Transplantationstechnologien und Forschung

A Histone Deacetylase Inhibitor, FR276457, Altered Characteristics of Infiltrating Cells into Allograft in a Rat Cardiac Transplant Model

Abstract

Fumitaka Kinugasa, Toshiko Yamada, Takahisa Noto, Yasuharu Urano and Shoji Takakura

Background: A recent study indicated that FR276457, a pan-histone deacetylase inhibitor, prevented allograft rejection in an ACI-to-Lewis rat heart transplant model, seemingly without affecting cellular infiltration into the transplanted heart. In this report, we investigated alterations in infiltrating cells in allografts by treatment of FR276457.

Materials and Methods: Heterotopic cardiac allografts which were removed from August Copenhagen Irish rats were transplanted into the necks of Lewis rats. FR276457 40 mg/kg or vehicle was subsequently administered orally for 5 consecutive days beginning on the operation day after recovery from anesthesia (Day 0). The allograft recipients were sacrificed under anesthesia on Day 5 after transplantation. At first, we identified infiltrating cells into the allografts by the histopathological analysis. In addition, we isolated the infiltrating cells from allografts, sorted CD8 positive (CD8+) T cells, and then investigated cytotoxicity of CD8+ T cells against spleen cells from an August Copenhagen Irish rat.

Results: Histopathological analysis of allografts on Day 5 after the heart transplant showed that infiltration of T cells was not suppressed in FR276457-treated allograft recipients, compared with those in vehicle-treated allograft recipients, although the infiltration of ED1 positive cells was tended to decrease. Ex vivo analysis revealed that alloantigen-specific cytotoxicity of CD8+ T cells, isolated from allografts in FR276457-treated allograft recipients, against ACI rat splenocytes was much lower than that in vehicle-treated allograft recipients.

Conclusion: FR276457 treatment suppressed the alloantigen-specific cytotoxicity of CD8+ T cells infiltrated into the allograft.