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In vitro Testing for Adverse Drug Reactions
Published in Kirsti Kauppinen, Kristiina Alanko, Matti Hannuksela, Howard Maibach, Skin Reactions to Drugs, 2020
Brender et al.16 have studied the T-lymphocyte responses in penicillin allergy in a more detailed fashion. The data indicated a heterogeneous response. The response could be elicited with both penicillin G itself and penicillin G coupled with human serum albumin. Both CD4 and CD8 T-cells were stimulated with penicillin G, but only CD4 T-cells with the albumin-coupled drug. The penicillin G-speeific clones were human leukocyte antigen (HLA) class I or class II restricted and the albumin-coupled drug had to undergo antigen processing prior to antigen presentation. Various cell types could serve as antigen presenting cells. The cytokine pattern secreted was also heterogeneous, most T-cell clones producing large amounts of interleukin-2, interferon-gamma, and tumor necrosis factor-alpha, and variable amounts of interleukin-4 and -5. The immunological heterogeneity may explain the variety of clinical pictures in penicillin allergy.
Immunomodulation in Gene Therapeutics
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Andreas Block, Susan S. Rich, Shu-Hsia Chen, Savio L. C. Woo
The MHC and non-MHC restricted host immune celis cooperate to achieve tumor rejection. CD8+ and CD4 + T lymphocytes may recognize specific tumor antigens presented by MHC class I and 11 molecules either on the tumor cell surface or after uptake of tumor-derived proteins and display on antigen presenting cells such as macrophages and dendritic cells. Tumor cells are then directly lysed by CD8+ cells. Alternatively, activated CD4+ and CD8+ cells secrete cytokines such as TNF-α, interferon γ (IFN-γ), granulocyte macrophage colony stimulating factor (GM-CSF), and IL-2. These cytokines induce T cell proliferation, activation, and accumulation of LAK cells, macrophages, and neutrophils. Activated accessory immune cells can kill tumor cells independently of specific tumor antigen recognition.
Biologic Therapies for Rheumatoid Arthritis
Published in Thomas F. Kresina, Monoclonal Antibodies, Cytokines, and Arthritis, 2020
Ian R. Mackay, Merrill J. Rowley, Claude C. A. Bernard
The CD4 molecule mediates the restricted recognition of MHC class II products on antigen presenting cells. Hence monoclonal antibodies against CD4 have been used to block antigen recognition by CD4-bearing T cells. Such antibodies have been shown to suppress various types of immune response, including responses to soluble antigens, responses causing allograft rejection, various immune-mediated diseases (cited in Refs. 32 and 33), and relapsing multiple sclerosis (34). Since this chapter is concerned with rheumatoid arthritis, the example is taken of collagen arthritis as a close experimental model. The suppression of collagen-induced arthritis in DBA/1 mice was achieved by a MAb raised to L3T4 (CD4) (35). Treatment with anti-L3T4 resulted in a >90% depletion of L3T4+ T cells in lymph nodes and spleen, and administration of anti-L3T4 before immunization with type II collagen reduced the incidence of arthritis from 14 of 20 in the control group to 3 of 25 in the treated mice and delayed the onset of the disease (35). However, treatment begun after a strong anticollagen IgG humoral response was underway, but before the onset of arthritis, did not alter disease expression.
Immunotherapy of High Risk Non-Muscle Invasive Bladder Cancer
Published in Expert Review of Clinical Pharmacology, 2021
Michael Ahdoot, Dan Theodorescu
Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is a cell surface molecule expressed on multiple T cell types including cytotoxic and T regulatory cells. CTLA-4 activation typically results in an upregulation of T regulatory cell function and a suppression of cytotoxic T-cell activity. During normal cellular function, antigen presenting cells (APCs), such as dendritic cells, B cells, and macrophages, present antigens on MHC I molecules to T cells. The antigen presenting MHC I binds to the T cell receptor creating an activation signal for the T cell. Simultaneously, the APC cell surface peptide, B7-1(also known as CD-80) will bind the T cells CD-28, acting as a co-stimulator for CD4 T cell activation [47–49]. However, after activation T cells can produce surface CTLA-4 receptors which compete to bind APCs’ B7-1 sites preventing further B7-1 and CD-28 interactions, which in turn prevent T cell activation [50]. CTLA-4 inhibitors such as Ipilimumab and Tremelimumab are monoclonal anti-CTLA-4 antibodies which neutralize the effect of CTLA-4 binding B7-1 and prevent the T cell suppressive effects of CTLA-4 interaction with B7-1 on the antigen presenting cell [51] (Figure 2).
Pembrolizumab in the treatment of refractory primary mediastinal large B-cell lymphoma: safety and efficacy
Published in Expert Review of Anticancer Therapy, 2021
Vincent Camus, Camille Bigenwald, Vincent Ribrag, Julien Lazarovici, Fabrice Jardin, Clémentine Sarkozy
PMBL tumor cells are thought to derive from thymic B cells. Thymic B cells reside at the cortico-medullary junction of the thymus and represent about 1% of total thymic cells [28]. They are mostly naïve B cells and are distinct from peripheral blood B cells [29]. Moreover, they seem to present a phenotype close to antigen-presenting cells with an overexpression of MHC II and CD86. In addition, they highly express Aire, whereas peripheral B cells do not express Aire. These data do not support the hypothesis of a peripheral B cells-homing [30] to the thymus. However, evaluation of thymic B cells remains scarce in the literature. Of note, in PMBL, the high level of BCL6 expression, as well as the high mutation burden, contrasts with the hypothesis of a naïve B cell-of-origin. However, the spectrum of mutations observed in BCL6 was not found in GC B-cell lymphoma (FL and DLBCL), suggesting a distinct COO [31].
Epstein–Barr virus-positive diffuse large B-cell lymphoma features disrupted antigen capture/presentation and hijacked T-cell suppression
Published in OncoImmunology, 2020
Xiang-Nan Jiang, Bao-Hua Yu, Wan-Hui Yan, Jimmy Lee, Xiao-Yan Zhou, Xiao-Qiu Li
B cells may modulate immune function through various means. They may function as antigen-presenting cells by capturing antigens via the BCR and presenting them to T cells through MHC II.4 Antigen capturing also triggers the BCR signaling cascade to help maintain B cell survival and differentiation. In addition to antigen presentation, B cells can also express PD-L1 to suppress T cell function and maintain immune homeostasis5 These immune-regulatory properties may be retained during B cell transformation and hijacked by the malignant cells as a survival mechanism. In particular, B cell infected with EBV often show disrupted function and differentiation, such as abnormal plasmacytic differentiation and aberrant expression of latent membrane protein 1 (LMP1).6,7 We hypothesize that EBV infection may also cause changes in the immunomodulatory activities of transformed B-cells, including antigen capture, antigen presentation, and T-cell suppression in EBV+ DLBCL, leading to the aggressive phenotype observed clinically. Here we compare tissue samples from EBV+ and EBV- DLBCL patients to determine if EBV+ DLBCL has altered BCR activity or aberrant expression of MHC II and PD-L1.