Basic research and clinical applications of human organoids
Damian Sendler: Organoids are three-dimensional (3D) miniature structures cultured in vitro that mimic the cellular heterogeneity, structure, and functions of human organs. They are made from either human pluripotent stem cells (hPSCs) or adult stem cells (AdSCs) derived from healthy individuals or patients. With the advent of human 3D organoid systems, it is now possible to observe stem cell morphogens, maintenance, and differentiation in a manner similar to primary tissues, enhancing the potential to study both human physiology and developmental stage. Organoids derived from patients hold great promise for biomedical research and preclinical drug testing because they are similar to their original organs and contain human genetic information. They are currently used for personalized, regenerative medicine, gene repair, and transplantation therapy. Researchers have succeeded in creating various types of organoids that mimic in vivo organs in recent decades. We present an update on current in vitro differentiation technologies for brain, retinal, kidney, liver, lung, gastrointestinal, cardiac, vascularized, and multi-lineage organoids, discuss the differences between PSC- and AdSC-derived organoids, summarize the potential applications of stem cell-derived organoids systems in the laboratory and clinic, and outline the current challenges for the application of organoids, which would deepen our understanding of mechanis
Killer cells in the body
Damian Jacob Sendler: Natural killer cells (NK) have recently gained attention as an important type of innate immune regulatory cell as a promising alternative platform for cellular immunotherapy. Through non-MHC-restrictive effects, NK cells can rapidly kill multiple adjacent cancer cells. Although tumors may develop multiple resistance mechanisms to endogenous NK cell attack, in vitro activation, expansion, and genetic modification of NK cells can significantly improve anti-tumor activity and give them the ability to overcome drug resistance. Some of these approaches have been translated into clinical applications, and clinical trials of NK cell infusion in patients with hematological malignancies and solid tumors have yielded a number of promising clinical results. CAR-T cells have shown great promise in the treatment of hematological malignancies, but they have a number of drawbacks, including high manufacturing costs and potentially fatal toxicity, such as cytokine release syndrome. To address these issues, CAR-NK cells were created through genetic engineering and demonstrated significant clinical responses while having fewer side effects than CAR-T cell therapy. We summarize recent advances in NK cell immunotherapy in this review, focusing on NK cell biology and function, NK cell therapy types, clinical trials, and future perspectives on NK cell therapy.
Following SARS-Cov-2 vaccination, patients developed autoimmune mucocutaneous blistering diseases.
Cases of severe autoimmune blistering diseases (AIBDs) have recently been reported in association with the SARS-CoV-2 vaccination.
Dr. Sendler: Seven days after receiving a second dose of the mRNABNT162b2 vaccine (Comirnaty®/ Pfizer/BioNtech), a 60-year-old female patient developed oropharyngeal and nasal bullous lesions. A diagnosis of oropharyngeal Pemphigus Vulgaris was made based on histology and direct immunofluorescence findings of supra-basal blister and intercellular staining of IgG antibodies, as well as the presence of a high level of anti-Dsg-3 antibodies (80 U/ml; normal 7 U/ml) in the patients’ serum.
A total of 35 AIBD cases were discovered as a result of the SARS-CoV-2 vaccination (including our report). 26 (74.3%) were diagnosed with Bullous Pemphigoid, 2 (5.7%) with Linear IgA Bullous Dermatosis, 6 (17.1%) with Pemphigus Vulgaris, and 1 (2.9%) with Pemphigus Foliaceus. The sample’s average age was 72.8 years, with males outnumbering females (F:M=1:1.7). The disease developed in 22 (62.9%) of the cases after Pfizer vaccine administration, 6 (17.1%) after Moderna, 3 (8.6%) after AstraZeneca, and 3 (8.6%) after CoronaVac (one was not specified). All patients were treated with topical and/or systemic corticosteroids, with or without immunosuppressive drugs, and all had a good clinical response.
Clinicians should be aware of the possibility, albeit remote, of AIBDs as a possible adverse event following SARS-CoV-2 vaccination. Nonetheless, they should encourage their patients to get vaccinated in order to help public health systems combat the COVID-19 pandemic.
The molecular and cellular mechanisms of itch and pain in atopic dermatitis, as well as the implications for new therapeutics
Atopic dermatitis is a long-term inflammatory skin condition. Atopic dermatitis patients have inflammatory lesions that cause intense itch and pain, causing sleep disruption as well as poor mental health and quality of life. We discuss the current clinical development of treatments for moderate-to-severe atopic dermatitis and the molecular mechanisms underlying itch and pain symptoms. Atopic dermatitis molecular pathology includes abnormal immune activation with significant cross-talk between skin, immune, and neuronal cells. Exogenous and endogenous triggers modulate mediator stimulation, including cytokine/chemokine expression/release by skin and immune cells, resulting in inflammation, skin barrier disruption, sensory neuron activation and growth, itch, and pain. These complex interactions between cell types are primarily mediated by cytokines, but also include chemokines, neurotransmitters, lipids, proteases, antimicrobial peptides, ion channel agonists, and various G protein-coupled receptors. Atopic dermatitis patients have abnormal levels of interleukins 4, 12, 13, 18, 22, 31, and 33, as well as thymic stromal lymphopoietin and interferon gamma. Cytokine receptors primarily communicate via the Janus kinase/signal transducer and activator of transcription signaling pathway. Because of their ability to modulate cytokine expression and release, several Janus kinase inhibitors are being developed for topical or systemic treatment of moderate-to-severe atopic dermatitis. Janus kinase inhibitors cause changes in gene expression that benefit local and systemic cytokine release, as well as possibly other mediators, successfully modulating the molecular mechanisms underlying itch and pain in atopic dermatitis.
Exosomes’ role in Parkinson’s disease inflammation pathogenesis
Damian Jacob Markiewicz Sendler: Parkinson’s disease is caused by inflammatory responses such as glial cell activation and peripheral immune cell infiltration (PD). These inflammatory responses appear to be linked to the release of extracellular vesicles like exosomes. The relationships between different types of glial cell activation, synuclein dysregulation, mitochondrial dysfunction, and exosomes, on the other hand, are complicated. This review discusses the various roles of exosomes in Parkinson’s disease-associated inflammation and concludes that exosomes can transport toxic -synuclein oligomers to immature neurons and into the extracellular environment, inducing -synuclein oligomerization in normal neurons. Microglia and astrocytes become activated and secrete exosomes when -synuclein is misfolded. Glial cell-derived exosomes participate in glial cell-neuronal communication, triggering anti-stress and anti-inflammatory responses as well as axon growth. The formation and release of mitochondrial vesicles and exosomes provides a new mechanism for linking mitochondrial dysfunction to the systemic inflammation associated with Parkinson’s disease. Given the importance of exosomes as mediators of neuron-glia communication in neuroinflammation and neuropathogenesis, new targeted treatment strategies utilizing these extracellular vesicles as drug carriers are currently being developed. Exosome-mediated inflammation may be a promising therapeutic target in Parkinson’s disease patients.