Purpose: Heat shock protein 90 (HSP90) is a ubiquitously expressed molecular chaperone that is associated with the correct activation of client proteins. Important roles of this protein in the development of malignancies are reported and clinical trials of HSP90-targeting therapy are ongoing. We have previously demonstrated that HSP90 plays a role in the development of acute rejection (AR) in organ transplantation and that it is potentially a new biomarker to detect severe AR. In addition, we also previously verified that HSP90 inhibition prolonged the allograft survival in murine skin transplantation. To date, the immunosuppressive effect of HSP90 inhibitor in solid organ is still unknown. The aim of this study was to investigate the immunosuppressive effect of HSP90 inhibitor, 17DMAG in murine heart transplantation (HTx).

Methods: C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donors for and recipients of HTx, respectively. Heterotopic cardiac transplanatation model was used. Treatment with 17DMAG (2 mg/kg daily i.p.) or DMSO as vehicle was initiated two days before HTx. The graft survivals were compared between two groups. In addition, the cardiac allografts of the recipients were collected on day 7 for histopathological evaluation.

Results: In 17DMAG group, cardiac allograft survival was significantly longer than vehicle group (median survival time: 11.0 days vs 7.0 days, log-rank p < 0.001). Histologic examinations of the graft revealed that cell infiltration, vasculitis and myocardial injury was mild in 17DMAG group as compared with vehicle group. In immunohistochemical study, T cells infiltration in the graft was suppressed in the 17DMAG-treated mice. ELISPOT assay showed that 17DMAG suppressed donor-specific IFN-gamma production by splenocytes.

Conclusions: The results of our study suggest that 17DMAG treatment may prolong graft survival by suppression of T cell infiltration and IFN-gamma production. HSP90 inhibition by 17DMAG may provide a potential therapeutic application against acute rejection of allograft in solid transplantations.

CITATION INFORMATION: Maehana T, Tanaka T, Masumori N. Heat Shock Protein 90 Inhibitor, 17DMAG Suppresses Acute Allograft Rejection and Prolongs Allograft Survival in Solid Organ Transplantation. Am J Transplant. 2017;17 (suppl 3).

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