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Nanocarriers as an Emerging Platform for Cancer Therapy
Published in Lajos P. Balogh, Nano-Enabled Medical Applications, 2020
Dan Peer, Jeffrey M. Karp, Seungpyo Hong, Omid C. Farokhzad, Rimona Margalit, Robert Langer
It is also possible to increase binding affinity and selectivity to cell surface targets by engineering proteins that detect a specific conformation of a target receptor. In a recent in vivo study using a fusion protein consisting of an scFv antibody fragment to target and deliver small interfering RNA (siRNA) to lymphocytes—a type of white blood cell—a 10,000-fold increased affinity for the target receptor, integrin LFA-1, was observed [18]. Integrin LFA-1 is usually present in a low-affinity non-adhesive form on na¨ıve leukocytes (white blood cells that are not activated by cancer cells or pathogens that enter the body), but converts to the high-affinity adhesive form through conformational changes on activation of the immune system. Therefore, targeting the high-affinity form of LFA-1 enables drugs to be selectively delivered to the activated and adhesive leukocytes. New classes of targeting molecules can be engineered to target specific conformations. These include small protein domains, known as affibodies, that can be engineered to bind specifically to different target proteins in a conformational-sensitive manner. Other small proteins that act like antibodies—called avimers—are used to bind selectively to target receptors through multivalent effects. Nanobodies, which are heavy-chain antibodies engineered to one tenth of the size of an intact antibody with a missing light chain, have been used to bind to carcinoembryonic antigen (CEA), a protein used as a tumour marker [38–40] (Fig. 2.2b).
Integrins, Integrin Regulators, and the Extracellular Matrix
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Stephen W. Hunt, Sirid-Aimée Kellermann, Yoji Shimizu
In addition to FAK, a variety of other proteins become phosphorylated in T cells following integrin engagement. Nojima et al. (167) have demonstrated increased phosphorylation of a 105-kD protein following cross-linking of the α4β1 integrin in H9 cells as well as resting peripheral T cells. This 105-kD protein appears to be antigenically distinct from FAK (142). Phosphorylation of this protein could also be induced with the CS-1 containing fragment of Fn. Gismondi et al. (168) have shown increased tyrosine phosphorylation of two proteins (105 and 115 kD) following α4β1 or α5β1 integrin cross-linking in freshly isolated NK cells. Brando and Shevach (169) have also shown increased phosphorylation of a 115-kD protein following engagement of αvβ3 or TCR on a murine T-cell hybridoma. This phosphorylated protein was not FAK, and did not have intrinsic kinase activity. Similarly, Kapron-Bras et al. (159) have shown that ligation of the α2β1 integrin on Jurkat T cells with antibodies to either the α2 or β1 chains resulted in the accumulation of Ras in the active GTP-bound state, as well as increased phosphorylation of intracellular targets in the 47–52 kD range. Finally, LFA-1 engagement on T and B cells results in the increased phosphorylation of a number of as yet unidentified proteins (170,171).
Primary Immunodeficiencies
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Alain Fischer, Durandy Anne, Claude Griscelli
The disease is, above all, a defect of phagocytic cells which are unable to adhere and move because of the lack of membrane expression of LFA-1, CR3, and pl50,95 molecules. These molecules are heterodimers, sharing a common chain associated with distinct chains.28 The molecular basis of the disease is a quantitative or qualitative abnormality of the chain. The absence of chain synthesis or an abnormal chain leads to no association and no membrane expression.29-31 CR3 and pl50,95 are main components of polymorphonuclear cells (PMN) adhesion, their expression being increased by fusion with the membrane of secondary granules following activation. Such defect leads to severe bacterial infections, the site of which being free of phagocytic cells. In contrast, abnormal PMN accumulate in the bloodstream. Normal lymphocytes express mainly LFA-1. The defective expression of LFA-1 inhibits T-cell adhesion to interacting cells, such as B-cells or target cells for cytotoxic T-cells.32 The clinical consequences of LFA-1 deficiency are limited, perhaps because T-cells with high affinity for antigen do not need additional adhesive molecules. However, in some patients with a complete absence of LFA-1, cytotoxicity is impaired, resulting in an inability to reject HLA mismatched bone marrow, and antibody production to polypeptidic antigens is absent.32
Host-directed therapies for malaria and tuberculosis: common infection strategies and repurposed drugs
Published in Expert Review of Anti-infective Therapy, 2022
Piyush Baindara, Sonali Agrawal, O. L. Franco
Over-expression of ICAM-1 occurs in a wide variety of inflammatory disorders including malaria and tuberculosis [16,26,170]. Alicaforsen, an anti-sense oligonucleotide ICAM-1, selectively inhibits ICAM-1 by down-regulating ICAM-1 mRNA. Alicaforsen binds to the ICAM-1 mRNA, leading to the formation of a DNA: RNA heteroduplex which leaves the ICAM-1 mRNA ineffective and vulnerable to cleavage by ribonucleases, thus reducing ICAM-1 expression and preventing the inflammatory response [171]. Efalizumab, a humanized immunoglobulin mAb directed against LFA-1, was approved in 2003 for the treatment of psoriasis. LFA-1 binds the ICAM and plays a role in APC and T-cell adhesion, antibody production, T-cell trafficking, and co-stimulation. By blocking LFA-1, efalizumab inhibits T-cell proliferation and cytokine synthesis [172]. As both alicaforsen and efalizumab inhibit the expression of ICAM-1, thus their efficacy may also be tested for treating deadly infections like malaria, tuberculosis, and co-infections.
Targeted treatments for hidradenitis suppurativa: a review of the current literature and ongoing clinical trials
Published in Journal of Dermatological Treatment, 2018
Melody Maarouf, Ashley K. Clark, Dylan E. Lee, Vivian Y. Shi
PDE4 is an enzyme that reduces levels of intracellular cyclic adenosine monophosphate (cAMP), a pro-inflammatory molecule that stimulates production of cytokines elevated in the serum and/or lesions of patients with HS, including TNF-α, IL-17, IL-23, and IL-10 (10,11,13,19,20,24). C5a, a complement-activated product, is a strong chemoattractant of neutrophils, eosinophils, T-lymphocytes, and phagocytic cells. Inhibition of the activated complement system decreases recruitment of downstream mediators that closely contribute to HS (25). Additionally, C5a has been shown to upregulate TNF-α and IL-1 expression in fresh human peripheral blood mononuclear cells (25). LFA-1 is found on T-cells, B-cells, macrophages, neutrophils, and natural killer (NK) cells. Binding of LFA-1 to intercellular adhesion molecule 1 (ICAM-1), an adhesion receptor on keratinocytes and endothelial cells, signals increased leukocyte adhesion and migration of leukocytes, increasing inflammatory response (26).
Roles of macrophage migration inhibitory factor in Guillain-Barré syndrome and experimental autoimmune neuritis: beneficial or harmful?
Published in Expert Opinion on Therapeutic Targets, 2018
Donghui Shen, Yue Lang, Fengna Chu, Xiujuan Wu, Ying Wang, Xiangyu Zheng, Hong-Liang Zhang, Jie Zhu, Kangding Liu
Intercellular adhesion molecule (ICAM)-1 as a ligand of lymphocyte function-associated molecule (LFA)-1 is mainly expressed on the leukocytes and involved in their transmigration [70]. ICAM-1 expression is upregulated during the recruitment and migration of monocytes into the peripheral nerves in GBS patients [71]. Additionally, MIF upregulates the expression of ICAM-1 on endothelial cells and monocytes, while anti-MIF treatment improves glomerulonephritis, autoimmune myocarditis, experimental autoimmune encephalomyelitis (EAE), and acute encephalomyelitis by preventing ICAM-1 upregulation and decreasing inflammatory cell infiltration into the inflammatory sites [72,73]. MIF increases the expression of ICAM-1 by binding to CD44, which leads to the activation of ERK1/ERK2/MAPK pathway [34].