Targeting LIGHT for treatment of glomerulonephritis - Project Summary Crescentic glomerulonephritis (CGN) is a severe immune-mediated condition that causes a rapid deterioration in renal function, but the mechanisms that regulate this pathogenic immune response are poorly understood. This gap in knowledge has led to an absence of targeted treatments for this condition, as the current standard immunosuppressive agents (ISAs) are plagued by poor efficacy and off-target toxicity. In this project, we seek to solve this dilemma through the development of a first-in-class, kidney-draining lymph node (KLN)-targeted nanotherapeutic. Previous studies examining the pathogenesis of CGN have focused on identifying potential therapeutic targets in the kidney, but our group has demonstrated that the KLN is the major site for regulation of the adaptive immune response during CGN. Here, we have focused our studies on fibroblastic reticular cells (FRCs), the chief cells that create and maintain the stromal compartment of lymph nodes (LNs). FRCs form the microarchitecture of the LN, supporting specialized blood vessels called high endothelial venules (HEVs) that mediate the entrance of naïve T cells into the LN, and they produce extracellular matrix (ECM) fibers and conduits upon which these T cells interact with dendritic cells inside the LN. We found previously that FRCs are integral to renal damage, as their selective ablation ameliorated kidney injury during the acute phase of CGN. However, the specific signaling pathways that confer pro-inflammatory properties to FRCs are unknown. Our preliminary data shows that the cytokine TNFSF14 (LIGHT) induces a pro-inflammatory phenotype in FRCs, and that LIGHT is also expressed by kidney proximal tubular epithelial cells (PTECs) during CGN. Furthermore, we found that LIGHT produced by both CD4+ T cells and proximal tubular epithelial cells (PTECs) is integral to kidney injury during CGN, using cell-specific conditional LIGHT knockout mice. Meanwhile, we have created first-in-class antibody-coated nanoparticles (NPs) that traffic selectively to LNs through binding to a specific family of glycoproteins on HEVs known as peripheral node addressin (PNAd). Importantly, these NPs could satisfy the critical unmet need for targeted therapeutic development for CGN. In this proposal, we will test the hypothesis that LIGHT activity in both the KLN and kidney contributes to the pathogenesis of CGN, and the use of a KLN- targeted anti-LIGHT nanotherapeutic will ameliorate CGN. We will interrogate this hypothesis by pursuing three complementary specific aims. In Specific Aim 1, we will define the mechanism by which CD4+ T cell-produced LIGHT promotes a pro-inflammatory milieu in the KLN to exacerbate CGN. In Specific Aim 2, we will define the mechanism by which PTEC-produced LIGHT contributes to kidney injury during CGN. In Specific Aim 3, we will build a first-in-class, KLN-targeted nanodelivery platform for anti-LIGHT to treat CGN. These experiments will (1) illuminate the understudied contribution of KLN FRCs to the pathogenesis of CGN, (2) highlight PTECs as active initiators of the immune response via expression of LIGHT in the kidney, and (3) introduce LIGHT as a potential therapeutic target in CGN through the development of first-in-class, KLN-selective anti-LIGHT nanovehicles.
