Purpose: We have previously demonstrated that administration of a heat shock protein 90 (HSP90) inhibitor to recipients prolonged the allograft survival in murine skin and heart transplantations. In addition to effects on antigen presentation and proliferation of lymphocytes in the host, HSP90 is associated with production of damage-associated molecular patterns and regulation of the expression of MHC molecules. These mechanisms in the graft may influence the alloimmune response. We hypothesized that preconditioning of the graft with an HSP90 inhibitor might suppress the alloreaction and prolong the graft survival in solid organ transplantation. Materials and methods: Murine heterotopic heart transplantation (HTx) was performed. C57BL/6 (H-2b) and BALB/c (H-2d) mice were used as donors and recipients, respectively. The mice were divided into three groups, a graft preconditioning group (Group 1), recipient treatment group (Group 2) and control group (Group 3). In the group 1, the graft was perfused in situ with 1 mL of a cold solution of alvespimycin, an HSP90 inhibitor at a concentration of 250 [micro]g/ml. In the group 2, recipients were treated with alvespimycin (2 mg/kg daily i.p.) from 2 days before HTx until rejection. The graft survivals were compared among the three groups. In addition, the cardiac allografts of the recipients were collected on day 3 for histopathological evaluation and quantitative RT-PCR in the group 1 and 3. Results: Median graft survivals were 14, 11 and 7 days in the group 1, 2 and 3, respectively (log-rank p <0.001, Figure 1). Macrophage and neutrophil infiltrations in the graft were suppressed and the mRNA expression of IL-6 in the graft was downregulated by the graft preconditioning. Conclusion: The results of this study suggest that preconditioning of a graft with alvespimycin is a promising strategy in solid organ transplantation. Interestingly, anti-HSP90 preconditioning of the graft had more survival efficacy than treatment of the recipient, suggesting that the main role of HSP90 in allorejection is modulation of the immunogenity of the graft tissue.

CITATION INFORMATION: Tanaka T., Maehana T., Masumori N. Graft Perfusion with Alvespimycin, an HSP90 Inhibitor, Suppresses Acute Allograft Rejection and Prolongs Graft Survival in Murine Heart Transplantation Am J Transplant. 2017;17 (suppl 3).

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