The Host Response to Grafts and Transplantation Immunology
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
These promoter region polymorphisms, because they polarize responses toward cell-mediated or antibody-mediated responses, may influence allograft rejection. Thus, an individual who has a genetically encoded tendency to make higher levels of interleukin-10 and lower levels of interferon-y has a tendency to polarize toward antibody mediated responses. Studies have shown that transplant receipts with the genetic profile for high interferon-γ/low interleukin-10 production have significantly more frequent and more severe acute rejection episodes. In contrast, individuals with the genetic profile for low interferon-γ/high interleukin-10 production have significantly longer graft survival with fewer acute rejection episodes. Some transplant surgeons are now beginning to use cytokine promoter region allele typing to tailor immunosuppressive drug therapy for a specific recipient. Cytokine promoter region alleles also may influence chronic rejection. Individuals who have a high TGF-β production phenotype have more severe chronic rejection in a recent study. As mentioned earlier, TGF-β is a potent smooth muscle mitogen and probably accounts for some of the smooth muscle cell proliferation in the intima of vessels in the graft that occurs during chronic rejection. TGF-β is also involved in the fibrosis seen in the lesions.
Diseases of the Aorta
Mary N. Sheppard in Practical Cardiovascular Pathology, 2022
Although MFS and EDS are by far the most commonly recognized connective tissue disorders (CTD) associated with TAA/TAD, recent understanding in the molecular biology of dissection has allowed recognition of a new disorder described by Bart Loeys and Harry Dietz in 2005. This autosomal dominant disease is caused by mutation in the transforming growth factor beta (TGFβ) receptor 1 or 2 gene. The underlying genetic abnormality of LDS leads to altered signalling in the TGF-β cytokine family. TGF-β plays an important role in extracellular matrix formation and turnover, as well as cell proliferation and differentiation, along with apoptosis. This influence on proliferation and differentiation is particularly apparent in cardiovascular embryogenesis, including ventricular myocardial genesis. TGF-β signal alterations lead to disarrayed elastin fibres, with loss of elastin content, and dilation and dissection as a consequence. LDS prevalence is currently not well established. LDS does appear to be intimately related to MFS, and this becomes clear when it is understood that the genetic anomaly in LDS is a loss-of-function mutation in the TGFβr2 receptor – hence this mimics some of the effects of alteration in the levels of available TGFβ seen in fibrillin 1 deficiency syndromes such as MFS.
Tumors of the Nervous System
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
Growth factor and growth factor receptor overexpression are common in malignant gliomas and may accelerate tumorigenesis and tumor progression. Most of these are found predominantly in diffuse, high-grade, astrocytic tumors and include the following: EGFR.Platelet-derived growth factor (PDGF).Vascular endothelial growth factor (VEGF).Insulin-like growth factor (IGF-1).Basic fibroblast growth factor (bFGF, FGF-2).Transforming growth factor (TGF)-alpha.
Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: in-vitro anticancer evaluation and in-silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mohammed S. Taghour, Hazem Elkady, Wagdy M. Eldehna, Nehal M. El-Deeb, Ahmed M. Kenawy, Eslam B. Elkaeed, Aisha A. Alsfouk, Mohamed S. Alesawy, Ahmed M. Metwaly, Ibrahim. H. Eissa
Overexpression of the Bcl2 gene can inhibit the apoptotic cell death and partially the nonapoptotic cell death, which has a role in arrest of cell cycle. Meanwhile, overexpression of Bcl-xL enhances autophagic cell death60. Moreover, Survivin is a pro-survival protein that is overexpressed in many cancer cells in the G2-M phase. This protein has been linked to tumour progression control and resistance to cancer chemotherapeutics. Furthermore, the transforming growth factor (TGF) is one of various proteins that secreted by transformed cells and stimulate the growth of non-cancerous cells in addition to its role as initiators of the signalling pathway that suppresses the early development of cancer cells61. Dysregulation of TGF-β activation and signalling may result in apoptosis.
Oral delivery of the intracellular domain of the insulinoma-associated protein 2 (IA-2ic) by bacterium-like particles (BLPs) prevents type 1 diabetes mellitus in NOD mice
Published in Drug Delivery, 2022
Ruifeng Mao, Menglan Yang, Rui Yang, Yingying Chen, Enjie Diao, Tong Zhang, Dengchao Li, Xin Chang, Zhenjing Chi, Yefu Wang
Furthermore, analysis of cytokine secretion by splenocytes stimulated with IA-2 was performed. As shown in Figure 8(B–E), compared to the BLPs group and IA-2ic-3LysM group, splenocytes from the BLPs-IA-2ic group produced significant lower levels of IL-2, IFN-γ (Th1-associated cytokines), and significant higher levels of IL-4, IL-10 (Th2-associated cytokines) (all p < .05). TGF-β promotes the differentiation of Tregs and this is a critical step in inducing immunological tolerance to treat autoimmune diseases (Bilate & Lafaille, 2012). A significant higher level of TGF-β was detected in splenocytes from the BLPs-IA-2ic group compared with those from the BLPs group and IA-2ic-3LysM group (Figure 8(F), p<.01). Therefore, it indicates that the induced IA-2-specific tolerance by oral administration of BLPs-IA-2ic was associated with downregulation of Th1-associated cytokines and upregulation of Th2-associated cytokines.
Effects of prolonged treatment of TGF-βR inhibitor SB431542 on radiation-induced signaling in breast cancer cells
Published in International Journal of Radiation Biology, 2022
Poonam Yadav, Priya Kundu, Vipul K. Pandey, Prayag J. Amin, Jisha Nair, Bhavani S. Shankar
Apart from SB431542, direct inhibition of TGF-βRI using small molecule inhibitors or neutralizing antibodies also augments radiation responses. TGF-β receptor (TGF-βR) I kinase inhibitor LY2109761 reduced clonogenicity and increased radiosensitivity in glioblastoma (GBM) cell lines and in an orthotopic intracranial model (Zhang et al. 2011). Some TGF-β inhibitors are also being preclinically evaluated; these include monoclonal antibodies against TGF-β1 (CAT192, GC1008, ID11) or antisense oligodeoxynucleotides specific for TGF-β1 mRNA (AP11014) or TGF-β2 mRNA (AP12009) (Benigni et al. 2003; Nam et al. 2006; Flavell et al. 2010; Bogdahn et al. 2011). These trials suggest that TGF-β inhibition exhibits promising efficacy and safety. However, sustained LY2109761 administration paradoxically increased carcinoma pSmad2 levels in preclinical models resulting in a more aggressive carcinoma. They also observed enrichment of genes encoding key extracellular matrix proteins and receptors, cytoskeletal proteins, and chemokines in the drug-treated carcinomas of the sustained versus short-term dosing regimens (Connolly et al. 2011). These results thus indicate that study of the drug effects after prolonged treatment can provide important information regarding TGF-β independent effects prior to large clinical trials that can clarify the feasibility and safety of such treatments.
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