Tolerogenic Dendritic Cells via Synergistic Drug Loaded Microparticles for Transplantation Tolerance

Project Summary Kidney transplants, despite their utility in treating renal failure, carry significant risks, particularly after successful surgery due to the potential for immunological rejection. Aggressive immunosuppressive regimens have been designed to limit this risk but are fraught with side effects such as increased risk of cancer and infection. More precision immunosuppression that selectively generates tolerance towards donor kidney antigens are necessary, but to date no selective therapies have been developed. Here, we present a proof-of-concept study for a cell- based therapy to generate donor-specific immune tolerance. We will engineer potent tolerogenic dendritic cells (tolDCs) that can be infused into donor kidneys prior to transplantation, facilitating presentation of donor antigens and influencing antigen specific T regulatory responses; thereby selectively suppressing only donor specific immunity. Our engineered tolDCs, also known as Push/Pull particle tolDCs (PPP-tolDCs) will contain microparticles loaded with a combination of two synergistic tolerogenic drugs (known as the push/pull particle) that will provide sustained drug release. These push/pull drug combinations were identified via molecular screening and generate tolDCs which influence more potent antigen specific Treg responses. We hypothesize that these two innovations, the push/pull drug combination and encapsulation in sustained release microparticles, will function cooperatively to generate highly potent, long-lived tolDCs, which in turn generate T regulatory responses. In this proposal, we will validate that push/pull drugs can be loaded into microparticles and effectively influence naïve dendritic cells towards tolDCs phenotypes by modulating the inhibitor/agonist loading ratio. We will further explore PPP-tolDCs interaction with donor-specific kidney antigens from various sources and ability to influence donor-specific T regulatory responses. This is the first step in developing PPP- tolDCs towards a cell therapy that can generate donor kidney tolerance by being infused into donor kidneys prior to transplantation.