Il-6 Production by the Cardiac Allograft is Critical for Chronic Rejection in Mice

Background Interleukin-6 (IL-6) mediates numerous immunologic effects relevant to transplant rejection; IL-6 is a critical promoter of graft infiltration and a shaper of T cell lineage development in cardiac graft chronic rejection (CR). Recent studies demonstrate that IL-6 produced by the recipient, but not the donor graft is associated with acute cardiac rejection. However, it is not known whether IL-6 produced by the recipient cells or donor heart drives CR. Methods We used IL-6 deficient (-/-) mice to serve as either donors or recipients and a wild type control group in settings of CR. We performed serial echocardiogram and measured gene expression of indicators of CR including collagen-1a, IL-6, IL-17 and ANP, a marker of hypertrophy. In addition, we quantified cardiac myocyte size as a measure of cardiac hypertrophy. Results Echocardiograms revealed that allografts continued to function until the termination of the experiments. However the functional parameters, fractional shortening and ejection fraction, were increased in IL-6-/- recipients relative to IL-6-/- donor grafts. Gene expression of all molecules explored (collagen 1a, IL-6, IL-17 and ANP) in the IL-6-/- donor graft were significantly decreased (p<0.05).Figure: No Caption available.In contrast, these indicators of CR in the IL-6-/- recipient mice were virtually identical to the CR group indicating that IL-6 produced by the graft is critical. Furthermore, the cardiomyocyte area measurement revealed an increase in size in the IL-6-/- recipient mice compared to the IL-6-/- donor mice suggesting hypertrophy, further supporting that IL-6 from the graft contributes to cardiac hypertrophy associated with CR. Conclusion The importance of the IL-6 source has never been demonstrated in CR. These data support that IL-6 production by the donor hearts is critical for cardiac chronic rejection in mice. These findings indicate that targeting donor derived IL-6 may prove to be therapeutic in the context of CR.