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Principal Investigator: JAMES FRANCIS MARKMANN
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2023
Award: $637,715
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY / ABSTRACT
It has been suggested that the future of medicine rests in cell and gene therapy. While this assertion may be premature,
it seems clear that these innovative therapies have extraordinary, paradigm shifting potential. For cell-based therapies,
this is best exemplified by the powerful impact of chimeric antigen receptor (CAR) T cells in the treatment of hematological
malignancies refractory to current standard of care (5). In the transplant realm, MSC’s, stem cell derived islets, and
facilitator cells to promote bone marrow tolerance to renal grafts have shown encouraging results as cell-based
therapeutics (6-8). In addition, numerous early phase clinical trials are underway exploring the potential of regulatory T
cells (Tregs) to mitigate rejection of liver and kidney allografts (9, 10). More recently, CAR technology has been employed
to generate CAR Tregs as more potent, off-the-shelf, donor antigen-specific regulatory populations (11).
In the current proposal, we investigate the regulatory properties in the other arm of adaptive immunity to focus on the
regulatory activities of B cells. After finding that B cells were required for tolerance in varied experimental transplant
models and that B cells (or Bregs) isolated from mice tolerant to islets could adoptively transfer tolerance to otherwise
untreated B cell deficient hosts, we sought to expand the tolerogenic Breg population ex vivo. In so doing, we made the
unexpected observation that even naïve B cells stimulated ex vivo by Toll-like receptors (TLRs) manifested potent
suppressive activity in MLRs and prevented graft rejection in vivo (12). With further study, we demonstrate that a variety
of B cell activating signals induce Breg suppression and that, depending on the activating trigger, the mechanism of
suppression in vivo varies. Our overarching hypothesis is that Breg suppression is executed through antigen presentation
in the context of local immunoregulatory cytokine elaboration, such as TGF-ß and IL-10. Supporting this notion, we found
that B cell specificity for the donor was essential to suppressive function, perhaps indicating cognate Breg-T cell/Treg
communication (13, 14). Also noteworthy is our finding that clonal Breg populations with specificity for donor antigens
exhibited the greatest suppressive potency in vitro and in vivo (13). Based on these findings, in Aim 3, we will conduct
innovative studies to determine whether Bregs, imbued with donor specificity, through either transient or permanent
expression of a donor-specific CAR, prevent allograft rejection. Furthermore, recent studies indicate that CAR can be
delivered effectively in vivo using lipid nanoparticles (LNP) decorated with antibodies to target select cell populations,
such as host B cells (15). The LNP approach developed for vaccine delivery also lends itself to parallel transfer and
expression of mRNA payloads encoding suppressive molecules (IL-10, TGF-ß, etc.) to augment potency (16). Collectively,
our proposed work will advance understanding of Breg mechanisms of differentiation and suppression, optimize Breg
function and evaluate the potential of Bregs and CAR Bregs as cellular therapeutics.
Terms: <(TNF)-α><ARHGEF5><ARHGEF5 gene><Adoptive Transfer><Allergy><Antibodies><Antigen Presentation><Antigen Targeting><Antigens><Area><Assay><Autoimmune Status><Autoimmunity><B blood cells><B cell><B cells><B-Cell Activation><B-Cell Deficiency><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><B7-H1><B7H1><Bioassay><Biologic Assays><Biological Assay><Biological Markers><Blood><Blood Reticuloendothelial System><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone-Derived Transforming Growth Factor><Bp50><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CD25><CD274><CD40><CDW40><CSIF><CSIF-10><Cachectin><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell Therapy><Cell Transplantation><Cell-to-Cell Interaction><Cells><Clinical Research><Clinical Study><Clinical Treatment Moab><Comparative Study><Critical Paths><Critical Pathways><Cytokine Synthesis Inhibitory Factor><DNA Therapy><Data><Dermatoplasties><Dermatoplasty><Development><Endowment><Engineering><Environment><Exhibits><Experimental Models><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Future><GEF5><Gene Transfer Clinical><Generations><Genetic Intervention><Goals><Graft Rejection><Graft Survival><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hypersensitivity><IL-10><IL10><IL10A><IL2R><IL2RA><IL2RA gene><Immune response><Immunological response><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Innovative Therapy><Interleukin 10 Precursor><Interleukin-10><Intracellular Communication and Signaling><Investigation><Islands of Langerhans Transplantation><Islands of Pancreas Transplantation><Islets of Langerhans Grafting><Islets of Langerhans Transplantation><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Location><Lymphatic cell><Lymphocyte><Lymphocytic><MGC9013><Macrophage-Derived TNF><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Tumor><Medicine><Messenger RNA><Mice><Mice Mammals><Milk Growth Factor><Modeling><Monitor><Monoclonal Antibodies><Monocyte-Derived TNF><Murine><Mus><Ovalbumin><P60><PD-L1><PDL-1><PDL1><Pancreatic Islets Transplantation><Pathway interactions><Phenotype><Platelet Transforming Growth Factor><Population><Process><Progenitor Cells><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Property><Receptor Protein><Refractory><Regulatory T-Lymphocyte><Renal Grafting><Renal Transplantation><Renal Transplants><Rest><Role><Series><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Skin Transplantation><Specificity><T cell response><T cells for CAR><T-Cell Activation><T-Cell Proliferation><T-Cells><T-Lymphocyte><TCGFR><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><TIM1><TLR protein><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFRSF5><TNFRSF5 gene><TNFα><Technology><Therapeutic><Tissue Grafts><Tissue Transplantation><Tissues><Toll-Like Receptor Family Gene><Toll-like receptors><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Translations><Transplant Rejection><Transplantation><Transplantation Rejection><Transplantation Tolerance><Treg><Tumor Necrosis Factor><Tumor Necrosis Factor Receptor Superfamily Member 5 Gene><Tumor Necrosis Factor-alpha><Vaccines><Validation><Work><activate T cells><activated B cells><adaptive immune response><adaptive immunity><allograft rejection><anti-CD20><arm><autologous islet transplantation><bio-markers><biologic marker><biological signal transduction><biomarker><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><cytokine><deliver vaccines><develop a vaccine><develop vaccines><development of a vaccine><developmental><early clinical trial><early phase clinical trial><experiment><experimental research><experimental study><experiments><flow cytophotometry><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><hepatic allograft><host response><humoral immunity deficiency><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><in vivo><innovate><innovation><innovative><interest><islet><islet auto transplantation><islet beta cell transplantation><islet cell transplant><islet cell transplantation><islet transplantation><kidney allograft><kidney tx><lipid based nanoparticle><lipid nanoparticle><liver allograft><lymph cell><mAbs><mRNA><mRNA Expression><malignancy><monoclonal Abs><neoplasm/cancer><novel><organ rejection><organ transplant rejection><p50><pathway><pharmacologic><premature><prematurity><prevent><preventing><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><receptor><regulatory T-cells><renal allograft><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><standard of care><stem cells><thymus derived lymphocyte><tissue grafting><transcriptome profiling><transcriptomic profiling><translation><translational opportunities><translational potential><transplant><transplant model><vaccine delivery><vaccine development><validations>