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Principal Investigator: Andrew B Adams
Organization: UNIVERSITY OF MINNESOTA
Fiscal Year: 2024
Award: $3,635,295
Funding agency: National Institute of Allergy and Infectious Diseases
While short-term outcomes following organ transplant have greatly improved with the development of more
effective immunosuppression, long-term outcomes remain problematic with a significant number of patients
developing diabetes, accelerated heart disease as well as increased rates of cancers and infections. For
decades transplant researchers and clinicians have sought to develop strategies to induce immune tolerance
to transplanted organs and avoid the requirement for life-long immunosuppression. It is likely that any
successful tolerance regimen will incorporate targeted immunosuppression strategies like costimulation
blockade. One of the most important interactions is the CD40-CD154 pathway. We will evaluate novel,
clinically relevant therapeutics targeting either CD40 or CD154 and explore their role in facilitating tolerance.
Based on our recent publication showing that CD11b is a novel alternate receptor for CD154 during
alloimmunity, we will also test novel nanotechnology to block the CD154:CD11b interaction, an important
mechanism of cross-talk between the innate and adaptive immune responses during transplantation.
Moreover, based on our published data showing that memory T cells are a potent barrier to transplantation
tolerance, we will determine the role of OX40-OX40L blockade to control alloreactive memory CD8+ T cells and
promote a pro-regulatory environment. In addition, we will assess the importance of the VISTA pathway on the
induction of donor-specific tolerance using an agonistic anti-human VISTA antibody. VISTA has a dual role in
negatively regulating antigen-specific T cell responses while also impacting the innate immune response by
inhibiting ischemia reperfusion injury, monocyte activation and neutrophil migration thereby suppressing the
early inflammatory response. We will also investigate the contribution of IL-1 and the inflammasome on
tolerance induction and employ clinically applicable therapeutics to control early inflammation during the
induction of tolerance. The combination of cellular therapy and costimulation blockade is a powerful strategy to
promote donor-specific tolerance. Myeloid derived suppressor cells (MDSCs) have inherent
immunosuppressive properties and have been used to facilitate tolerance. They modulate innate immunity and
inhibit T cell activation and effector cell function while also promoting regulatory T cell expansion for
maintenance of long-term donor specific tolerance. Apoptotic donor leukocytes (ADLs) represent another
promising cellular therapy that has been proven to control alloreactive T cells and promote donor specific T cell
deletion. We will use donor bone marrow derived MDSCs or ADLs in combination with the above novel
therapeutics to promote tolerance in nonhuman primate kidney transplantation.
Terms: <Acceleration><Address><Antibodies><Apoptotic><Autoimmune Diseases><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood leukocyte><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone Marrow Stem Cell Transplantation><Bp50><CD11b><CD134><CD134L><CD154><CD40><CD40L><CD40LG><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CDW40><CR3A><Cancers><Cardiac Diseases><Cardiac Disorders><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell Therapy><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chronic><Collaborations><Data><Development><Diabetes Mellitus><Disease><Disorder><Drugs><ESRD><Effector Cell><Elements><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Environment><Fertilization><Fingerprint><GP34><Goals><Grafting Procedure><Health><Heart Diseases><Human><IL-1><IL1><ITGAM><ITGAM gene><Immune><Immune Tolerance><Immune response><Immunes><Immunologic Tolerance><Immunological response><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Infection><Inflammasome><Inflammation><Inflammatory Response><Innate Immune Response><Innate Immunity><Interleukin I><Interleukin-1><Intracellular Communication and Signaling><Investigators><Ischemia-Reperfusion Injury><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Leukocytes><Leukocytes Reticuloendothelial System><Lymphocyte-Stimulating Hormone><MAC1A><MGC9013><MO1A><Macrophage Cell Factor><Maintenance><Malignant Neoplasms><Malignant Tumor><Marrow Neutrophil><Marrow leukocyte><Marrow monocyte><Mediating><Medication><Memory><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Myeloid Cells><Myeloid-derived suppressor cells><Nanotechnology><Native Immunity><Natural Immunity><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Non-Specific Immunity><Nonspecific Immunity><OX40><OX40L><Organ><Organ Transplantation><Organ Transplants><Outcome><Pathway interactions><Patients><Personal Satisfaction><Pharmaceutical Preparations><Phase><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Property><Publications><Publishing><RNA Seq><RNA sequencing><RNAseq><Reagent><Receptor Protein><Regenerative Medicine><Regimen><Regulatory T-Lymphocyte><Renal Grafting><Renal Transplantation><Renal Transplants><Reperfusion Damage><Reperfusion Injury><Research><Research Personnel><Researchers><Role><Scientific Publication><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Subcellular Process><System><T Helper Factor><T cell response><T memory cell><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TNFRSF5><TNFRSF5 gene><TNFSF4><TNFSF4 gene><TNFSF5><TNFSF5 gene><TRAP Gene><TXGP1><Techniques><Testing><Therapeutic><Tissues><Transplant Recipients><Transplantation><Transplantation Tolerance><Treg><Tumor Necrosis Factor Receptor Superfamily Member 5 Gene><White Blood Cells><White Cell><activate T cells><adaptive immune response><adaptive immunity><alloimmunity><antigen-specific T cells><autoimmune condition><autoimmune disorder><autoimmunity disease><biological signal transduction><cardiovascular disorder><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><clinical applicability><clinical application><clinical relevance><clinically relevant><design><designing><developmental><diabetes><digital><drug/agent><fertilizations><heart disorder><host response><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune system tolerance><immune unresponsiveness><immunologic reactivity control><immunological paralysis><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive myeloid cells><immunosuppressive response><improved><industrial partnership><industry partner><industry partnership><innovate><innovation><innovative><insight><interest><isoimmunity><kidney tx><lymphocyte activating factor><malignancy><memory T lymphocyte><migration><monocyte><mortality><myeloid suppressor cells><myeloid-derived suppressive cells><nano particle delivery><nano tech><nano technology><nano-technological><nanoparticle delivered><nanoparticle delivery><nanotech><nanotechnological><neoplasm/cancer><neutrophil><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation><next generation therapeutics><non-human primate><nonhuman primate><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><organ allograft><organ graft><organ xenograft><p50><pathway><prevent><preventing><programs><prospective><receptor><regulatory T-cells><response><scATAC sequencing><scATAC-seq><side effect><single cell ATAC-seq><single cell ATAC-sequencing><single cell Assay for Transposase Accessible Chromatin sequencing><single cell sequencing assay for transposase accessible chromatin><single-cell Assay for Transposase-Accessible Chromatin with sequencing><single-cell assay for transposase-accessible chromatin using sequencing><single-cell assay for transposase-accessible chromatin-seq><social role><stem cell bone marrow transplantation><suppressive myeloid cells><synergism><therapeutic target><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><transplant><transplant patient><well-being><wellbeing><white blood cell><white blood corpuscle>