Date: Monday, June 3, 2019
Session Time: 2:30pm-4:00pm
Presentation Time: 3:30pm-3:42pm
Location: Room 309
*Purpose: We have previously demonstrated that administration of a heat shock protein 90 (HSP90) inhibitor 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 the production of damage-associated molecular patterns and regulation of the expression of MHC molecules. These mechanisms in the graft may influence the host alloimmune response. We therefore hypothesized that preconditioning of the graft with an HSP90 inhibitor might suppress the alloreaction and prolong the graft survival in solid organ transplantation.
*Methods: Murine heterotopic heart transplantation was performed using C57BL/6 (H-2b) and BALB/c (H-2d) mice as donors and recipients, respectively. In the graft preconditioning group,the graft was perfused in situ with 1 mL of a cold solution of alvespimycin, an HSP90 inhibitor, in which the agent was dissolved in heparinized Ringer’s lactate solution at a concentration of 250 µg/ml. The graft survivals of the graft preconditioning group and the control group were compared. In addition, cardiac allografts of the recipients were collected on day 3 and 5 for histopathological evaluation and quantitative RT-PCR.
*Results: Median allograft survivals were 14 and 7 days in the graft preconditioning group and control group, respectively (log-rank p <0.001). Histologic examination of the grafts revealed that cell infiltration was milder in the graft precondition group than in the control group. In immunohistochemical study, infiltration of neutrophils and dendritic cells in the graft was suppressed in the graft preconditioning group on day 3. Subsequently, expression of IL-2 mRNA and IL-12p40 mRNA in the graft was downregulated in the graft preconditioning group on day 5 as compared with the control group.
*Conclusions: The results of this study suggest that preconditioning of a graft with alvespimycin may suppress the adaptive immune response, leading to inhibition of acute allograft rejection. Preconditioning of the graft targeting HSP90 may be a promising strategy in solid organ transplantation.
To cite this abstract in AMA style:Tanaka T, Maehana T, Masumori N. Graft Perfusion with Alvespimycin, an HSP90 Inhibitor, Suppresses IL-2 and IL-12p40 Production in Graft-Infiltrating Cells, Leading to Prolongation of Graft Survival in Murine Heart Transplantation [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/graft-perfusion-with-alvespimycin-an-hsp90-inhibitor-suppresses-il-2-and-il-12p40-production-in-graft-infiltrating-cells-leading-to-prolongation-of-graft-survival-in-murine-heart-transplantation/. Accessed January 28, 2022.
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