Purpose: We have previously demonstrated that Heat shock protein 90 (HSP90) plays a role in the development of acute rejection (AR) in organ transplantation. To date, the immunosuppressive effect of HSP90 inhibitors in solid organ and tissue transplantations remains unknown. The aim of this study was to investigate the immunosuppressive effect of the HSP90 inhibitor 17DMAG in murine skin transplantation (STx). Methods: C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donors for and recipients of STx, respectively. Treatment with 17DMAG (1mg/kg daily i.p.) or DMSO as a vehicle was initiated three days before STx. Histopathological evaluation (Banff 2007), flow cytometric analysis, quantitative RT-PCR, ELISA and ELISPOT assay were performed on day 7. CFSE-based mixed lymphocyte reactions (MLRs) using splenocytes were performed on day 14. Results: In 17DMAG-treated mice, allograft survival was significantly longer than in the vehicle group (median survival time: 14.0 days vs. 9.5 days, log-rank p<0.0001). The Banff grade of skin allografts at day 7 was significantly lower in the 17DMAG group than in the vehicle group (median grade 1.5 vs. 2.5, p<0.01). In 17DMAG-treated mice, intragraft mRNA expression, the serum concentration of IFN-γ, and donor-reactive splenocytes producing IFN-γ were significantly reduced. In MLRs analysis, 17DMAG significantly inhibited the proliferation of CD4 and CD8 T lymphocytes and CD19 B cells. Conclusions: Our study suggest that HSP90 may play a role in regulating the differentiation and activation of T and B cells and the production of IFN-γ in STx. HSP90 inhibition by 17DMAG may have therapeutic potential against acute rejection in allotransplantation.

CITATION INFORMATION: Maehana T, Tanaka T, Kitamura H, Masumori N. Heat Shock Protein 90 Inhibitor 17DMAG Is a Potential New Therapeutic Agent Against Acute Allograft Rejection. Am J Transplant. 2016;16 (suppl 3).

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