Adrian Hibberd, David Clark, Paul Trevillian, Raewyn Billings, Christopher Oldmeadow, Rodney Scott, Katherine Baines, Munish Heer, Simon Chiu, John Attia
This study provides evidence that heparanase plays a key role in rejection and that specific heparanase inhibition prolongs organ allograft survival. Castanospermine, a transplant immunosuppressant, significantly reduces intragraft heparanase and heparan sulphate.
BACKGROUND: Improvements in transplant immunosuppression may help to address the causes of allograft loss. This study aimed to determine if heparanase plays a role in rejection and if specific heparanase inhibition prolongs allograft survival.
METHODS: For heparanase or heparan sulphate expression four Groups were studied after renal transplantation: Isograft Control; Non-treated Control; Castanospermine-treated Allograft; Cyclosporin A-treated Allograft. Heparanase was measured by flow cytometry, digital image pathology, or ELISA, and group comparisons made using linear regression models. Survival of rat cardiac allografts were measured after treatment with OGT2115, a specific heparanase inhibitor, at 2 mg/kg, 5.0 mg/kg, and 10 mg/kg daily compared with Non-treated controls or Dimethyl Sulphoxide (DMSO) vehicle controls. Statistical comparisons by Mann-Whitney tests.
RESULTS: Compared with Isograft Control at day 6, the Non-treated(rejecting) Group had higher heparanase levels within allograft mononuclear cells (p < 0.001), higher heparan sulphate (HS) levels in the allograft (p < 0.001), and higher levels in serum HS (p < 0.001). Compared with Rejecting Group at day 6, Castanospermine reduced heparanase levels within allograft mononuclear cells (p < 0.01) and HS levels in the allograft (p < 0.001). Treatment with specific heparanase inhibitor OGT2115 (10 mg/kg) increased allograft survival compared with non-treated controls (2 day increment; p = 0.001) and DMSO controls (3 day increment; p < 0.001). Lower doses of OGT2115 prolonged allograft survival compared with DMSO controls (2.5 mg/kg: 2 day increment; p = 0.008; 5 mg/kg: 1 day increment (p = 0.001).
CONCLUSIONS: This study provides evidence that heparanase plays a key role in rejection and that specific heparanase inhibition prolongs organ allograft survival. Castanospermine, a transplant immunosuppressant, significantly reduces intragraft heparanase and heparan sulphate.