Novel immunoregulatory mechanisms that modulate myeloid trained immunity following transplantation

About This Grant

Project Summary/Abstract The immune system can be categorized into innate and adaptive immunity. Innate immune cells detect and respond according to danger associated signals and initiate a coordinated antigen-specific response by the adaptive system to eliminate threats such as viruses, bacteria and tumor cells. Immunosuppressive drugs inhibit adaptive responses and are used following organ transplantation to prevent acute transplant rejection but do not generally target innate immunity. It was recently discovered that innate cells can be licensed to detect foreign allogenic tissue and initiate responses against the transplant in the absence of danger- associated signals. Additionally, innate cells show accelerated activation responses following re-exposure to the identical foreign tissue, called innate memory or trained immunity. These findings suggest that innate cells are chronically stimulated and activated following transplantation, and it is possible that persistent innate responses participate in or drive chronic transplant rejection, the main reason for graft loss. Little is known about the mechanisms that control and modulate innate allo-activity and no therapeutic is clinically available to resolve persistent innate alloimmunity following transplantation. In this proposal, we hypothesize that Semaphorin 3F (SEMA3F)-Neuropilin 2 (NRP2) interactions on monocytes can inhibit and/or resolve persistent innate alloimmune responses following transplantation. In preliminary experiments, we find that monocytes express NRP2 following initial alloimmune activation in recipients of fully MHC mismatched cardiac allografts. We also find that the administration of the NRP2-ligand SEMA3F prolongs allograft survival in models of cardiac transplantation. In Aim 1, we will assess SEMA3F- induced innate responses following transplantation and we will employ transcriptomics and confirmatory protein-based methods to define SEMA3F-dependent signaling networks within monocytic subsets. In Aim 2, we will use a monocyte-specific tamoxifen-inducible NRP2 KO mouse model and evaluate intrinsic effects of NRP2 signaling on monocyte responses following transplantation. We predict that the administration of SEMA3F prolongs allograft survival by inhibiting monocyte and macrophage alloimmune memory responses. We also predict that deletion of NRP2 from monocytes results in accelerated graft rejection and that SEMA3F- NRP2 interactions are required for long term graft survival. If successful, the impact and relevance of these studies are the identification of SEMA3F as a novel immunoregulatory ligand that suppresses innate immunity following transplantation, the identification of NRP2 as a co-inhibitory receptor on innate cells, and that they enable the development of immunomodulatory drugs that resolve persistent innate alloimmune responses post transplantation.