Innovative approaches to enhance regulatory immune cell function and renal transplant survival in nonhuman primates

OVERALL SUMMARY/ABSTRACT In this P01, we will address the overall hypothesis that innovative regimens incorporating new agents and cutting-edge technologies that selectively enhance regulatory immune cell function, will extend kidney allograft survival and allow immunosuppressive drug withdrawal in rhesus macaques. The candidate regimens will be tested in combination with progressive tapering and withdrawal of conventional immunosuppression (IS). Our hypothesis in Project 1 is that graft survival can be extended and IS withdrawn in MHC-mismatched graft recipients using innovative strategies that selectively enhance inherent dendritic cell (DC) tolerogenicity. These approaches are 1) to target DCs in situ, either with an exciting, novel myeloid cell checkpoint agonist, or with innovative, DC-directed nanobiologics and 2) to adoptively transfer autologous regulatory DCs (DCregs) pulsed with donor-derived small extracellular vesicles (sEVs). Our Specific Aims are: Aim 1: To determine whether the novel myeloid cell checkpoint agonist (anti-LILRB3 mAb) that promotes DC tolerogenicity and allotolerance in mice, can extend graft survival/allow IS withdrawal; Aim 2: To ascertain whether selective targeting of DCs in situ using novel, DC (DEC205)-directed nanobiologics can extend graft survival/allow IS withdrawal; Aim 3: To assess whether infusion of autologous DCregs pulsed with donor-derived immunoregulatory sEVs can extend graft survival/allow IS withdrawal. Our hypothesis in Project 2 is that suppression of innate and adaptive immune mechanisms that would otherwise destabilize induction of tolerance, will be conducive to DCreg and Treg function and consequent prolongation of graft survival/IS withdrawal. We will use new, rhesus-specific mAbs to modulate inflammation, attenuate donor-reactive Tmem and augment donor Ag alloreactive Treg (darTreg); we will also test next generation donor Ag (Bw6)-specific chimeric Ag receptor (CAR)Tregs. Our Specific Aims are: Aim 1:To mitigate post-Tx inflammatory responses and eliminate IS-resistant, donor-reactive pathogenic Tmem through cytokine modulation using new, rhesus-specific neutralizing anti-IL-6 or IL-7R and IL-15R blocking mAbs; Aim 2: To augment Ag-specific Treg through infusion of ex vivo-expanded, genetically- engineered Bw6-specific CARTreg; Aim 3: To achieve durable, donor-alloreactive T cell regulation through CARTreg infusion, combined with either cytokine modulation or in situ targeting of DC, depending on the results of Project 2 Aim 1, and Project 1 Aim 1 and 2 results. Both Projects will incorporate highly-interactive mechanistic studies and assess potential novel biomarkers.The two Projects will be supported by an Administrative, Biostatistics and Bioinformatics Core (Core A), a Transplant Pathology and Tissue Imaging Core (Core B) and a Nanotechnology Core (Core C) and will utilize new agents from the NIAID NHP Reagent Resource. Our Program displays conceptual unity and strong component synergy and incorporates special/unique features of the investigative team and environment. Project Number: 1P01AI181829-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Angus Thomson | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $1,455,073 | Activity Code: P01 | Study Section: Special Emphasis Panel[ZAI1 JTS-I (J2)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1P01AI18182901A1