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Immunology (primary Immunodeficiency Syndromes
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephan Strobel, Alison M. Jones
Omenn syndrome is a variant of SCID associated with the presence of oligoclonal autoreactive T-cells, associated with a generalised erythrodermic dermatitis (Figs 16.7, 16.8) and other inflammatory changes. Expanded oligoclonal populations of activated and antigen-stimulated T-cells generate inflammatory changes, eosinophilia and elevated IgE levels. Mutations that causes a partial loss of function (hypomorphic mutations) in the recombinase-activating genes (RAG-1 and RAG-2) are the most frequent underlying genetic defects in infants with Omenn syndrome. However, mutations in a number of other SCID-causing genes have also been associated with Omenn syndrome, including adenosine deaminase, common gamma chain, IL-7 receptor alpha, Artemis and DNA ligase 4 genes.
Wiskott–Aldrich Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Differential diagnoses for WAS include idiopathic thrombocytopenic purpura (ITP; males presenting early in life with transient and self-limited thrombocytopenia; increased platelet size, and increased reticulated platelet count), Wiskott−Aldrich syndrome 2 (WAS2; recurrent infections, eczema, and thrombocytopenia; show low numbers of B and T cells, defective T cell proliferation and chemotaxis, low NK cell function, and abnormal WASP; normal platelet volumes; rare autosomal recessive immunodeficiency due to biallelic pathogenic variants in WIPF1 on chromosome 2q31.1), X-linked severe combined immunodeficiency (X-SCID, persistent infections, lymphocytopenia, growth failure, and thymic hypoplasia; near-complete absence of T and natural killer lymphocytes; nonfunctional B lymphocytes; due to hemizygous pathogenic variant in the common gamma chain gene IL2RG), X-linked hyper IgM syndrome (recurrent otitis media, sinusitis, pneumonias; autoimmune hematologic disorders such as neutropenia, thrombocytopenia, and hemolytic anemia; lymphomas and other malignancies; serious gastrointestinal complications, and neurologic deterioration; elevated IgM in the absence of other immunoglobulins; due to pathogenic variants in CD40LG), autosomal recessive severe combined immunodeficiencies (T- and B-cell dysfunction, recurrent infections, but rarely persistent thrombocytopenia), GATA1-related X-linked cytopenia (thrombocytopenia [easy bruising and mucosal bleeding, such as epistaxis], anemia [mild dyserythropoiesis, hydrops fetalis requiring in utero transfusion]; platelet dysfunction, mild β-thalassemia, neutropenia, and congenital erythropoietic porphyria [CEP] in males), and human immunodeficiency virus (HIV; gradual destruction of the immune system; risk for opportunistic infections and neoplasms) [1,15].
Gene Transfer into Human Hematopoietic Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Serguei Kisselev, Tatiana Seregina, Richard K. Burt, Charles J. Link
Questions concerning the safety of integration of transgene into a host genome remain to be answered. The complete potential integration sites for retroviral cDNAs are unknown and thought to be mostly random. This random integration creates a number of concerns about insertional mutagenesis and integration of the transgene into either oncogenes or sequences coding the inhibitors of genes such as cyclin kinases (tumor suppressor genes) causing their disruption. These warnings are very real and serious in the context of recent reports concerning cases of acute T cell leukemia lymphoma (ATLL) that developed in two SCID children infused with common gamma chain gene transduced into autologous CD34+ cells.126 In both cases, insertion of the transgene occurred in the first intron of rhombotin 2 (LIM-only protein 2 (LMO2)) transcription factor gene. Previous studies of LMO2 physiology and function have revealed that ATLL development is closely associated with LMO2 translocations and over expression.127,12 The disruption of regulatory sequences of the gene by transgene insertion followed by its uncontrolled activation is the probable reason for leukemia development in these children. Preclinical data had previously demonstrated such risks. Acute myeloid leukemia development in mice transplanted with autologous bone marrow transduced by a mutant non functional nerve growth factor receptor (NGFR) gene used as a cell surface marker.129 Since risks do exist after stem cell transduction with integrating retroviral vectors, the development and application of vectors containing both a gene of interest and inducible suicide genes such as herpes simplex virus thymidine kinase (HSV-tk) as a safety feature are in development. The idea would be to eliminate transduced cells by activation of the suicide gene if leukemia developed. Other procedures to confirm insertion site prior to product release being discussed for human trials.
New nonchemotherapy treatment options for cutaneous T-cell lymphomas
Published in Expert Review of Anticancer Therapy, 2021
E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A and B and the receptor-binding domain of IL-2. IL-2 is involved in the differentiation of effector T-cell subsets and the survival of T-regs[85]. Components of IL-2 include the common gamma chain (CD132), the beta chain (CD122), and the alpha chain (CD25)[85]. The fusion protein shares the same amino acid sequence with denileukin diftitox (DD), which was previously approved by the FDA for use in persistent/recurrent CD25+ CTCL but discontinued due to production issues[7,86]. Both E7777 and DD enter cells by binding to IL-2 receptors and undergoing receptor-mediated endocytosis[87]. The diphtheria toxin domain is then cleaved and translocated to the cytoplasm, where it inhibits protein synthesis and causes cell death. In addition to targeting CD25+ malignant cells, DD is also theorized to eliminate CD25+ T-regs and enhance the antitumor immune response[87,88]. In a phase III trial of DD in patients with stage IA to III CTCL positive for CD25 by immunohistochemistry of skin biopsies, DD achieved a higher ORR compared to placebo (44% vs 15.9%)[89]. Two doses of DD were tested (18 μg/kg/d and 9 μg/kg/d) and the larger dose had a higher ORR (49.1% vs 37.8%).
A review of upadacitinib in rheumatoid arthritis
Published in Modern Rheumatology, 2020
There are 4 members of the JAK family—JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)—and different combinations of JAKs are associated with different receptor chains, resulting in distinct biologic roles [16,20]. For example, JAK1 and JAK3 are involved in the signaling of common gamma chain cytokines such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, which play a key role in adaptive immunity [17,20]. JAK1 also regulates several key proinflammatory cytokines, including IL-6 and interferon gamma (IFNγ), by pairing with either JAK2 or TYK2 [16,21]. In contrast, hormone-like cytokines such as erythropoietin, thrombopoietin, and granulocyte-macrophage colony-stimulating factor signal through JAK2 homodimers, meaning JAK2 plays a key role in the development of red blood cells, platelets, and myeloid cells [13,16,21]. Inhibition of JAKs therefore affects multiple cytokines involved in the pathogenesis of RA, but may also lead to effects on other biologic processes unrelated to RA.
Diverse HIV-1 escape pathways from broadly neutralizing antibody PGDM1400 in humanized mice
Published in mAbs, 2020
Yme U. van der Velden, Julien Villaudy, Esther Siteur - van Rijnstra, Cynthia A. van der Linden, Monique A. Vink, Edith E. Schermer, Kees Weijer, Ben Berkhout, Rogier W. Sanders, Marit J. van Gils
HIS mice were generated using non-obese diabetic (NOD), severe combined immunodeficiency (SCID), interleukin receptor common gamma chain knockout (IL2rγnull), termed NSG mice (The Jackson Laboratory). NSG newborns before 5 days were sublethally irradiated with 1 Gy using a Cs137 source and intrahepatically injected within 24 h with 5 × 104 CD4+CD38− fetal hematopoietic stem cells (hHSC). The humanization levels of the immune system in the peripheral blood were verified at week 12 and only mice with >20% human CD45+ cells, termed HIS-NSG mice, entered the experiments. At 13 weeks the HIS-NSG mice were infected with 10–100 ng CA-p24 of virus of the four different replication competent HIV virus isolates (3 mice per group) by intraperitoneal injection. Blood was collected every other week before PDGM1400 treatment and weekly during treatment. Humanization and CD4 + T cell dynamics were monitored by flow cytometry (LSR Fortessa, BD Biosciences) as described previously.3 Viral RNA was extracted from plasma by QIAamp Viral RNA Mini Kit (Qiagen) and viral load was determined by quantitative RT-PCR as described previously.3 Statistical analysis on the viral loads was performed using a Wilcoxon test (paired non-parametric t-test). From 12 weeks after infection onwards, PGDM1400 was administered in 50 µl PBS at a dose of 20 mg/kg via retro-orbital injection on a weekly basis for 4 weeks.