China
Africa
Explore chapters and articles related to this topic
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
CD40 ligand (CD40L, CD154) is a cell-surface molecule predominantly expressed by activated CD4+ T lymphocytes. Interaction of CD40L with its counter-receptor CD40 on the surface of B cells is essential for germinal center formation and class-switch recombination. Furthermore, CD40 is also expressed on dendritic cells, macrophages, and activated endothelial and epithelial cells. Interaction of CD40L-expressing CD4+ T cells with these cell types promotes B- and T-cell priming triggering protective responses against intracellular pathogens. Mutations in the CD40LG gene, mapping at Xq26, result in X-linked hyper-IgM syndrome (also known as type 1 hyper-IgM syndrome), a combined immunodeficiency characterized by an increased occurrence of bacterial and opportunistic infections, neutropenia, a high incidence of liver and biliary tract disease, increased risk of malignancies, and a high mortality rate.
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
The X-linked form: Absence of CD40 ligand expression on activated T-cells.May have abnormal antigen-induced T-cell proliferation.Positive family history in approximately 30% of cases.Disease-causing mutation in the CD154 gene.
Future therapies in lung transplantation
Published in Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell, LUNG Transplantation, 2016
Elizabeth A. Lendermon, John F. McDyer
CD154 (CD40L) is a protein that belongs to the tumor necrosis factor (TNF) superfamily and is expressed on the surface of activated CD4+ T cells. It binds to CD40 on APCs to effect activation in these cells, as well as on B cells, in which case binding is necessary for immunoglobulin class switching. In addition, interaction between CD154 and CD40 has been shown to be important for the development of the type 1 helper T-cell (Th1) responses14,15 that are critical in transplant rejection. In multiple experimental transplant models (both rodents and nonhuman primates), blockade of the CD154-CD40 pathway via use of a monoclonal antibody (mAb) against CD154 at the time of transplantation has been shown to result in improved allograft acceptance.16–19 Multiple mechanisms of anti-CD154-induced allograft acceptance appear to exist. Early animal studies examining anti-CD154 in combination with CTLA4Ig revealed an important role for activation-induced cell death.20,21 Subsequent studies demonstrated that anti-CD154 therapy provided an infectious tolerance that is now attributable to regulatory T cells.22–24 In a mouse orthotopic transplant model, use of anti-CD154 alone at the time of transplantation resulted in abrogation of allospecific CD4+ and CD8+ effector cytokine responses, a massive increase in the population of regulatory T cells in the allograft, and improved allograft acceptance.25 Therefore, it is clear that anti-CD154 therapy has many desirable tolerogenic effects in animal models.
The molecular basis of immuno-radiotherapy
Published in International Journal of Radiation Biology, 2023
Ioannis M. Koukourakis, Dina Tiniakos, Vassilis Kouloulias, Anna Zygogianni
A large number of additional IC-pathways have been identified (Marin-Acevedo et al. 2021). Inhibitory pathways include: 1) LAG-3 (CD223) and TIGIT expressed by T-cells and NK-cells, 2) Adenosine A2aR/P1-R receptor on T-cells and the CD39 and CD73 expressed by lymphocytes and CCs promoting the production of immunosuppressive adenosine molecules, and 3) Killer immunoglobulin-like receptors KIR/CD158 expressed mainly by NK-cells. Co-stimulatory pathways include: 1) OX40/CD134 expressed by activated CD4 and CD8 T-cells, that also inhibits the suppressive activity of Tregs, 2) Glucocorticoid-induced TNF receptor family-related protein GITR that enhances cytotoxic T-cell activity, 3) Inducible co-stimulator (ICOS) that has a similar function to CD28 enhancing T-cell cytotoxicity, 4) CD27/CD70 pathway that induces T-cell differentiation to effector and memory cells, and 5) CD40/CD154 pathway that induces secretion of cytokines by B-cells and activates cytotoxic T-cells. TIM-1 expressed by T-cells, and TIM-3 and 4 expressed by NK-cells and macrophages (and CCs) have a distinct still unclear or even dual role as stimulatory or inhibitory molecules of tumor immune surveillance (Das et al. 2017). Toll-like receptors TLR7/8 and TLR9 are also involved in the induction of anti-tumor T-cell activity (Paulos et al. 2007). Arginase and inducible iNOS, enzymes highly expressed by CCs that deplete the aminoacid arginine essential for T-cell activation and proliferation, are also targets for immunotherapy (Timosenko et al. 2017; So et al. 2019).
Investigational drugs for the treatment of kidney transplant rejection
Published in Expert Opinion on Investigational Drugs, 2022
Lukas K van Vugt, Maaike R Schagen, Annelies de Weerd, Marlies EJ Reinders, Brenda CM de Winter, Dennis A Hesselink
Iscalimab (CFZ533) is a non-B lymphocyte-depleting anti-CD40 monoclonal antibody [60]. Its mechanism of action is to bind the transmembrane glycoprotein CD40, which prevents binding with its ligand CD154 (CD40L) (Figure 1). CD40 belongs to the TNF receptor superfamily and is expressed on APCs and B lymphocytes [61–63]. CD154 is expressed on various cell types such as platelets, B lymphocytes, and activated T lymphocytes [63–65]. This CD40-CD154 costimulatory pathway has a function in the primary T lymphocyte-dependent antibody response: it generates germinal center formation, differentiation of memory B lymphocytes and Ig-isotype switching [66–68]. Stimulation of the CD40 pathway also induces the secretion of various cytokines and plays a role in dendritic cell maturation and macrophage survival [69,70]. The cascade of this immune response is known to contribute to lymphocyte activation in inflamed tissue and is involved in the pathology of some autoimmune diseases [71,72]. This cascade has been recognized as important in SOT rejection [73–78]. Available evidence of iscalimab is therefore discussed in this review, even though no evaluation of iscalimab as treatment for kidney transplant rejection has yet been undertaken.
Recent advances in porcine cardiac xenotransplantation: from aortic valve replacement to heart transplantation
Published in Expert Review of Cardiovascular Therapy, 2022
Sam Kavarana, Jennie H Kwon, Kasparas Zilinskas, Lillian Kang, Joseph W Turek, Muhammad M Mohiuddin, T Konrad Rajab
The use of a costimulation blockade has also been shown to increase efficacy of heart xenotransplants. T cells in the adaptive immune system require supplementary stimuli from costimulatory factors in order to proliferate, and these costimulatory signals can lead to a robust immune response, rejection, and decreased graft survival [44]. There are various costimulatory pathways, but one that has proved to be extremely significant is the CD40:CD154 pathway [45]. Although complex, CD40 and its ligand, CD154 have been demonstrated to be extremely potent stimulators of both T and B cell activity [44]. The original costimulation blockade involving this pathway was introduced by Buhler et al. in 2000. However, there were various issues with the anti-CD154 antibody, including thrombocytopenia, coagulopathy, and systemic inflammation [45]. The most recent developments in costimulation blockade therapy involve anti-CD40 regimens, which have proved to be more effective [45]. The chimeric 2C10R4 anti-CD40 antibody was able to significantly prolong porcine heart graft survival in baboons, indicating its usefulness as another method of combating the recipient’s immune response [46,47].