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Rabies and other lyssaviruses
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Thiravat Hemachudha, Jiraporn Laothamatas, Henry Wilde
After budding from plasma membranes of the muscle cells, the whole virion rather than the viral capsid is taken up into unmyelinated nerve endings at the neuromuscular (NM) junction [47]. Co-localization of virus and endosome tracers within the nerve terminals, along with progressive accumulation of virus and tracers in axons and nerve cells, indicated retrograde transport of endocytosed virus from motor nerve terminals [48]. Rabies virus may also use carbohydrates, phospholipid, gangliosides, NCAM or CD 56, and low-affinity nerve growth factor receptor-P75 neurotrophin receptor (P75NTR) to gain entry into the cells [47].
Histology and Pathology of the Human Neuromuscular Junction with a Description of the Clinical Features of the Myasthenic Syndromes
Published in Marc H. De Baets, Hans J.G.H. Oosterhuis, Myasthenia Gravis, 2019
F.G.I. Jennekens, H. Veldman, John Wokke
The cryostat material is used for a limited program of histological stainings including a silver-cholinesterase method for visualization of both intramuscular nerves and endplates. The latter can also be achieved in PLP-fixed material by a double staining technique with immunohistochemical methods for neurofilaments and the synaptic vesicle protein synaptophysin. Schwann cells can be stained with an immunohistochemical method for S-100 (Table 2), and dedifferentiated (“denervated”) Schwann cells at motor endplates can be identified by combining a technique for low affinity nerve growth factor receptor or B50, with a Cholinesterase stain73,74 (Figure 11). AChRs can be nicely visualized in PLP fixed material, both at the light microscopic and electronmicroscopic levels using the rat monoclonal antibody number 35, directed against the main immunogenic region of the alpha subunit of AChR.111
Nuclear Imaging of Adoptive Cell Therapies
Published in Martin G. Pomper, Juri G. Gelovani, Benjamin Tsui, Kathleen Gabrielson, Richard Wahl, S. Sam Gambhir, Jeff Bulte, Raymond Gibson, William C. Eckelman, Molecular Imaging in Oncology, 2008
Stable genetic labeling of adoptively transferred cells with various reporter genes has been used to circumvent the temporal limitations of ex vivo radiolabeling or magnetic labeling. The effectiveness of cell-mediated gene therapy largely depends on efficient gene delivery to targeted cell populations and targeted transgene expression in an appropriate progeny of transduced cells. Retroviral-mediated transduction has proven to be one of the most effective means to deliver transgenes into mouse and human cells and results in high levels of sustained transgene expression (26,27). For example, long-term circulation of the EBV-specific cytotoxic donor-derived T cells has been shown to occur in patients treated for post–bone marrow transplantation (BMT) EBV-induced lymphoproliferative diseases. Retrovirally transduced with the neomycin resistance or low-affinity nerve growth factor receptor (LNGFR) and HSV1-tk genes, these T cells were detectable for prolonged periods of observation (years) in peripheral blood samples from patients by polymerase chain reaction (PCR) or fluorescence-activated cell sorting (FACS) analysis (28–30).
Prospect of CAR T-cell therapy in acute myeloid leukemia
Published in Expert Opinion on Investigational Drugs, 2022
Talha Badar, Alak Manna, Martha E. Gadd, Mohamed A. Kharfan-Dabaja, Hong Qin
A ‘safety switch’ or ‘suicide gene’ could be incorporated into the CAR T-cell design to limit off-target toxicity. An example of such a safety switch is the truncated, signal-deficient, epidermal growth factor receptor (tEGFR), which allows ablation of CAR T cells with EGFR targeting monoclonal antibody cetuximab [54]. This strategy is being explored in several CD19 CAR T-cell trials in B-cell ALL (NCT02146924, NCT02146924, NCT03579888). Another safety switch investigated in clinical trial to minimize CAR T-cell-associated neurotoxicity is by targeting inducible caspase-9 (iC9) by rimiducid (tacrolimus analogue) [55,56]. A patient with RR B-cell ALL received CD19 CAR T cells on a clinical trial (NCT03016377) with a truncated low-affinity nerve growth factor receptor (NGFR) and iC9 [55]. This patient had persistent grade 3–4 neurotoxicity post CAR T cells for 72 hours despite standard-of-care therapy and then rimiducid 0.4 mg/kg was given per protocol. Neurotoxicity was fully resolved 4 days after rimiducid administration. While this technology hold promises in improving outcome of patients with steroid refractory neurotoxicity post CAR T-cell therapy, more data is warranted to see its effectiveness in a larger group of patients.
Novel adapter CAR-T cell technology for precisely controllable multiplex cancer targeting
Published in OncoImmunology, 2021
Christian M. Seitz, Joerg Mittelstaet, Daniel Atar, Jana Hau, Selina Reiter, Clara Illi, Verena Kieble, Fabian Engert, Britta Drees, Giulia Bender, Ann-Christin Krahl, Philipp Knopf, Sarah Schroeder, Nikolas Paulsen, Alexander Rokhvarguer, Sophia Scheuermann, Elena Rapp, Anna-Sophia Mast, Armin Rabsteyn, Sabine Schleicher, Stefan Grote, Karin Schilbach, Manfred Kneilling, Bernd Pichler, Dominik Lock, Bettina Kotter, Sandra Dapa, Stefan Miltenyi, Andrew Kaiser, Peter Lang, Rupert Handgretinger, Patrick Schlegel
AdCAR-T comprises a two-component signal transduction system based on a split recognition/activation design in which labeled AMs are applied to transmit antigen recognition into T-cell activation via an anti-label CAR. AdCAR-T mediated T-cell activation and target-cell lysis is the result of a two-step process (Figure 1a), i) antigen-specific binding of the AM on the target cell and ii) binding of the AdCAR-expressing T cell to the AM. We used mAbs and mAb fragments as AMs to utilize their specific surface antigen-binding capacity. AMs are generated by biotinylation using a specific linker chemistry, resulting in a molecule comprising an antigen-binding moiety, a linker moiety and a label moiety (biotin) (Figure 1a). The AdCAR is based on unique characteristics of the mAb mBio3. mBio3 binds to biotin in the context of a specific linker, referred to as a Linker-Label Epitope (LLE). We designed AdCAR-T by conjugating the murine clone mBio3-derived scFvs on seond- and third-generation CAR backbones consisting of different extracellular spacer domains, as indicated, CD8 transmembrane, 4–1BB or CD28 and 4–1BB costimulatory as well as CD3-ζ signaling domain. Truncated human low-affinity nerve growth factor receptor (ΔLNGFR) was integrated downstream of a F2A site for detection and enrichment. In vitro testing was performed using the AdCAR-4–1BB-CD3-zeta, IgG4 hinge only, construct if not annotated otherwise. For initial evaluation, we LLE-conjugated the Fc-optimized CD19–4 G7SDIE mAb (LLE-CD19 mAb) and the FDA/EMA-approved GD2 mAb ch14.18/dinutuximab beta (LLE-GD2 mAb), both in clinical use at our institution.24,25
In vitro affinity optimization of an anti-BDNF monoclonal antibody translates to improved potency in targeting chronic pain states in vivo
Published in mAbs, 2020
Edwina Stack, Sheridan McMurray, Gordon McMurray, Jason Wade, Melissa Clark, Gareth Young, Kim Marquette, Sadhana Jain, Kerry Kelleher, Ting Chen, Qingcong Lin, Laird Bloom, Laura Lin, William Finlay, Rie Suzuki, Orla Cunningham
Neurotrophins represent a family of structurally-related proteins that have diverse biological functions. During development, neurotrophins critically regulate processes underlying cell survival and neuronal differentiation. In the adult nervous system, neurotrophin signaling is required for maintenance of synaptic function and plasticity.1-3 Damage to peripheral nerves triggers changes in the expression of ion channels, neuropeptides, growth factors, cytokines and chemokines that ultimately culminates in enhanced excitability of the peripheral and central nervous system.4 Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family that is upregulated following peripheral nerve injury.5-10 Following synthesis in small- to medium-sized dorsal root ganglion (DRG) neurones,9 BDNF is anterogradely transported to the dorsal horn where it is released upon noxious stimulation in an activity-dependent manner.11 The physiological actions of BDNF are mediated via interaction with two receptors, the high affinity tyrosine receptor kinase B (TrkB) and p75NTR, also known as low-affinity nerve growth factor receptor (LNGFR). BDNF engagement of TrkB results in receptor dimerization, leading to autophosphorylation of tyrosine residues in the cytoplasmic domain. This results in the presentation of docking sites for adapter proteins containing phosphotyrosine-binding (PTB) or src-homology-2 (SH2) motifs that couple the receptor to multiple intracellular signaling cascades, including Ras/ERK (extracellular signal–regulated kinase), PI3 K (phosphatidylinositol-3-kinase) and PLC-γ (phospholipase C γ).1,2 p75NTR, on the other hand, is a member of the tumor necrosis receptor superfamily that binds all members of the neurotrophin family with similar affinities. Activation of p75NTR may potentiate Trk signaling and furthermore promote the discrimination of Trk receptors for their preferred neurotrophin ligands.12,13