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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Tremelimumab (formerly ticilimumab, CP-675206) is a fully human anti-CTLA-4 IgG2 monoclonal antibody being developed by Pfizer for its potential therapeutic application in melanoma, non-small-cell lung cancer (NSCLC) and colorectal cancer. Tremelimumab blocks the binding of the antigen-presenting cell ligands B7.1 and B7.2 to CTLA-4, resulting in inhibition of B7-CTLA-4-mediated down-regulation of T-cell activation. Subsequently, B7.1 or B7.2 may interact with another T-cell surface receptor protein, CD28, resulting in a B7-CD28-mediated T-cell activation unopposed by B7-CTLA-4-mediated inhibition. Thus, tremelimumab is thought to stimulate patients’ immune systems to attack their tumors.
The Immune System and Immune Modulation
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
François Hirsch, Guido Kroemer
Such coreceptors expressed on the T cell surface include CD2 (which interacts with LFA-3 on the APC) [12], CD45RO (CD22) [13], CD40 (CD40L), and others. Several reports have documented the role of CD28/B7 interaction in providing one of the cosignals [14,15]. Thus, blocking anti-B7 antibodies or CTLA-41g fusion molecules, which neutralize B7 [16], induce T cell anergy [17]. Two distinct CD28 ligands were identified on APC, B7-1 (CD80) and B7-2 (CD86). While B7-2 is constitutively expressed on dendritic ceils (DCs), macrophages, and resting B cells, B7-1 is only constitutively expressed on DCs and is induced on other APCs on activation [18]. B7-2 initiates CD28-dependent costimulation during the induction of the immune response [19]. Recent studies have delineated the specific contribution of B7 molecules on CD4+ T helper (Th) cell differentiation. B7-1 and B7-2 favor either cell-mediated immunity dependent on Th1 cells or humoral immune response regulated by Th2 cells, respectively [20,21]. Another ligand of B7, CTLA-4, involved in costimulation, was discovered on activated T cells. It appears that CTLA-4 expressed on the surfrace of T cells functions as an endogenous “death receptor” in the sense that its activation causes apoptosis of activated T cells [22]. Thus, in specified circumstances, costimuli can abort immune responses.
Gene Therapy for Lung Cancer
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Choon Taek Lee, David P. Carbone
Effective antitumor immunity is usually dependent on T-cell-mediated responses. Two kinds of signals are required for the activation of T cells. As described above, the first signal is the antigen-specific binding of a peptide antigen-MHC complex on the surface of antigen presenting cells with antigen specific T-cell receptors. This interaction is necessary but not sufficient to induce primary T-cell activation and production of essential cytokines such as IL-2. It is hypothesized that the presence of this first signal alone may induce a state of readiness to respond to the second signal, known as costimulation. The second signal is transmitted by the antigen-independent binding of costimulatory molecules on APC with their corresponding receptors on T-cells. This signal is required to induce primary T-cell proliferation and other effector functions of the immune response. Without this second signal, the binding of antigen with TCR alone may cause prolonged unresponsiveness or specific T-cell anergy. A number of molecules have been found to mediate this second signal, including the B7 family (unrelated to the HLA-B7 class I molecule described above), which interact with the CD28 receptor on T cells (8,9). B7 is expressed on activated B cells, macrophages, and dendritic cells and is the ligand for CD28 and CTLA-4 on T-cells (10,11).
Juvenile idiopathic arthritis and its associated uveitis
Published in Expert Review of Clinical Immunology, 2023
Arash Maleki, Priya D. Patel, C. Steven Foster
The HLA-DRB1 and the HLA – DR-β1 peptide-binding groove are associated with an increased risk for the development of uveitis in girls [21]. Additionally, polymorphisms in HLA-A and HLA-DR-β1 are also associated with a risk of uveitis in Japanese JIA patients [22]. Retrospective studies on non-HLA genes associated with JIA, including PTPN22, STAT4, TRAF1/C5 locus, TGFB, TNFAIP3, and C12orf30, did not demonstrate any correlation with uveitis [23]. However, the TRAF1/C5 gene on chromosome 9 increases the risk of uveitis in ANA positive JIA patients. The proximity of the TRAF1/C5 locus to genes encoding TNF-receptor associated factor 1, a negative regulator of the TNF pathway, may explain the role of TNF signaling in JIA-associated uveitis [24]. B7-H4 or V-set domain-containing T-cell activation inhibitor-1 (VTCN1) can also increase the risk of JIA-associated uveitis [25]. It is important to note that B7-H4 is a negative regulator of the T-cell immune response [26].
CD44 Drives M1 Macrophage Polarization in Diabetic Retinopathy
Published in Current Eye Research, 2023
Zhujuan Pan, Yaoxin Zhao, Shaobo Zhou, Jing Wang, FeiHong Fan
CD86, also known as B7-2, is an important member of the growing B7 family.28 Since it was initially cloned in the early 1990s, B7-2 was thought to be a factor that could stimulate the growth of decidual stromal cells.29 Interestingly, B7-2 is primarily located on class II human leukocyte antigen + decidual cells and helps to stimulate allogeneic T cells.29 CD86 can interact with CD28 and CD152/cytotoxic T lymphocyte-associated antigen 4 molecules on T cells, which influences T cell survival and response via co-stimulatory and co-inhibitory pathways.30,31 The T cell receptor complex first recognizes the antigen peptide expressed on antigen-presenting cells and binds to MHC, and then the co-stimulatory molecule CD86/CD80 on APC interacts with CD28 on naive T cells to generate stimulatory signals for T cells.32 Diabetes contributed to B cell activation and increased the expression of CD80 and CD86.33 Here, it was discovered that the expression of CD86 was characterized by significant up-regulation in the DR group relative to the control group.
Barriers and Opportunities for CAR T-Cell Targeting of Solid Tumors
Published in Immunological Investigations, 2022
Jose R. Conejo-Garcia, Jose A. Guevara-Patino
Another trial has been recently open at UNC Lineberger Cancer Center to test B7-H3 CAR T cell administration in patients with relapsed or refractory glioblastoma (NCT05366179), with a parallel trial targeting B7-H3 in ovarian cancer patients (NCT04670068). Relatively high expression in multiple cancers make B7-H3 a very interesting target for CAR T-cell immunotherapy (Du et al. 2019). A potential concern, however, is that while translation of B7-H3 mRNA is prevented in the steady state, B7-H3 mRNA is detected in many normal tissues, including coronary arteries, nerves, and the digestive tract, according to GTEX. B7-H3 protein expression could therefore theoretically appear in vital tissues under conditions of inflammation. These important ongoing trials will soon define the potential of B7-H3 as an immunotherapeutic target and the safety of these interventions.