Increased systemic TNFα levels correlate with transplant rejection and severity of GVHD, and TNFα blockade can prolong graft survival and reduce severity of GVHD. These two findings indicate that TNFα driven inflammation may play a critical role in predicting transplant outcomes. While TNFα has pleiotropic effects on immunity, the molecular mechanisms through which TNFα causes inflammation are incompletely understood. Sharpin is a downstream modulator of the linear ubiquitin chain assembly machinery (LUBAC) initiated by TNFα signaling. It has been reported that mice deficient in Sharpin develop spontaneous skin and multi-organ inflammation that is rescued in Sharpin^-/- mice also deficient in TNFα (Gerlach et al, 2011), thereby indicating that the loss of Sharpin/LUBAC leads to TNFα-dependent inflammation. To test for a role of Sharpin in heart transplant rejection, we exposed Sharpin^-/- and Sharpin^+/+ control H-2b hearts to 8h of cold ischemia and then transplanted them into fully allogeneic BALB/c recipients, and treated the recipients with a single dose of CTLA4Ig. Whereas Sharpin^+/+ hearts underwent CTLA4-Ig-resistent rejection at 42±8 days, Sharpin^-/- grafts were rejected significantly faster by 17±4 days (p<0.05 vs Sharpin^+/+, n=4 for Sharpin^-/-, n=3 for Sharpin^+/+). The accelerated rejection in the recipients of Sharpin^-/- allografts underscores the importance of Sharpin/LUBAC as a negative regulator of intra-graft inflammation early after transplant. The unique findings support the need to study the molecular mechanisms of LUBAC expression and function in post-transplant intra-graft inflammation, and to determine how this pathway links to adaptive alloimmunity that results in graft rejection. As LUBAC analogously modulates TNFα induced inflammation in human immune cells, our results support the need for testing whether/how LUBAC influences post-transplant inflammation and delayed graft function in human transplant recipients.

CITATION INFORMATION: Ang R, Heeger P, Ting A. Donor Sharpin Expression Modulates TNFα Mediated Inflammation and Cardiac Allograft Rejection in Mice. Am J Transplant. 2016;16 (suppl 3).

« Back to 2016 American Transplant Congress