Heparanase promotes engraftment and prevents graft versus host disease in stem cell transplantation.
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.
Bitan
Menachem
M
Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Weiss
Lola
L
Zeira
Michael
M
Zcharia
Eyal
E
Slavin
Shimon
S
Nagler
Arnon
A
Vlodavsky
Israel
I
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
D016207:Cytokines; D005966:Glucuronidase; D000099175:Heparanase