Abstract
The critical roles of heat shock protein 90 (HSP90) in immune reactions associated with viral infection and autoimmune disease are well known. To date, however, its roles in the alloimmune response and the immunosuppressive effect of HSP90 inhibitors in allotransplantation have remained unknown. The purpose of this study was to examine the therapeutic efficacy of the HSP90 inhibitor 17-DMAG in allotransplantation models. C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donors for and recipients of skin and heart transplantation, respectively. Treatment with 17-DMAG (daily i.p.) or a vehicle was initiated 3 days before transplantation. Immunological outcomes were assessed by histopathological examinations, flow cytometric analysis, quantitative RT-PCR, ELISA, ELISPOT assay, and MLR. 17-DMAG treatment significantly prolonged the survival of both skin and heart allografts. In 17-DMAG-treated mice, donor-reactive splenocytes producing IFN-γ were significantly reduced along with the intragraft mRNA expression level and serum concentration of IFN-γ. Intragraft mRNA expression of cytokines and chemokines associated with both innate and adaptive immunity was suppressed in 17-DMAG-treated group. MLR showed suppression of the donor-specific proliferation of CD4 + T and CD19 + B cells in the spleens of 17-DMAG-treated mice. 17-DMAG treatment also reduced the number of activated NK cells. Furthermore, the treatment lowered the titers of donor-specific antibodies in the serum and prolonged a second skin allograft in mice sensitized by previous skin transplantation. HSP90 inhibition by 17-DMAG can affect various immune responses, including innate immunity, adaptive immunity, and humoral immunity, suggesting its therapeutic potential against acute rejection in allotransplantation.
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Acknowledgements
The authors thank Mr. Kim Barrymore for correction of the English of this manuscript.
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This work was supported by JSPS KAKENHI Grant Numbers 15K20099 to T.M. and Grant Numbers 17K11202 to T.T.
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This project was submitted to and approved by the Animal Ethics Committee of Sapporo Medical University (protocols 14–035 and 17–096).
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Maehana, T., Tanaka, T., Hashimoto, K. et al. Heat shock protein 90 is a new potential target of anti-rejection therapy in allotransplantation. Cell Stress and Chaperones 27, 337–351 (2022). https://doi.org/10.1007/s12192-022-01272-2
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DOI: https://doi.org/10.1007/s12192-022-01272-2