A5075072757- Transplantation: Methods and Outcomes
- Xenotransplantation and immune response
- Organ Transplantation Techniques and Outcomes
- T-cell and B-cell Immunology
- Immune Cell Function and Interaction
- Renal Transplantation Outcomes and Treatments
- CAR-T cell therapy research
- Pancreatic function and diabetes
- Organ and Tissue Transplantation Research
- Trypanosoma species research and implications
- Mechanical Circulatory Support Devices
- Virus-based gene therapy research
- Blood transfusion and management
- Complement system in diseases
- Cytomegalovirus and herpesvirus research
- Tissue Engineering and Regenerative Medicine
- Research on Leishmaniasis Studies
- Viral Infections and Immunology Research
- Animal Genetics and Reproduction
- Viral Infectious Diseases and Gene Expression in Insects
- Blood Coagulation and Thrombosis Mechanisms
- Cell Adhesion Molecules Research
- Vector-borne infectious diseases
- Immune Response and Inflammation
- Immunodeficiency and Autoimmune Disorders
University of California, Davis
2017-2025
University of Maryland, Baltimore
2012-2023
VA Maryland Health Care System
2016-2023
University of Fribourg
2023
Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital
2023
The University of Sydney
2023
UCLouvain
2023
Hudson Institute
2023
Abstract We describe the incidence of early graft failure ( EGF , defined as loss function from any cause within 3 days after transplant) in a large cohort Gal TKO pig organs transplanted into baboons three centers, and effect additional expression human complement pathway‐regulatory protein, CD 46 or 55 (Gal . hCPRP ). Baboon recipients life‐supporting kidney (n = 7) heterotopic heart 14) grafts received either no immunosuppression 4), one several partial full immunosuppressive regimens...
Evaluation of lungs from GalTKO.hCD46 pigs, genetically modified to lack the galactose-α(1,3)-galactose epitope (GalTKO) and express human CD46, a complement regulatory protein, has not previously been described. Physiologic, hematologic biochemical parameters during perfusion with heparinized fresh blood were measured for 33 GalTKO.hCD46, GalTKO (n = 16), WT pig 12 perfused autologous blood. Median lung survival was 171 min compared 120 (p 0.27) 10 < 0.001). Complement activation, platelet...
Differentiation into plasma cells (PCs) enables secretion of ∼10,000 immunoglobulin molecules per second. This extraordinary capacity requires the upregulation PC transcriptional determinants that specify fate, increase mRNA synthesis, coordinate alternative 3' end processing heavy chain transcript from distal to proximal polyadenylation site (PAS), and remodel secretory pathway. We developed a dual-fluorescent protein reporter mouse prospectively study post-transcriptional-level transition...
Abstract Background Here, we ask whether platelet GPI b and GPII b/ III a receptors modulate sequestration activation during Gal TKO . hCD 46 pig lung xenograft perfusion. Methods transgenic lungs were perfused with heparinized fresh human blood. Results from perfusions in which α Fab (6B4, 10 mg/l blood, n = 6), (ReoPro, 3.5 or both drugs (n 4) administered to the perfusate compared two additional groups donor received 1‐desamino‐8‐ d ‐arginine vasopressin ( DDAVP ), 3 μ g/kg (to...
Abstract Background Although transplantation of genetically modified porcine livers into baboons has yielded recipient survival for up to 7 days, is limited by profound thrombocytopenia, which becomes manifest almost immediately after revascularization, and subsequent coagulopathy. Porcine von W illebrand's factor ( VWF ), a glycoprotein that adheres activated platelets initiate thrombus formation, been shown constitutively activate human via their Ib GPI b) receptors. Here, we report our...
Specific blockade of T cell costimulation pathway is a promising immunomodulatory approach being developed to replace our current clinical immunosuppression therapies. The goal this study compare results associated with 3 monoclonal antibodies directed against the CD40/CD154 pathway.
Abstract Background Elevated pulmonary vascular resistance ( PVR ), platelet adhesion, coagulation activation, and inflammation are prominent features of xenolung rejection. Here, we evaluate the role thromboxane histamine on , their contribution to other lung xenograft injury mechanisms. Methods Gal TKO . hCD 46 single pig lungs were perfused ex vivo with fresh heparinized human blood: either treated 1‐Benzylimidazole (1‐ BIA ) combined receptor blocker famotidine (n = 4) or diphenhydramine...
Selective CD28 inhibition is actively pursued as an alternative to B7 blockade using cytotoxic T lymphocyte antigen 4 Ig based on the hypothesis that checkpoint immune regulators and programmed death ligand 1 will induce tolerogenic signals. We previously showed blocking a monovalent nonactivating reagent (single-chain anti-CD28 Fv fragment linked alpha-1 antitrypsin [sc28AT]) synergizes with calcineurin inhibitors in nonhuman primate (NHP) kidney heart transplantation. Here, we explored...
Abstract Thrombomodulin is important for the production of activated protein C (APC), a molecule with significant regulatory roles in coagulation and inflammation. To address known molecular incompatibilities between pig thrombomodulin human thrombin that affect conversion into APC, GalTKO.hCD46 pigs have been genetically modified to express (hTBM). The aim this study was evaluate impact transgenic hTBM expression on dysregulation observed association lung xenograft injury an established...
Background: Compared to CTLA-4Ig reagents, selective CD28 blockade using antagonist anti-CD28 Abs might favour B7-mediated coinhibitory signals through the receptors of CTLA-4 and/or PDL-1 and facilitate induction peripheral allograft tolerance. Here we evaluated efficacy a humanized pegylated Fab Ab fragment, FR104, in cynomolgus monkey heart transplants. Methods: Heterotopic cardiac recipients were untreated or received αCD28 (FR104), αCD154 (hu5C8), combination. Graft function was...
Molecular-level understanding of plasma cell (PC) differentiation has been modeled using lipopolysaccharide (LPS) stimulation in vitro. However, this system does not involve the B-cell receptor (BCR)-a critical component B biology. Here, we present a protocol for vitro PC dependent on BCR signaling that easily scales up number-demanding applications, including protein complex purification. We describe how to set and detail applications endogenous purification chromatin-associated proteins....
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...
Abstract Selective CD28 blockade, which preserves CTLA-4-dependent immune regulation, is a promising approach to induce tolerance. FR104, novel antagonist, was evaluated in monkey heart transplant recipients that received αCD28 alone (n=3, FR104) or combination with αCD154 (n=5, hu5C8), dosed achieve receptor coverage for 84 days; results were compared (n=4). Acute (AR) and chronic (CAV) rejection scores quantified histologically. Median graft survival time (MST) FR104 (167d), hu5C8 (133d),...
Abstract The germinal center (GC) reaction is a coordinated and dynamic ensemble of cells processes that mediate the maturation selection high-affinity GC B (GCBs) from lower-affinity precursors ultimately results in plasma cell memory fates exit GC. It great interest to identify intrinsic extrinsic factors control process. transcription factor IRF4, induced upon BCR CD40 signaling, essential for acquisition GCB fates. We hypothesized beyond this early requirement, IRF4 continuously operates...
Purpose: Xenogenic lung perfusion studies revealed that inflammation and activation of platelets coagulation cascade are important factors xenogenic rejection mechanisms, contributing to increased pulmonary vascular resistance (PVR) organ injury. Here we evaluate effects combined thromboxane synthase inhibitor histamine blocker administration on pig function phenomena associated with “hyperacute rejection” (HALR). Methods: 6 GalTKO.hCD46.hCD55 lungs were perfused for 4h fresh heparinized...