The free radical scavenger S-PBN significantly prolongs DSG-mediated graft survival in experimental xenotransplantation
2012 (English)In: Xenotransplantation, ISSN 0908-665X, E-ISSN 1399-3089, Vol. 19, no 3, 166-176 p.Article in journal (Refereed) Published
Background: Nitrones such as 2-sulfo-phenyl-N-tert-butyl nitrone (S-PBN) are known to trap and stabilize free radicals and to reduce inflammation. Recently, S-PBN was shown to reduce infiltration of T lymphocytes and the expression of adhesion molecules on the endothelium in experimental traumatic brain injury. We hypothesized that S-PBN could reduce infiltration of T lymphocytes during cell-mediated xenograft rejection and thereby increase graft survival. The concordant mouse-to-rat heart transplantation model was used to test the hypothesis. In this model, grafts undergo acute humoral xenograft rejection (AHXR) almost invariably on day 3 and succumb to cell-mediated rejection on approximately day 8 if AHXR is inhibited by treatment with 15-deoxyspergualin (DSG). Material and methods: Hearts from Naval Medical Research Institute (NMRI) mice were transplanted to the neck vessels of Lewis rats. Recipients were treated with S-PBN (n = 9), DSG (n = 9), S-PBN and DSG in combination (n = 10) or left untreated (n = 9) for survival studies. S-PBN was given daily intraperitoneally at a dose of 150 mg/kg body weight (BW) on day -1 to 30, and DSG was given daily intraperitoneally at a dose of 10 mg/kg BW on day -1 to 4 and 5 mg/kg BW on day 5 to 21. Nine additional recipients were given S-PBN only on days -1 and 0 in combination with continuous DSG treatment. Grafts were monitored until they stopped beating. Additional recipients were treated with S-PBN (n = 5), DSG (n = 5), S-PBN and DSG in combination (n = 6) or left untreated (n = 5) for morphological, immunohistochemical and flow cytometry analyses on days 2 and 6 after transplantation. Results: S-PBN treatment in combination with DSG resulted in increased median graft survival compared to DSG treatment alone (14 vs. 7 days; P = 0.019). Lower number of T lymphocytes on day 6 (P = 0.019) was observed by ex vivo propagation and flow cytometry when combining S-PBN with DSG, whereas immunohistochemical analyses demonstrated a significant reduction in the number of infiltrated CD4+, but not TCR+, cells. S-PBN treatment alone had no impact on graft survival compared to untreated rats (3 vs. 3 days). No differences were seen in ICAM-1 and VCAM-1 expression or in morphology between the groups. Conclusion: The combination of S-PBN and DSG treatment increases xenograft survival. The main effect of S-PBN appears to be in direct connection with the transplantation. Because of its low toxicity, S-PBN could become useful in combination with other immunosuppressants to reduce cell-mediated xenograft rejection.
Place, publisher, year, edition, pages
2012. Vol. 19, no 3, 166-176 p.
free radical scavenger, S-PBN, T-cell response, xenograft survival, xenotransplantation
IdentifiersURN: urn:nbn:se:uu:diva-177630DOI: 10.1111/j.1399-3089.2012.00700.xISI: 000305394500004OAI: oai:DiVA.org:uu-177630DiVA: diva2:541397