TGF-beta, IL-6, IL-17 and CTGF direct multiple pathologies of chronic cardiac allograft rejection

Abstract

Cardiac transplantation is an effective treatment for heart failure refractive to therapy. Although immunosuppressive therapeutics have increased first year survival rates, chronic rejection remains a significant barrier to long-term graft survival. Chronic rejection manifests as patchy interstitial fibrosis, vascular occlusion and progressive loss of graft function. Recent evidence from experimental and patient studies suggests that the development of cardiomyocyte hypertrophy is another hallmark of chronic cardiac allograft rejection. This pathologic hypertrophy is tightly linked to the immune cytokine IL-6, which promotes facets of chronic rejection in concert with TGF-beta and IL-17. These factors potentiate downstream mediators, such as CTGF, which promote the fibrosis associated with the disease. In this article, we summarize contemporary findings that have revealed several elements involved in the induction and progression of chronic rejection of cardiac allografts. Further efforts to elucidate the interplay between these factors may direct the development of targeted therapies for this disease.

Figure 1. Multiple processes contribute to the development of chronic rejection

Both alloantigen-dependent and -independent factors promote immune responses against allografts and activation of graft endothelium. Complex interplay of these factors results in graft infiltration/inflammation and injury. Injury prompts reparative processes characterized by fibroblast activation and recruitment, as well as proliferation and migration of smooth muscle-like cells in the vasculature. These processes lead to the development of chronic rejection hallmarks of chronic allograft vasculopathy and interstitial fibrosis. Graft hypertrophy, characterized by increased cardiomyocyte size and thickening of the left ventricle wall, accompanies these pathologies, although the interrelationship between these processes is not yet understood. Ultimately, these graft pathologies lead to organ dysfunction and failure.

Figure 2. Proposed interactions of TGF-β, IL-6, IL-17 and CTGF in the evolution of cardiac allograft hypertrophy and fibrosis

In the context of alloantigen, TGF-β and IL-6 induce CTGF and IL-17. The relationship between IL-17 and CTGF remains to be established, although both of these factors, along with TGF-β, promote graft fibrosis. IL-6 induces cardiomyocyte hypertrophy, which might involve induction of IL-17.