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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Rituximab binds to amino acids 170–173 and 182–185 on CD20, which are physically close to each other as a result of a disulfide bond between amino acids 167 and 183. The Fc portion of rituximab mediates the cell-killing ADCC and CDC mechanisms, and has a general regulatory effect on cell cycle. It increases MHC II and adhesion molecules LFA-1 and LFA-3 (lymphocyte function-associated antigen), elicits shedding of CD23, and can also induce apoptosis of CD20+ cells. The combined effect results in the elimination of B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells.
Tumor Necrosis Factor
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Peter G. Brouckaert, Claude Libert
TNF is produced mainly by macrophages activated by bacterial products, viruses, parasites, and probably other stimuli. CD2-LFA-3 interactions may form a physiological induction signal. This signal can also be produced by other cells such as lymphocytes, LAK cells, natural killer (NK) cells, neutrophils, astrocytes, endothelial cells, smooth muscle cells, and several tumor cells. In some cell types, the gene may have been developmentally silenced.7 Its induction is under both transcriptional and posttranscriptional regulation.8 Further details and references can be found in two recent reviews by Fiers9 and Vilcek and Lee.10
Dermal Fibroblast Function
Published in Brian J. Nickoloff, Dermal Immune System, 2019
Fibroblast binding to different types of cells, as well as to each other, is facilitated by heterophilic adhesion molecules. Many of these adhesion molecules have similar structures and belong to the immunoglobulin superfamily. HCAM (also known as CD44 or Hermes antigen) belongs to the cartilage link protein family and is expressed on fibroblasts.152 LFA-3 is present on fibroblasts and on different types of cells and is a ligand for CD2, which itself is present on all T cells.153 The binding of LFA-3 to CD2 is important in T cell adhesion to fibroblasts. ICAM-1 is present on a wide variety of cell types including fibroblasts, and is a ligand for LFA-1 (CD11a) which is present on all leukocytes.152 The binding of ICAM-1 to LFA-1 is important in leukocyte adhesion to fibroblasts. For reasons that are unknown, scleroderma fibroblasts express higher degrees of ICAM-1 than normal controls.154 IL-1β, TNF-α, or IFN-γ all cause increased expression of ICAM-1 and class I MHC molecules on surfaces of RA synovial fibroblasts.155 HLA class II antigen is increased on fibroblasts exposed to IFN-γ.155 The function of HCAM on fibroblasts is unknown, but may be involved in binding of fibroblasts to types I and VI collagen.156
Suppression of the CD28/B7 pathway reduces the occurrence and development of myasthenia gravis and cytokine levels
Published in International Journal of Neuroscience, 2021
Zhan-Xia Xue, Yong-Shan Gao, Xue-Liang Wu
We initially found that the increased lymphocyte proliferation of EAMG rats could be negated by CTLA4-Ig treatment. T regulatory cells were identified due to their crucial role in the development of self-tolerance and in the pathogenesis of MG [29]. CD28 is essential to promote T cell proliferation and cytokine production, while CTLA4 acts as a negative regulator for the activation of T cells [10]. CTLA4-Ig inhibits immune reactions by blocking the T-cell costimulatory CD28-CD80-86 pathway [30]. CTLA4-Ig is homologous CD28, where both ligands can bind B7-1 and B7-2 on antigen-presenting cells. It has been found that CTLA4 binds B7-1 and B7-2 with a greater affinity than CD28, thus enabling it to outcompete CD28 for its ligands, eventually transmitting inhibitory signals to T cells [15, 31, 32]. Previous studies have demonstrated that CD28/B7 interactions can co-stimulate T cell activation and prevent T cell clonal anergy [33]. CD28 could potentially deliver a costimulatory signal in the process of T cell activation, where it delivers TCR-independent autonomous signals that regulate the expression of pro-inflammatory cytokines and chemokines [34]. T cell activation can be mediated through co-stimulatory factors delivered by LFA 1/ICAM, LFA 3/CD2, CTLA4/CD40, CD28/B7 and ICOS/ICOSL interactions [35].
Bone marrow endothelial cells sustain a tumor-specific CD8+ T cell subset with suppressive function in myeloma patients
Published in OncoImmunology, 2019
Patrizia Leone, Giuseppe Di Lernia, Antonio Giovanni Solimando, Sebastiano Cicco, Ilaria Saltarella, Aurelia Lamanuzzi, Roberto Ria, Maria Antonia Frassanito, Maurilio Ponzoni, Paolo Ditonno, Franco Dammacco, Vito Racanelli, Angelo Vacca
We next analyzed the expression by EC of molecules potentially involved in the processing and presentation of antigens to CD8+ T cells. To this aim, freshly prepared BMMC were immunostained for EC markers along with HLA class I molecules, the co-stimulatory molecules CD40, CD80 and CD86, the inducible co-stimulator ligand (ICOSL), and the lymphocyte function-associated antigen 3 (LFA-3). Flow cytometric analysis revealed that the majority of EC expressed HLA class I antigens (92.40% ± 6.09% in MGUS, 91.27% ± 5.40% in MM; Figure 2A) and that the positive cells in MGUS and MM samples had similar expression levels of these antigens (6.08% ± 4.68% in MGUS, 6.56% ± 4.65% in MM) (Figure 2B). Regarding ICOSL, both the mean percentage of positive cells and the expression levels were significantly higher in MM than in MGUS samples (P = 0.0344 and P = 0.0245) (Figure 2A-B). Cells expressing LFA-3 were abundant in both MGUS (83.15% ± 15.16%) and MM (91.21% ± 8.78%) samples, but LFA-3 expression levels were significantly higher in MM samples (4.13% ± 2.61% in MGUS and 6.22% ± 2.45% in MM, P = 0.0322) (Figure 2A,B). Low percentages of cells were positive for the co-stimulatory molecules, with similar levels between groups for CD40 and CD80 but a significantly higher percentage of CD86-positive cells in MM samples (Figure 2C); a similar pattern emerged for the expression levels of the co-stimulatory molecules in the positive cells (Figure 2D). These results demonstrate that ex vivo EC have a phenotype of semi-professional APC, given that they express low levels of costimulatory molecules.