A5037198997- Pancreatic function and diabetes
- Diabetes and associated disorders
- CAR-T cell therapy research
- Diabetes Management and Research
- RNA Interference and Gene Delivery
- Cannabis and Cannabinoid Research
- Genetics and Neurodevelopmental Disorders
- Virus-based gene therapy research
- Neuroblastoma Research and Treatments
- Organ Transplantation Techniques and Outcomes
- Phagocytosis and Immune Regulation
- Immune Cell Function and Interaction
- Biomedical Ethics and Regulation
- Renal Transplantation Outcomes and Treatments
- Immunotherapy and Immune Responses
- Transplantation: Methods and Outcomes
- 3D Printing in Biomedical Research
- Chromosomal and Genetic Variations
- Acute Myeloid Leukemia Research
- Hematopoietic Stem Cell Transplantation
- Electrospun Nanofibers in Biomedical Applications
- Tissue Engineering and Regenerative Medicine
- Hormonal Regulation and Hypertension
- Lymphoma Diagnosis and Treatment
- Xenotransplantation and immune response
Fred Hutch Cancer Center
2019-2024
University of Mississippi Medical Center
2024
Jackson Memorial Hospital
2024
University of Louisville
2011-2020
University of Louisville Hospital
2018
Cellular Therapeutics (United Kingdom)
2017
Woodward (United States)
2015
Louisville Institute
2012
Abstract Allogeneic islet transplantation is an important therapeutic approach for the treatment of type 1 diabetes. Clinical application this approach, however, severely curtailed by allograft rejection primarily initiated pathogenic effector T cells regardless chronic use immunosuppression. Given role Fas-mediated signaling in regulating cell responses, we tested if pancreatic islets can be engineered ex vivo to display on their surface apoptotic form Fas ligand protein chimeric with...
Allogeneic islet transplantation is limited by adverse effects of chronic immunosuppression used to control rejection. The programmed cell death 1 pathway as an important immune checkpoint has the potential obviate need for immunosuppression. We generated oligomeric form ligand chimeric with core streptavidin (SA-PDL1) that inhibited T effector response alloantigens and converted conventional cells into CD4+Foxp3+ regulatory cells. SA-PDL1 protein was effectively displayed on surface...
We have previously shown that pancreatic islets engineered to transiently display a modified form of FasL protein (SA-FasL) on their surface survive indefinitely in allogeneic recipients without need for chronic immunosuppression. Mechanisms confer long-term protection allograft are yet be elucidated. herein demonstrated immune evolves two distinct phases; induction and maintenance. SA-FasL-engineered survived conferred second set donor-matched, but not third-party, unmanipulated islet...
Background Myelodysplastic syndromes (MDS) arise from somatic mutations acquired in hematopoietic stem and progenitor cells, causing cytopenias predisposing to transformation into secondary acute myeloid leukemia (sAML). Recurrent spliceosome genes, including U2AF1 , are attractive therapeutic targets as they prevalent MDS sAML, early neoplastic generally absent normal cells. sAML susceptible T cell-mediated killing, thus engineered T-cell immunotherapies hold promise for their treatment. We...
Abstract Neuroblastoma (NB) is a highly metastatic tumor of the peripheral sympathetic nervous system and responsible for 10% childhood cancer deaths. MYCN amplification remains one most substantial prognostic factors poor patient outcome detected in 20% all NB patients. Patients are designated as high-risk (HR) when greater than 18 months age with disease or MYCN-amplified. The overall survival rates HR patients remain below 50% even intensive multi-modal treatment. Despite central role...
Abstract Neuroblastoma (NB) is a highly metastatic tumor of the peripheral sympathetic nervous system (PSNS) and responsible for 10% childhood cancer deaths. Patients are designated as high-risk (HR) when MYCN-amplified or disease present at greater than 18-months-of-age. MYCN-amplification remains one strongest prognostic factors poor patient outcome detected in 20% all NB patients. A GWAS study identified SNP within LIM-domain-only 1 (LMO1) that permissive allele neuroblastoma formation...
Introduction and Objective Allogenic islet transplantation is an important therapeutic approach for the treatment of Type 1 Diabetes (T1D). However, graft rejection initiated perpetuated by pathogenic T effector (Teff) cells presents a major barrier. One that has proven successful promoting tolerance shifting cell balance away from induction Teff towards generation protective regulatory (Treg) cells. PD-1/PD-L1 immune checkpoint pathway plays role in Treg with demonstrated clinical efficacy...
Abstract Allogenic islet transplantation is an effective therapy for type 1 diabetes in the clinic. Sustained graft survival requires chronic immunosuppression that has adverse effects. Islet rejection initiated and perpetuated by T effector cells (Teffs). Teffs upregulate Fas death receptor on their surface undergo apoptosis following engagement with FasL. Therefore, FasL potential as immunomodulator to establish immune tolerance grafts eliminate alloreactive Teffs. This study used PEG...
Introduction: We have recently demonstrated that allogeneic islets engineered to display on their surface a novel form of FasL protein chimeric with streptavidin (SA-FasL) induces tolerance in chemically diabetic BALB/c-to-C57BL/6 mouse model. In this study, we tested if protocol is effective spontaneously NOD model where autoimmunity major barrier induction, and the control results recovery endogenous beta cells cure type 1 diabetes. Methods: Pancreatic were harvested from C57BL/6 mice,...
Introduction: We have recently shown that pancreatic islets engineered to display on their surface a chimeric form of FasL (SA-FasL) protein induce robust localized tolerance under the transient cover rapamycin. herein hypothesized nature is determined during induction phase and driven by local presence alloantigens specifically recruit Treg cells into graft. Methods: Two cohorts C57BL/6 mice were transplanted with SA-FasL-engineered BALB/c rapamycin administered daily starting day...
Introduction: We previously demonstrated that donor splenocytes engineered to display on their surface a novel form of FasL molecule chimeric with streptavidin (SA-FasL) induced tolerance in ˜ 60% ACI rats transplanted allogeneic WF heart grafts. The main objective this study is further improve the efficacy protocol by using different routes injections, short course rapamycin as immunosuppressant, and bone marrow cells SA-FasL clinically practical approach. Methods: A heterotopic cardiac...
Abstract The use of chronic immunosuppression is a major hurdle for clinical islet transplantation as curative modality the treatment type 1 diabetes. T effector cells (Teffs) are main culprit allograft rejection, and their pathogenic response kept in check by CD4+CD25+FoxP3+ regulatory (Tregs). PD-1/PD-L1 immune checkpoint pathway plays an important role Teff/Treg balance with demonstrated efficacy cancer immunotherapy. This study was designed to assess immunoregulatory function PD-L1...
Abstract Islets engineered to display on their surface a FasL protein chimeric with streptavidin (SA-FasL) induce robust localized allotolerance under the transient cover of rapamycin. We hypothesized that immunomodulation SA-FasL sets in action regulatory circuit involves apoptosis alloreactive T cells within graft microenvironment, clearance apoptotic bodies by phagocytes, secretion TGF-β, and generation/expansion Tregs. This study was designed test this hypothesis. SA-FasL-engineered...
Abstract Islets engineered to display on their surface an apoptotic form of FasL protein chimeric with streptavidin (SA-FasL) induce tolerance in the BALB/c-to-C57BL/6 allogeneic model. This study assessed efficacy this approach a xenogeneic setting. WF rat islets were modified biotin and SA-FasL protein. SA-FasL-islets survived indefinitely (n=10, >200 days) chemically diabetic C57BL/6 mice under transient cover rapamycin. SA-engineered (n=5) or unmanipulated control (n=6) islet...