Core B will provide antibody-coated nanoparticles (NPs) and FRCs for in vivo administration to reprogram the LN microenvironment towards a regulatory milieu that promotes transplant tolerance. These strategies represent cutting-edge approaches which have been set forth only by the teams here, and hence they represent a radical departure from the traditional approaches to induce tolerance. These techniques provided by Core B lay the groundwork for developing first class of therapeutics aimed towards reprogramming the microenvironment of the LN. In addition to the applications of these data to transplantation, they can also have a major impact in other immune conditions in which the LN plays a central role in the pathogenesis (e.g., autoimmune diseases and tumor immunity). This Core will fully characterize and synthesize large quantities of MECA-79-conjugated carriers of anti-laminin ?5 (LAMA5) and anti-CD40L mAbs (Project 2 - Bromberg), as well as senolytic agents (SAs) (Project 1- Abdi). Core B will also synthesize dye-incorporating NPs (including infrared dye) to verify trafficking to LNs as well as to control the quality of the batches. This will be the first platform that targets LNs for drug delivery to reprogram their microenvironment towards immune tolerance. In addition, Core B will expand FRCs isolated from the LNs of healthy mice and will be fully characterized for FRC-specific markers. These cells will be provided to Project 1 for experiments that assess their impact on downregulating LN fibrosis and its deleterious effects on transplant tolerance.
The specific aims of Core B are as follows:
Aim 1. To characterize and provide antibody-conjugated NPs for targeted delivery of immune therapeutics to the LN to promote transplant tolerance.
Aim 2. To characterize and provide healthy FRCs for in vivo administration to promote transplant tolerance by reprogramming the LN microenvironment.
