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. To date, the role of HSP90 in solid organ transplantations is still unknown. The purpose of this study was to verify the involvement of HSP90 in allograft rejection in kidney transplantation. Mothods: We obtained 90 serum samples from 16 patients who underwent kidney transplantation and examined the HSP90 concentrations by ELISA. Of these patients, there were 9 who experienced antibody-mediated rejection (AMR) from whom serum samples before and during AMR and after the treatment for AMR were collected. In addition, we created an in vitro AMR model using human aortic endothelial cells (HAEC) and a cell-specific anti-HLA antibody. The HLA type of the HAEC was identified and IgG was purified from serum of a kidney recipient who had the HAEC-specific anti-HLA antibody proven by Luminex®. Moreover, complement-mediated cytotoxicity (CMC) was assessed in this model. Furthermore, we assessed the effect of an HSP90 inhibitor, alvespimycin (17DMAG) on CMC. Results:Serum HSP90 levels at the time of acute AMR were significantly higher than those at the time with no evidence of rejection (36.59 ± 23.32 ng/ml vs. 9.028 ± 5.31, p = 0.0035). Serum HSP90 levels tended to be increased after the onset of AMR and decreased after the treatment. The in vitro study revealed that the HSP90 concentration was significantly higher in the supernatant of HAEC with ligation of anti-HLA (B44) IgG under complement attack compared to that with nonspecific IgG (3.11 ± 1.02 ng/ml vs. 0.61 ± 0.02 ng/ml, p = 0.0343). Although complement attack decreased the cell viability to 55% of the control level, treatment with 200 nM of 17DMAG preserved the cell viability, which was 100% of the control level. Conclusion:The results of our study suggest that HSP90 plays a role in the development of acute AMR. Elevation of serum HSP90 in AMR may be induced by CMC. In addition, the HSP90 inhibitor 17DMAG is a potential therapeutic agent against AMR.
To cite this abstract in AMA style:Tanaka T, Ishida H, Furusawa M, Tamura Y, Kitamura H, Takahashi S, Masumori N, Tanabe K, Sato N, Tsukamoto T. Heat Shock Protein 90 Is Involved in Antibody-Mediated Rejection and Is a Potential Target of Anti-Rejection Therapy in Kidney Transplantation [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/heat-shock-protein-90-is-involved-in-antibody-mediated-rejection-and-is-a-potential-target-of-anti-rejection-therapy-in-kidney-transplantation/. Accessed November 19, 2017.
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