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Specific Host Restance: The Effector Mechanisms
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The effect of all of these mechanisms is to maintain the health of the host in a world of potentially hostile pathogens. The purpose of MHC restriction of these actions seems to be to prevent the accidental killing of T helper cells and to prevent parasites from mimicking their host as a means of successful infection.
Introduction: Brief Overview on the Major Histocompatibility Complex
Published in Gérard Chaouat, The Immunology of the Fetus, 2020
Jean-Pierre Abastado, P. Kourilsky
Two different alleles of the same histocompatibility antigen may present a different peptide derived from the same foreign antigen. The final T-cell response is, therefore, specific for both the foreign antigen and the histocompatibility antigen. This double specificity is dubbed as “MHC restriction”. The lack of reactivity to a given antigen may be due to a “hole” in the T-cell repertoire or to the lack of presentation of this antigen (or its peptides) by the histocompatibility antigens. Histocompatibility antigens are thus the filter through which the immune system recognizes the self and nonself antigens. The immunogenicity of a given antigen depends on the MHC. Some alleles are high responders, some low. This has been shown for both humoral and cellular immunity. By transfection with the corresponding MHC gene, transgenic mice have been obtained which were converted from low to high responder.
Self-Recognition and Symmetry in the Immune System
Published in Irun R. Cohen, Perspectives on Autoimmunity, 2020
Yaakov Naparstek, Robert S. Schwartz
T-cells learn about MHC restriction in the thymus, before their exposure to exogenous antigens.46 Molecular analyses have demonstrated that the initial expression of murine T-cell receptors occurs intrathymically around the 17th day of fetal life.47 The T-cell receptor, with its capacity to recognize autologous MHC, must, therefore, play a vital role in the process of MHC restriction. How does it occur?
The interdependence of machine learning and LC-MS approaches for an unbiased understanding of the cellular immunopeptidome
Published in Expert Review of Proteomics, 2022
Morten Nielsen, Nicola Ternette, Carolina Barra
While MSrescue provides a simple yet powerful means to increase the yield of LC-MS/MS immunopeptidomics, it suffers from the limitation that it relies on accurate identification of the binding motifs for each of the MHC molecules included in the given sample from the (often) limited set of high-confidence PSMs. To resolve this limitation, we have recently proposed the MHCMotifDecon tool [60]. MHCMotifDecon benefits from state-of-the-art MHC class I and class II predictions, NetMHCpan and NetMHCIIpan, respectively (for details on these methods see below), to accurately deconvolute immunopeptidome datasets and assign individual ligands to the most likely MHC-restriction element while discarding co-purified MHC-irrelevant sequences. The deconvolution performed by this method is hence supervised and driven by predicted binding to the MHC expressed in the given sample/cell line under investigation, and thus benefits from the pan-specific power of the two MHC binding prediction methods to also make accurate deconvolution for molecules characterized with small peptide quantities (such as HLA-C and HLA-DRB3/4/5). With its ease of use and intuitive result representation, MHCMotifDecon can be applied by computationally novice users efficiently guiding their interpretation of immunopeptidome datasets and serving the discovery of novel T cell targets.
Therapeutic challenges at the preclinical level for targeted drug development for Opisthorchis viverrini-associated cholangiocarcinoma
Published in Expert Opinion on Investigational Drugs, 2021
Watcharin Loilome, Hasaya Dokduang, Manida Suksawat, Sureerat Padthaisong
Another promising immunotherapy approach in Ov-related CCA is using adoptive T cell transfer using chimeric antigen receptor (CAR) T cells which can recognize specific surface antigen without major MHC restriction [148]. Selection of suitable antigens on cancer cells is essential for designing an effective CAR T cell approach and avoidance of side effects. Mucin 1 (MUC1) is the convincing candidate antigen which highly expressed and associated with poor prognosis and survival in CCA [149]. The recent study [150] has established anti-MUC1-CAR4 and used lentiviral vector and introduced into human T cells, anti- MUC1-CAR4 T cell showed anti-cancer activity against MUC1-expressing CCA cells by enhanced anti-tumor cytokines (TNF-α and IFN-γ) and pro-apoptotic protein (granzyme B) production and induced CCA cell lysis both in 2D and 3D (spheroid) co-cultures. Regarding to improve specificity of CAR T cell against CCA cell, they also created CAR T cells targeting integrin αvβ6 which overexpression in CCA tissues and correlated with poor survival of CCA patient. CAR T cells targeting integrin αvβ6 was established by engineered lentivirus encode CARs containing an integrin αvβ6-binding peptide and delivery to T cell. The results revealed that this can promote cytotoxicity and showed anti- tumor activity on of CAR T cell against integrin αvβ6-positive CCA cell [151].
Investigational drugs for the treatment of diffuse large B-cell lymphoma
Published in Expert Opinion on Investigational Drugs, 2021
Andrea Patriarca, Gianluca Gaidano
Tumor regression can be mediated by transfer of major histocompatibility complex (MHC)–restricted T cells recognizing tumor-associated antigens. This notion has prompted the development of strategies of adoptive cell therapy (ACT). These attempts have faced the issue of obtaining adequate numbers of T cells with defined specificity and MHC restriction for individual patients. A major step ahead to overcome these difficulties has been represented by the technology allowing the transfer of chimeric antigen receptors (CARs) into T-cells [93]. Briefly, a CAR is a transmembrane protein build up by: i) a single-chain immunoglobulin-derived variable fragment (scFv) targeting the chosen antigen; ii) a transmembrane hinge; iii) an intracellular signaling domain consisting of CD3ξ and co-stimulatory molecules such as CD-28 and 4–1BB (Figure 3). Such a receptor offers major advantages, since: i) it is fully independent from HLA, circumventing cancer-induced HLA reduced expression; ii) costimulatory molecules in the transduction tail improve T-cell proliferation, cytokine production and long-term persistence. Approved CAR-T cell therapies target CD-19 and include (Figure 2): tisagenlecleucel for recurrent pediatric acute lymphoblastic leukemia (ALL) and R/R large B cell lymphoma [94]; axicabtagene ciloleucel for R/R large B cell lymphoma [95,96]; lisocabtagene maraleucel for R/R DLBCL [97,98]. The efficacy data of CAR-T cells in DLBCL are reported in table 2.