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. On the other hand, HSP90 was reported to regulate expression of MHC class I and class II molecules. We hypothesized that HSP90 might be associated with expression of MHC molecules in allografts and that its inhibition might suppress their expression. The aim of this study was to verify whether HSP90 inhibition could suppress expression of MHC class I and II molecules on endothelial cells in allografts.

Methods: Human aortic endothelial cells (HAEC) were used and the HLA type was determined. Cell-specific anti-HLA class I IgG was purified from a sensitized kidney recipient. HAEC were coincubated with cell-specific anti-HLA class I IgG after pretreatment with the HSP90 inhibitor 17DMAG or DMSO as a vehicle. The cell-surface expression of HLA class I was assessed using flow cytometry and immunohistochemical study. In addition, murine heterotopic heart transplantation (HTx) was performed. C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donors and recipients, respectively. Recipients were treated with 17DMAG (2 mg/kg daily i.p.) or DMSO as a vehicle. On posttransplant day 7, the graft was collected and immunohistochemical study was done to evaluate the MHC class II expression on endothelial cells.

Results: In vitro study showed that cell-surface expression of HLA class I on HAEC was suppressed by 17DMAG treatment. On the other hand, MHC class II expression in endothelial cells of the cardiac allografts was not reduced in 17DMAG-treated recipients as compared with the vehicle group.

Conclusion: HSP90 inhibition by 17DMAG-treatment may contribute to prevention of antibody-mediated allograft rejection via reduction of MHC class I expression on endothelial cells in allografts. However, this strategy may not be effective for prevention of anti -MHC class II antibody-mediated allograft rejection.

CITATION INFORMATION: Tanaka T, Maehana T, Masumori N. Inhibition of Heat Shock Protein 90 Suppresses the Expression of MHC Class I Molecules, but Not MHC Class II Molecules, on Endothelial Cells in Allografts. Am J Transplant. 2017;17 (suppl 3).

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