pober,et al.  Endothelial injury mediated by cytotoxic T lymphocytes and loss of microvessels in chronic graft versus host disease , 2002, The Lancet.

[30]  N. Mounier,et al.  CD95 engagement induces disseminated endothelial cell apoptosis in vivo: immunopathologic implications. , 2002, Blood.

[31]  L. McCormick,et al.  Murine Sclerodermatous Graft-Versus-Host Disease, a Model for Human Scleroderma: Cutaneous Cytokines, Chemokines, and Immune Cell Activation1 , 2002, The Journal of Immunology.

[32]  J. Jass,et al.  Altered mucin expression in the gastrointestinal tract: a review , 2001, Journal of cellular and molecular medicine.

[33]  Erwin G. Van Meir,et al.  Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research. , 2001, The American journal of pathology.

[34]  W. Paul,et al.  Lack of Skin Fibrosis in Tight Skin (TSK) Mice with Targeted Mutation in the Interleukin-4Rα and Transforming Growth Factor-β Genes , 2001 .

[35]  W. Paul,et al.  Lack of skin fibrosis in tight skin (TSK) mice with targeted mutation in the interleukin-4R alpha and transforming growth factor-beta genes. , 2001, The Journal of investigative dermatology.

[36]  S. Jimenez,et al.  Lack of endothelial cell apoptosis in the dermis of tight skin 1 and tight skin 2 mice. , 1999, Arthritis and rheumatism.

[37]  Point Mutations and Deletion Responsible for the Bombay H null and the Reunion H weak Blood Groups , 1998, Vox sanguinis.

[38]  F. Larcher,et al.  VEGF/VPF overexpression in skin of transgenic mice induces angiogenesis, vascular hyperpermeability and accelerated tumor development , 1998, Oncogene.

[39]  R K Jain,et al.  Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. , 1998, The Journal of investigative dermatology.

[40]  E. Leroy.  SYSTEMIC SCLEROSIS : A Vascular Perspective , 1996 .

[41]  J. Crawford,et al.  An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. , 1996, Blood.

[42]  L. Kobzik,et al.  THE ROLES OF ALLOREACTIVITY AND ENDOTOXIN IN AN EXPERIMENTAL MODEL OF IDIOPATHIC PNEUMONIA SYNDROME AFTER BONE MARROW TRANSPLANTATION. • 909 , 1996, Pediatric Research.

[43]  J. Isner,et al.  Regional differences in the distribution of the proteoglycans biglycan and decorin in the extracellular matrix of atherosclerotic and restenotic human coronary arteries. , 1994, The American journal of pathology.

[44]  C. Kielty,et al.  Attachment of human vascular smooth muscles cells to intact microfibrillar assemblies of collagen VI and fibrillin. , 1992, Journal of cell science.

[45]  J. Pearson,et al.  von Willebrand factor is an acute phase reactant in man. , 1989, Thrombosis research.

[46]  M. Sporn,et al.  Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[47]  J. Fries,et al.  Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. , 1969, The American journal of medicine.