title: Heparanase promotes engraftment and prevents graft versus host disease in stem cell transplantation.
abstract: BACKGROUND
  Heparanase, endoglycosidase that cleaves heparan sulfate side chains of heparan sulfate proteoglycans, plays important roles in cancer metastasis, angiogenesis and inflammation.
  
  
  METHODS
  Applying a mouse model of bone marrow transplantation and transgenic mice over-expressing heparanase, we evaluated the effect of heparanase on the engraftment process and the development of graft-versus-host disease.
  
  
  RESULTS
  Analysis of F1 mice undergoing allogeneic bone marrow transplantation from C57BL/6 mice demonstrated a better and faster engraftment in mice receiving cells from donors that were pretreated with heparanase. Moreover, heparanase treated recipient F1 mice showed only a mild appearance of graft-versus-host disease and died 27 days post transplantation while control mice rapidly developed signs of graft-versus-host disease (i.e., weight loss, hair loss, diarrhea) and died after 12 days, indicating a protective effect of heparanase against graft-versus-host disease. Similarly, we applied transgenic mice over-expressing heparanase in most tissues as the recipients of BMT from C57BL/6 mice. Monitoring clinical parameters of graft-versus-host disease, the transgenic mice showed 100% survival on day 40 post transplantation, compared to only 50% survival on day 14, in the control group. In vitro and in vivo studies revealed that heparanase inhibited T cell function and activation through modulation of their cytokine repertoire, indicated by a marked increase in the levels of Interleukin-4, Interleukin-6 and Interleukin-10, and a parallel decrease in Interleukin-12, tumor necrosis factor-alfa and interferon-gamma. Using point mutated inactive enzyme, we found that the shift in cytokine profile was independent of heparanase enzymatic activity.
  
  
  CONCLUSIONS
  Our results indicate a significant role of heparanase in bone marrow transplantation biology, facilitating engraftment and suppressing graft-versus-host disease, apparently through an effect on T cell activation and cytokine production pattern.
authors.affiliation: Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Menachem
authors.initials: M
authors.lastname: Bitan
authors.forename: Lola
authors.initials: L
authors.lastname: Weiss
authors.forename: Michael
authors.initials: M
authors.lastname: Zeira
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods*; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D005966:Glucuronidase / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006085:Graft Survival / Q000187:drug effects*; D006086:Graft vs Host Disease / Q000517:prevention & control*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D015996:Survival Rate; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D000099175:Heparanase
chemical_list: D016207:Cytokines; D005966:Glucuronidase; D000099175:Heparanase