A5086633379- Xenotransplantation and immune response
- Transplantation: Methods and Outcomes
- Tissue Engineering and Regenerative Medicine
- Renal Transplantation Outcomes and Treatments
- Virus-based gene therapy research
- Organ and Tissue Transplantation Research
- Organ Transplantation Techniques and Outcomes
- Animal Genetics and Reproduction
- Anesthesia and Neurotoxicity Research
- Viral Infections and Immunology Research
- CRISPR and Genetic Engineering
- T-cell and B-cell Immunology
- Complement system in diseases
- Immune Response and Inflammation
- Cardiac Ischemia and Reperfusion
- Neuroinflammation and Neurodegeneration Mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Cell Adhesion Molecules Research
Massachusetts General Hospital
2022-2025
Harvard University
2023-2025
Athinoula A. Martinos Center for Biomedical Imaging
2023
Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to supplement or replace current clinical immunosuppression in solid organ transplantation. We evaluated tolerability and activity novel humanized anti-CD154 monoclonal antibody, TNX-1500 (TNX), nonhuman primate heterotopic cardiac allogeneic (allo) transplant model. contains rupluzimab fragment antigen-binding region an immunoglobin G4 crystallizable engineered reduce binding gamma receptor IIa associated risks...
Long-term renal allograft acceptance has been achieved in macaques using a transient mixed hematopoetic chimerism protocol, but similar regimens have proven unsuccessful heart recipients unless kidney transplant was performed simultaneously. Here, we test whether modified protocol based on targeting CD154, CD2, and CD28 is sufficient to prolong or promote the expansion of regulatory T cells. Eight underwent heterotopic allo-heart transplantation from major histocompatibility...
Abstract Introduction Expression of human complement pathway regulatory proteins (hCPRP's) such as CD46 or CD55 has been associated with improved survival pig organ xenografts in multiple different models. Here we evaluate the hypothesis that an increased gene dose, through homozygosity additional expression a second hCPRP, is protein and protection from injury when GTKO lung are perfused blood. Methods Twenty three lungs heterozygous for (GTKO.heteroCD46), 10 homozygous hCD46...
Introduction: Previous studies showed that ischemia minimization (IM), accomplished by perfusing the heart xenograft during storage, prevents ‘initial cardiac dysfunction’ (ICXD) and enables prolonged survival following orthotopic xenotransplantation. Here we report initial observations in a model designed to evaluate effects on performance associated with IM genetic modifications targeted address xeno-injury mechanisms working ex vivo of ICXD. Method: Hearts from genetically modified...
Introduction: Significant advances have been made recently in xenotransplantation using gene-edited (GE) pigs with up to 3 carbohydrate gene knockouts various combinations, alone or additional human complement (CD46, CD55, CD59), coagulation (TBM, EPCR, TFPI), and anti-inflammatory (CD47, CD39, HLAE/β2M, A20, PD-1, HO-1) ‘transgenes’. In this pilot study we evaluated hearts from 3-GE multi-GE treated an established costimulation-based immunosuppressive (IS) regimen cold-perfused ‘ischemia...
Background: Xenotransplantation has made significant advances recently using pigs genetically engineered to remove carbohydrate antigens, alone or with addition of various human complement, coagulation, and anti-inflammatory ‘transgenes’. Here we evaluated results associated 3-, 9-, 10-GE pig hearts treated an established costimulation-based immunosuppressive regimen a cold-perfused storage technique designed minimize graft ischemia, as used for the recent clinical heart xenograft case....
Introduction Previous studies showed that ischemia minimization (IM: perfusing the heart during storage), prevents ‘initial cardiac xenograft dysfunction’ (ICXD). Here we report initial observations in a working ex vivo model of ICXD designed to evaluate effects associated with IM and genetic modifications targeted address xeno-injury on pig performance perfusion human blood. Method Hearts from genetically modified pigs were flushed cold preservation solution (4oC) then stored for 3 hours...
Background: The first clinical genetically-engineered pig heart transplant has stimulated consideration of which patients might be medically and ethically appropriate to enroll in the initial trials. Beyond exceptional ‘compassionate use’ applications, as University Maryland case, selected for formal ‘qualifying’ trials ‘destination’ or ‘bridging’ xenotransplantation? Approach Results: Patients eligible a allograft whom mechanical circulatory support is contraindicated associated with high...
Purpose: Expression of human complement pathway regulatory proteins (hCPRP’s) such as CD46 or CD55 has been associated with improved survival pig organ xenografts in multiple different models. Here we compare the results ex vivo perfusion blood lungs from GTKO swine heterozygous for hCD46 (with on one haplotype: GTKO.het-hCD46), homozygous (GTKO.hom-hCD46), and hCD55 (GTKO.hom-hCD46.het-hCD55), to explore hypothesis that an increased ‘hCPRP gene dose’ is protection xenograft against...
Purpose: Blockade of the CD40/CD154 T cell costimulation pathway is a promising approach to replace conventional clinical immunosuppressive therapy. TNX-1500 (TNX)* novel humanized anti-CD154 mAb that contains hu5c8 Fab region and an Fc engineered modulate FcγR2 binding reduce risk thromboembolic events seen with IgG1 in previous trials. Its efficacy was evaluated cynomolgus monkey heterotopic heart allograft recipients. Methods: Cynomolgus cardiac recipients were treated TNX 30mg/kg iv 2x...