Targeted delivery of IL-21 neutralizing nanotherapeutics to lymph nodes and kidney allografts attenuates B cell alloimmunity.

Abstract

Antibody-mediated rejection (ABMR) after allogeneic kidney transplantation is a substantial clinical problem for which there are no specific treatments. High endothelial venules (HEV) are specialized veins which are normally present only in lymph nodes (LN) facilitating immune cell entry. Here, we show that kidneys undergoing rejection develop HEV-like structures derived from host cells. We developed a nano-delivery system targeting HEVs to simultaneously deliver therapeutics to draining LN and kidney allografts. Using this system, we preferentially delivered IL-21 neutralizing antibody (NP-HEV[αIL21]) to draining LN and kidney allografts resulting in improved graft function and recipient survival. The NP-HEV[αIL21] system also decreased alloreactive B cell responses, donor-specific antibody production, and ABMR-like lesions in kidney grafts. Our study provides a therapeutic strategy to selectively target distinct effector sites to attenuate B-cell alloimmunity while limiting effects of broad systemic immunosuppression in kidney transplantation.