J Korean Soc Transplant.  2012 Dec;26(4):248-253. 10.4285/jkstn.2012.26.4.248.

Changes in Serum Cytokine Profile after AEB071 (Sotrastaurin) or Tacrolimus versus Their Combinations in Rat Heterotopic Cardiac Allografts

Affiliations
  • 1The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea. yukim@yuhs.ac
  • 2Department of Transplantation Surgery, Yonsei University Health System, Seoul, Korea.
  • 3Graduate Program of Nanoscience and Technology, Yonsei University, Seoul, Korea.
  • 4BK21 for Medical Science, Yonsei University Health System, Seoul, Korea.

Abstract

BACKGROUND
AEB071, an orally available PKC inhibitor, prevents organ rejection after transplantation in rodents and man. Furthermore, pro-inflammatory cytokines and inflammatory processes are important mediators of transplanted organ rejection. We therefore examined whether single or combination therapies of AEB071 and/or tacrolimus affect cytokine profiles in a rat cardiac allograft model.
METHODS
AEB071 (60 mg/kg twice a day) and tacrolimus (0.6 or 1.2 mg/kg once a day) were orally administered daily after cardiac transplantation. Interferon (IFN)-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor (TNF)-alpha levels in serum were subsequently measured 5 days after cardiac transplantation using a multiplex protein assay system.
RESULTS
All cytokine levels were significantly depressed in cardiac transplanted rats treated with AEB071, whereas tacrolimus only reduced IFN-gamma, IL-2, IL-4, IL-6, and IL-10 levels. When administered in combination, AEB071 and low- or high-dose tacrolimus had additive effects on IFN-gamma, IL-4, IL-6, and TNF-alpha.
CONCLUSIONS
These results suggest that AEB071 inhibits T cell activation by blocking the production of proinflammatory cytokines, and that tacrolimus combined with AEB071 can effectively regulate inflammatory cytokines in the transplantation setting.

Keyword

Sotrastaurin; Cytokines; Heart transplantation; Immunosuppression; Tacrolimus
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