Original pre-clinical science
PPAR-γ signaling and IL-5 inhibition together prevent chronic rejection of MHC Class II–mismatched cardiac grafts

https://doi.org/10.1016/j.healun.2011.01.704Get rights and content

Background

Chronic rejection can prevent long-term survival of organ transplants. Although the beneficial effects of peroxisome proliferator-activated receptor-gamma (PPAR-γ) in reducing graft rejection have been reported, the details of the underlying mechanisms remain unclear, especially in the context of modulating cellular infiltration and preventing vasculopathy and interstitial fibrosis.

Methods

The therapeutic effects of the PPAR-γ agonist, rosiglitazone, combined with anti–interleukin-5 are explored in a mouse model of MHC Class II–histoincompatible cardiac transplantation.

Results

Rosiglitazone treatment alone marginally increased long-term survival and reduced CD8 T-cell infiltration and vasculopathy in the grafts. However, there was no reduction in collagen deposition and interleukin (IL)-4, IL-5 and eosinophil infiltration were increased. Anti–IL-5 antibody treatment alone reduced eosinophil infiltration and collagen deposition, but had no effect on CD8 T-cell infiltration or vasculopathy. Combined treatment with anti–IL-5 antibody and rosiglitazone prevented graft rejection. Furthermore, rosiglitazone treatment increased adiponectin receptor II expression in grafts and on dendritic cells and T cells in vitro. Graft survival correlated with increased expression in grafts of the inhibitory molecule PD-L1.

Conclusions

The findings obtained increase the knowledge on the mode of action of rosiglitazone in promoting the survival of MHC Class II–mismatched cardiac transplants in which the CD8 T cells and eosinophils play key roles. PPAR-γ signaling combined with IL-5 blockade prevents graft rejection.

Section snippets

Mice and reagents

Inbred male C57BL/6 (B6, H-2b) and B6.C-H-2bm12KhEg (BM12, H-2bm12) mice (6 to 8 weeks old, weight 20 to 25 g) were used in our study. The experimental protocol was approved by the Committee on the Use of Live Animals in Teaching and Research, University of Hong Kong.

Mouse heterotopic cardiac transplantation treatment protocols

Mouse cardiac transplantation was performed as previously described.13 Cardiac allografts from BM12 mice were transplanted heterotopically into C57BL/6 mice using standard microsurgical techniques for the transplantation of

Combined rosiglitazone and anti–IL-5 antibody treatment prolongs graft survival

In the MHC Class II–mismatched cardiac transplantation model for the syngeneic group (B6 to B6 as donor and recipient, respectively), 100% of the grafts survived >100 days. In the chronic rejection group (BM12 to B6) without treatment, the long-term survival rate was 35.7% (n = 14). The median survival time was 35 days with the earliest and latest times of rejection occurring at 20 and 48 days, respectively. With rosiglitazone treatment, the percentage of grafts surviving increased to 57.1% and

Discussion

In this report we have demonstrated that combined treatment with the PPAR-γ agonist rosiglitazone plus anti–IL-5 antibody prevents rejection of MHC Class II–histoincompatible cardiac grafts. We then analyzed the ability of these two compounds to modulate responses in the graft recipients that are associated with chronic rejection.

The ability of PPAR-γ agonists to reduce eosinophil recruitment into the airways has been observed in experimental models of ovalbumin-induced asthma.19, 20 In

Disclosure statement

The first two authors (Y.C. and D.-X.L.) contributed equally to this work. The project was supported by the General Research Fund (HKU 762108M) and the Seed Funding Programme for Basic Research, University of Hong Kong (200811159035).

The authors have no conflicts of interest to disclose.

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