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

• Joo DJ
• Fang YH
• Huh KH
• Kim MS
• Suh H
• Kim YS

• KMID: 2202427
• DOI: http://doi.org/10.4285/jkstn.2012.26.4.248

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

MeSH Terms

Animals
Cytokines
Heart Transplantation
Immunosuppression
Interferons
Interleukin-10
Interleukin-2
Interleukin-4
Interleukin-6
Interleukins
Pyrroles
Quinazolines
Rats
Rejection (Psychology)
Rodentia
Tacrolimus
Transplantation, Homologous
Transplants
Tumor Necrosis Factor-alpha
Cytokines
Interferons
Interleukin-10
Interleukin-2
Interleukin-4
Interleukin-6
Interleukins
Pyrroles
Quinazolines
Tacrolimus
Tumor Necrosis Factor-alpha

Figure

• 

  Fig. 1 Serum levels of cytokines after AEB071 or tacrolimus monotherapies. The AEB071 60 mg monotherapy group had significantly lower serum levels of all cytokines than the untreated controls and significantly lower interleukin (IL)-4 levels than tacrolimus at 0.6 mg daily. Furthermore, the AEB071 60 mg group had lower serum levels of IL-6 and tumor necrosis factor (TNF)-α than either the tacrolimus 0.6 or 1.2 mg groups. Data are presented as mean±standard errors. Abbreviations: Tac, tacrolimus; IFN-γ, interferon-gamma; NS, not significant. aP<0.05 compared with the untreated control group.

• 

  Fig. 2 (A-G) Serum levels of cytokines after tacrolimus monotherapy and after tacrolimus/AEB071 60 mg combination therapy. Data are presented as mean±standard errors. Abbreviations: IFN-γ, interferon-gamma; Tac, tacrolimus; IL, interleukin; NS, not significant; TNF, tumor necrosis factor. aCharacters present comparisons between low-dose (0.6 mg) tacrolimus plus AEB071 60 mg and high-dose (1.2 mg) tacrolimus.

• 

  Fig. 3 Heart allograft survival time in response to AEB071 monotherapy or to tacrolimus/AEB701 combinatorial therapies with different tacrolimus doses. AEB071/low dose tacrolimus (Tac) enhanced heart allograft survival more so than high dose Tac monotherapy in the Brown-Norway-to-Lewis rat heterotopic cardiac transplant model. When AEB071 60 mg/kg twice a day was administered in combination with either low-dose or high-dose tacrolimus allograft survivals were similar. Adapted from Fig. 1 of reference [13]. Data are presented as mean survival times±standard errors. Abbreviation: NS, not significant.

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