Notebook

Active Grants

HL158504-01 P01 (Madsen: Overall PI; Kean: Project 2 PI)                                                
NIH/NHLBI 
Durable Chimerism-Induced Tolerance to Heart Allografts
Specific Aims: (1) To induce durable mixed chimerism, optimize Treg homeostasis and preserve protective immunity with OX40L blockade and mTOR inhibition. In this Aim we will interrogate a novel approach to tolerogenic immunomodulation, OX40L blockade plus sirolimus. We will test its ability to promote chimerism, induce lung transplant tolerance and preserve protective immunity. (2) Toxicity-free induction: Using antibody-drug conjugate (ADC)-based non-genotoxic conditioning to induce durable mixed-chimerism and transplant tolerance. In this Aim, we will interrogate the ability of anti-CD117 and anti-CD45 ADCs to successfully create the marrow space necessary for durable donor engraftment and mixed-chimerism induction in NHP.
(3) Chimerism induction with a highly purified subset of stem cells capable of rapid multilineage engraftment: In this Aim we will interrogate a subset of hematopoietic cells that is highly enriched for rapid multilineage engraftment and durable chimerism-induction without GVHD.
Role:  Project PI

 

5R01HL095791 (PI:  Kean)                     
NIH/NHLBI                                                    
Novel Biologic Therapies for GVHD
Specific Aims: to prioritize and validate next-generation GI-targeted therapeutics with a novel translational pipeline, to test the hypothesis that a pipeline from patient/NHP-derived therapeutic candidates à mouse à NHP can prioritize new GI AGVHD therapeutics; to determine the impact of Notch ligand blockade on the blood and GI Teff versus Treg immune landscape in NHP and transplant patients, to will test the hypothesis that the anti-DLL4 mAb REGN421 protects against GI AGVHD by inhibiting Teff infiltration into the GI tract while maintaining Treg GI trafficking; to identify predictors of steroid-responsive versus resistant GI AGVHD in patients, to test the hypothesis that unifying mechanisms of steroid response versus resistance can be identified in patients by comprehensive linked immune studies of the blood and GI tract at AGVHD diagnosis
Role:  Principal Investigator

5U19AI051731 (Larsen: Overall PI; Kean: Project 2 PI)                
NIH/NIAID/                    
Project 2:  Transplant Tolerance in Non-Human Primates
The goal of this project is to use mixed-chimerism- and Treg-based approaches to induce specific immunologic tolerance during bone marrow and renal transplantation in a rhesus macaque MHC-defined transplant model.
Specific Aims: The specific aims of this project are (1) to engineer an optimally suppressive regulatory T cell product, able to provide allograft-specific immune tolerance after renal transplantation; (2)  to induce immune tolerance to a renal allograft through the induction of stable, multilineage mixed-hematopoietic chimerism and preservation of protective immunity in the setting of T cell costimulation blockade.
Role:  Principal Investigator

Core B:  Transplant Tolerance in Non-Human Primates - CORE B                                   
The goal of this core is to support all projects being performed as part of the Transplant Tolerance in Non-Human Primates U19 in the following areas:  (1) MHC immunogenetic analysis; (2) Determining the impact of transplantation on anti-viral protective immunity; (3) Transplant-specific histopathology; and (4) Multiparameter flow-cytometric immune analysis. 
Specific Aims: The specific aims of this project are (1) to engineer an optimally suppressive regulatory T cell product, able to provide allograft-specific immune tolerance after renal transplantation; (2)  to induce immune tolerance to a renal allograft through the induction of stable, multilineage mixed-hematopoietic chimerism and preservation of protective immunity in the setting of T cell costimulation blockade.
Role:  Principal Investigator

 

6583-20 (Multi PIs: Drs. Maillard and Kean Kean/Maillard)                           
Leukemia Lymphoma Society          
Preclinical Notch inhibition to prevent graft-versus-host disease in mice and non-human primates
This project focuses on advanced preclinical studies of new therapeutic strategies to prevent graft-versus-host disease in non-human subjects.
The specific aims of this project involve (1) the analysis of necropsy material from past and future experiments to characterize the impact of Notch ligand inhibition on intestinal GVHD; (2) new experiments with non-human primates involving the combination of a new anti-DLL1 antibody (also from our partners at Regeneron) with REGN421; (3) additional experiments in non-human primates testing REGN421 (or REGN421 plus anti-DLL1) in combination with other therapeutic interventions that are used in patients.
Role:  Co-Principal Investigator

 

1OT2HL154984 (Bauer: PI)            
NIH                                                     
Therapeutic BCL11A enhancer gene editing to induce fetal hemoglobin in Beta-hemoglobinopathy patients- CureSci
Specific Aims: The objective of this project is to develop a curative therapy for sickle cell disease (SCD) and β-thalassemia based on gene editing of the BCL11A erythroid enhancer in autologous hematopoietic stem cells. 
Role:  Co-Investigator

 

2111-04870            
L. & H. Helmsley Charitable Trust    PIs:  Drs. Ordovas-Montanes, Moffitt, Kean                 
Molecular and spatial single-cell remodeling in pediatric Crohn's Disease
The goal of this project is to broaden the understanding of pediatric Crohn’s Disease (pediCD) and lay the foundation for molecular-, cellular-, and spatial-specific treatments with state-of-the-art single-cell methods, including droplet and spatial transcriptomics and high-dimensional mass cytometry, with a unique treatment-naïve patient cohort. In addition, it is also to deliver a spatially resolved atlas of the terminal ileum.
Role: Co-Principal Investigator