In this proposal we will advance the nano-immunotherapy to the field of solid organ transplantation.
MHC-based nanomedicines have been re-designed and re-built to induce local immunosuppression in solid organ transplantation. We are then validating the approach in a series of pre-clinical studies of two organs (kidney and liver), two animal species (mice and pigs) and three technical approaches (nanomedicines based on organ-specific epitopes, nanomedicines based on universal epitopes, and nanomedicines based on αGalCer glycolipid).
We are carrying out experiments testing and comparing ubiquitous PDC-E2 peptide and kidney specific uromodulin-based NPs in murine kidney and liver transplants. Specifically, donor or host MHCII molecules carrying PDC-E2 and uromodulin peptides have been directionally coated onto NPs to induce the formation of TR1 cells to inhibit effector T cells with direct or indirect/semidirect specificity, respectively. We will also evaluate the immunomodulatory effects of αGalCer/CD1d-NPs in murine and porcine liver transplant to ascertain whether liver-specific iNKT cells are re-programmed by αGalCer/CD1d-NPs and blunt liver allograft rejection. Following the completion of the above studies, we will analyse the data to identify the optimal approach to clinical therapy. After a fully capture of Regulatory requirement and based on their guidance, we will create a draft protocol for a first-in-human clinical trial with this immunotherapy in clinical kidney and liver transplantation.
PHOENIX commenced on 1 April 2023, in the first scientific step led by WP1, we commenced the project by engineering, optimising and producing novel murine kidney and liver transplantation -relevant pMHCII complexes, using PDC-E2 and uromodulin epitopes. For liver transplants, we have refined and produced murine and porcine CD1d/β2microglobulin complexes loaded with αGalCer. The murine kidney experiments have progressed well with good results and the murine liver transplant procedure is being optimised.
In the first half of the PHOENIX project, the initial set up from the perspective of communication and dissemination, data management and first considerations toward innovation management have been completed, as has preparatory work to establish the regulatory strategy roadmap for post-project. Preparations have been made to commence the porcine experiments, including scheduling and securing ethical approval.
