Lymph Node Delivery in Transplantation

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Abstract The transplantation field has witnessed many major breakthroughs, including the development of immunoregulatory molecules (IRMs), which have been key to the success of organ transplantation. However, the use of IRMs is hindered by lack of efficiency and toxicity, and it is implicated in the pathogenesis of organ failure and accelerated cardiovascular disease, which is the leading cause of death in transplant recipients. Therefore, a substantial unmet medical need exists to develop novel strategies to increase the efficacy and reduce the toxicity of IRMs. The existing drugs are often adequately potent when directed specifically to their intended sites, so methods of targeted drug delivery could potentiate their safety and efficacy profiles significantly, while reducing the need for creating new drugs, a process that can be extremely expensive, labor- intensive, and time-consuming. Although targeted drug delivery using nanotechnology represents a highly promising and innovative strategy for site-specific drug delivery, its application to transplantation remains to be developed. The overall goal of this proposal is to develop a targeted drug delivery system for IRMs in transplantation, with the ultimate goal of increasing their efficacy and diminishing their toxicity. In transplantation, presentation of donor allo-antigens to recipient T cells in the draining lymph nodes (DLNs) is fundamental to the generation of alloreactive T cells that traffic to the allografts and cause allograft rejection. The overall hypothesis of this proposal is that targeted delivery of IRMs to the DLN would not only increase their efficacy, but also decrease their toxicity by significantly reducing systemic dosage. In Aim 1, we plan to devise a clinically applicable active targeted method of delivering IRMs to the DLNs to promote heart allograft acceptance. We will focus primarily on murine heart allograft survival by devising a combinatorial therapeutic strategy with our targeted delivery platform to address the immediate unmet need for safer and more efficacious therapies in transplantation. In Aim 2, we plan to evaluate the mechanism of prolongation of heart allograft survival by our active targeted delivery platform to DLNs. Mechanistic studies will also permit improvement of the design of our targeted delivery method. These experiments will employ murine heart transplant models, established functional assays, and sophisticated imaging studies to understand better the biodistribution of IRMs and their nanocarriers. In Aim 3, we plan to pursue our preliminary data to generate proof-of-concept data in devising a method of targeting IRMs to DLNs in non-human primates. This multidisciplinary, collaborative approach sets forth a novel targeted delivery platform that could potentially shift the paradigm of the approach to immunosuppressive therapy in transplantation.