Future therapies in lung transplantation
Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell in LUNG Transplantation, 2016
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.
Mucosal manifestations of immunodeficiencies
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
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.
Inflammation and immunology
C. Simon Herrington in Muir's Textbook of Pathology, 2020
B lymphocytes become activated and proliferate when antigen binds to and cross-links the B-cell receptor molecules on the surface. The B-cell receptor is composed of monomeric IgM (see below) existing in a transmembrane form with the antigen-binding fragment (Fab) at the external surface and the Fc fragment at the cytoplasmic face. The crosslinking of the B-cell receptor provides one signal for B-cell activation but, for complete activation, a second signal termed co-stimulation is needed. This is usually provided by B-cell CD40 co-stimulated by a CD40 ligand (CD154) on a helper T cell and is particularly important for activated B cells to switch the type of immunoglobulin isoforms they make. Activated B cells subsequently differentiate into plasma cells that synthesize and secrete large quantities of immunoglobulin into the plasma.
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].
The CD40/CD40L system regulates rat cerebral microvasculature after focal ischemia/reperfusion via the mTOR/S6K signaling pathway
Published in Neurological Research, 2018
Run-Hao Jiang, Xiao-Quan Xu, Chen-Jiang Wu, Shan-Shan Lu, Qing-Quan Zu, Lin-Bo Zhao, Sheng Liu, Hai-Bin Shi
CD40, a member of the tumor necrosis factor-alpha (TNF-a) receptor superfamily, is a cell surface determinant originally identified on B cells. It has been detected on several cell types, including monocytes, macrophages, dendritic cells, and fibroblasts [1]. CD40 activation, which occurs through its engagement with CD40 ligand (CD40L, also known as CD154), appears to participate in the pathogenesis of several autoimmune diseases [2]. Recent reports indicate that patients with acute cerebral ischemia exhibit increased expression of CD40L on platelets, whereas its receptor, CD40, is upregulated on monocytes. Although it was inferred from these observations that the CD40/CD40L dyad might play an important role in creating and/or maintaining the pro-inflammatory/pro-thrombotic milieu and promoting tissue injury in patients with transient ischemic attacks or stroke, this possibility has not been directly addressed in an established experimental model of acute ischemic stroke [3–5].
Advances in the use of chloroquine and hydroxychloroquine for the treatment of COVID-19
Published in Postgraduate Medicine, 2020
JingKang Sun, YuTing Chen, XiuDe Fan, XiaoYun Wang, QunYing Han, ZhengWen Liu
CQ/HCQ regulate the release of various pro-inflammatory factors, which are important immunomodulators. Intracellular alkalinization by CQ/HCQ inhibits lysosomal activity, preventing antigen processing, major histocompatibility complex (MHC) class II expression and immune activation [40]. This process can inhibit T cell activation and block expression of CD154 on the surface of CD4 + T cells [41]. CQ also reduces cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor-α (TNF-α) produced by T cells and B cells [42]. At the same time, changes of endosomal pH can interfere with Toll-like receptor (TLR) signaling, such as TLR7 and TLR9 processing, inhibiting the activation and production of cytokines [43]. CQ/HCQ also weaken the cyclic GMP-AMP (cGAMP) synthase (cGAS) activity by inhibiting cytosolic DNA, thereby reducing type I interferon production [44]. In vitro, CQ/HCQ can also inhibit phospholipase A2, altering the metabolism of arachidonic acid, and reducing the production of prostaglandins [45]. Some clinical studies have found that high concentrations of cytokines and pro-inflammatory factors such as IL-6 and IL-10 are elevated in the plasma of critically ill patients infected with SARS-CoV-2 [46,47], suggesting that cytokine release syndrome (CRS) is associated with disease severity. In the aspect of immune response, HCQ/CQ therefore are likely to inhibit CRS, delaying the progression of COVID-19 (Figure 1).
Related Knowledge Centers
- B Cell
- Immunoglobulin Class Switching
- Protein
- T Cell
- Tumor Necrosis Factor Superfamily
- Cd40
- Antigen-Presenting Cell
- Alpha-5 Beta-1
- Glycoprotein Iib/Iiia
- Follicular B Helper T Cells