Project Grant R01AI184406

INNOVATIVE APPROACHES TO ENHANCE REGULATORY MYELOID CELL FUNCTION AND RENAL TRANSPLANT SURVIVAL IN NONHUMAN PRIMATES - R01 SUMMARY THERAPEUTIC REGULATION OF INNATE IMMUNITY REMAINS UNDEREXPLORED. OUR OVERALL HYPOTHESIS, BASED ON KEY PRELIMINARY DATA, IS THAT NHP KIDNEY ALLOGRAFT SURVIVAL CAN BE EXTENDED AND IMMUNOSUPPRESSION (IS) WITHDRAWN BY INNOVATIVE STRATEGIES AND CUTTING-EDGE TECHNOLOGIES THAT POTENTIATE DENDRITIC CELL (DC) TOLEROGENICITY. THESE STRATEGIES WILL ENABLE 1) SELECTIVE INHIBITORY TARGETING OF DCS IN SITU, OR 2) ADOPTIVE TRANSFER OF AUTOLOGOUS REGULATORY DC (DCREGS) PULSED WITH DONOR SMALL EXTRACELLULAR VESICLES (SEVS). THE REGIMENS WE PROPOSE WILL (I) PROVIDE NEW MECHANISTIC INSIGHT INTO THE INDUCTION AND MAINTENANCE/STABILITY OF DONOR-SPECIFIC UNRESPONSIVESS AND (II) POTENTIALLY IDENTIFY NOVEL PREDICTIVE BIOMARKERS. IN DUE COURSE, OUR FINDINGS MAY PROVIDE OPPORTUNITIES TO INTERACT WITH/PARTICIPATE IN NIAID-FUNDED CLINICAL TRIALS, SUCH AS THOSE CURRENTLY ASSESSING DCREG THERAPY IN ORGAN TRANSPLANTATION AT THE UNIVERSITY OF PITTSBURGH. RECENT DATA SHOW THAT ACTIVATION OF THE INHIBITORY LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR B (LILRB) FAMILY MEMBER LILRB3 (ILT5; CD85A) THAT IS HIGHLY EXPRESSED ON DCS, CONFERS PROFOUND IMMUNOINHIBITORY FUNCTIONS ON MYELOID CELLS THAT INDUCE T CELL TOLERANCE TO ALLOAGS IN HUMANIZED MICE. WE WILL TEST OUR HYPOTHESIS THAT AN AGONISTIC LILRB3 MAB CAN EXTEND GRAFT SURVIVAL/ALLOW IS WITHDRAWAL. AN ALTERNATIVE NOVEL APPROACH TO SELECTIVE TARGETING DCS IN SITU IS USE OF AB-DIRECTED, DC-TARGETING NANOBIOLOGICS. WE HYPOTHESIZE THAT NANOPARTICLES (NP) FUNCTIONALIZED WITH MAB AGAINST THE ENDOCYTIC RECEPTOR DEC205 (CD205) AND LOADED WITH THE MTOR INHIBITOR RAPAMYCIN (MTORI-NP) WILL PROMOTE TREG GENERATION, EXTEND GRAFT SURVIVAL AND ALLOW IS WITHDRAWAL. WE DISCOVERED THAT ACQUISITION OF DONOR MHC AG (VIA SEVS) AND UPREGULATION OF CO-INHIBITORY/ANTI-INFLAMMATORY MOLECULES BY RECIPIENT DCS SUBVERTS ANTI-DONOR T CELL RESPONSES IN RODENT LIVER TRANSPLANT TOLERANCE. IN PATIENTS, WE HAVE SHOWN THAT INFUSION OF DCREG RESULTS IN ACQUISITION (VIA SEVS) OF DONOR MHC, CO-EXPRESSED WITH ENHANCED LEVELS OF CO-INHIBITORY MOLECULES ON HOST DCS. WE THEREFORE HYPOTHESIZE THAT INFUSION OF AUTOLOGOUS DCREGS PULSED WITH DONOR SEVS (SEV-DCS) WILL EXTEND GRAFT SURVIVAL/ALLOW IS WITHDRAWAL. OUR SPECIFIC AIMS ARE: AIM 1: TO DETERMINE WHETHER AGONISTIC LILRB3 MAB COMBINED WITH BASELINE IS CAN EXTEND KIDNEY GRAFT SURVIVAL/ALLOW IS WITHDRAWAL (N=12 TRANSPLANTS) AIM 2: TO ASCERTAIN WHETHER SELECTIVE TARGETING OF DCS IN SITU USING NOVEL DC (DEC205)-DIRECTED NANOPARTICLES (MTORI-NPS) CAN EXTEND GRAFT SURVIVAL/ALLOW IS WITHDRAWAL (N=6 TRANSPLANTS) AIM 3: TO ASSESS WHETHER POST-TRANSPLANT INFUSION OF AUTOLOGOUS DCREGS PULSED WITH DONOR SEVS (SEV- DCREGS) CAN EXTEND GRAFT SURVIVAL/ALLOW IS WITHDRAWAL (N=12 TRANSPLANTS)