Innate and acquired immune cell responses induce severe long term transplanted organ damage and loss, with recurrent episodes of acute rejection and chronic allograft vascular (AV) disease and scarring (ie both innate and acquired pathways). Both excess inflammation and recurrent antibody-mediated rejection contribute to late graft loss causing prolonged illness, increased mortality, and need for repeat transplants. With limited organs available for transplantation, there is a clear need for treatments to prevent later stage transplant loss. The glycosaminoglycans in the endothelial polysaccharide surface layer (EPSL) alter inflammatory cell adhesion and binding to the endothelial glycocalyx. Changes in heparin sulfate (HS) content and sulfation patterns (specifically 2-O and 6-O) alter neutrophil binding to endothelial cells. HS GAGs also bind chemokines forming a signal array that attracts inflammatory monocytes and T cells, thus orchestrating the inflammatory cell migration that precedes tissue damage and rejection. Blockade of selected chemokines and their receptors is associated with reduced chronic rejection and AV in diverse animal models.Recent work from our lab demonstrates that modifying HS sulfation in the EPSL in donor organs, significantly reduces acute rejection after solid organ allo-transplant. Donor renal grafts from mice with conditional N-deacetylase-N-sulfotransferase-1 (Ndst1) deficiency in endothelial cells have significantly decreased acute rejection in allogeneic recipients. We have also demonstrated that systemic treatment with a purified virus-derived chemokine inhibitor, M-T7, blocks chemokine: GAG interactions, reduces acute rejection and improves long-term transplant function, even without adjuvant immune-suppressant. This reduced rejection correlates closely with changes in HS. The central hypothesis for this proposal is that modifying HS content and sulfation in the EPSL of donor organs will reduce acute and chronic rejection. The central aims are to demonstrate; 1) long term benefit in donor organs with Ndst1 deficiency, 2) improved benefit, reduced rejection, with ectopic sulfatase treatment in donor organs, 3) reduced chemokine: GAG mediated immune cell damage and reduced rejection in transplants with altered HS GAG content and sulfation. Modifying HS-GAGs and their sulfation patterns in donor organs, prior to transplant engraftment, offers a new therapeutic option for reducing acute and chronic transplant rejection.
|Effective start/end date||01/01/2017 → 12/31/2018|