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Overview of Cell Adhesion Molecules and Their Antagonism
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
A relevant consideration in antiadhesion therapy is the potential for adverse effects, particularly increased susceptibility to infection. This is supported by two human immunodeficiencies, leukocyte adhesion deficiency (LAD) types 1 and 2, that are characterized, respectively, by deficiencies of CD11/CD18 and selectin ligand. Moreover, in some animal studies, an increased proclivity for infection has been noted as a sequela of antiadhesion therapy (50). The risk of infection may be affected by the choice of target. For example, it might be expected that targeting ICAM-1, which is up-regulated at inflammatory sites in comparison to normal tissue, might be less immunosuppressive than targeting CD18, which is present on all leukocytes. Support for this comes from knockout animals, where it has been shown that ICAM-1 deficient mice do not appear excessively susceptible to infection. Similarly, targeting VLA-4, which is expressed on all leukocytes with the exception of neutrophils, might conceivably engender less global immune suppression by leaving neutrophil function intact. Nevertheless, heightened vigilance for sequelae of immunosuppression is required for all studies using antiadhesion therapies.
Pathogenic role of antigen-antibody complexes
Published in Gabriel Virella, Medical Immunology, 2019
Gabriel Virella, George C. Tsokos
The interaction between integrins expressed by neutrophils and molecules of the immunoglobulin superfamily expressed by endothelial cells (ICAM-1 and related antigens bind LFA-1 and related molecules; VCAM-1 binds VLA-4) causes firm adhesion of inflammatory cells to the endothelial surface, which is an essential step leading to their extravascular migration. VLA-4 is also expressed on the membrane of lymphocytes and monocytes, and its interaction with endothelial VCAM-1 allows the recruitment of these cells to the site of inflammation.
Cellular Trafficking
Published in Martin Berry, Ann Logan, CNS Injuries: Cellular Responses and Pharmacological Strategies, 2019
In non-CNS experimental models of inflammation, suppressing the expression of leucocyte adhesion molecules impairs leucocyte-endothelial cell interaction and reduces leucocyte numbers in inflammatory infiltrates. However, blocking CD11a/CD18 expression in EAE has not been successful in abrogating demyelination. Of the β integrins it is only VLA-4 which promotes lymphocyte interaction with the BBB in EAE and, based on the clinical effectiveness of anti-VLA-4 antibodies in this model, phase I studies are currently assessing the potential use of anti-VLA-4 therapy for MS patients. Hopefully, a successful outcome will not only provide clinical benefit but will also generate additional information concerning the contribution of VLA-4 in mediating lymphocyte attachment to endothelial cells of the BBB and of the general vasculature. A possible drawback of this form of immunotherapy is that VLA-4 is present on other leucocytes (e.g., monocytes and dendritic cells) and hence the infusion of specific antibodies could have physiological repercussions.
Increased Levels of VCAM-1 in Sera and VLA-4 Expression on Neutrophils in Dermatomyositis with Interstitial Lung Disease
Published in Immunological Investigations, 2022
Meiyi Lin, Chunshu Yang, Xudong Liu, Shan Zhao, Bailing Tian, Xiaoyu Hou, Jingyi Xu, Pingting Yang
VCAM-1 (CD106) is a 90-kDa glycoprotein predominantly expressing on endothelial cells. Its main ligand is VLA-4 (α4β1 integrin) which plays a major role in mediating rolling and firm adhesion of leukocytes to the endothelium, as well as leukocyte transmigration (Mitroulis et al. 2015). The soluble ectodomain of VCAM-1 (sVCAM-1) is released from the cell surface into the circulation by proteolysis, a process that is upregulated in inflammatory diseases (Singh et al. 2005). The expression of VCAM-1 is closely related to tumor angiogenesis and metastasis in gastric carcinoma and breast cancer (Byrne et al. 2000; Ding et al. 2003). In addition, VCAM-1 and VLA-4 are major factors in promoting the survival of endothelial and mural cell during angiogenesis (Garmy-Susini et al. 2005). VLA-4 is expressed mainly on lymphocyte, monocytes, eosinophils, and neutrophils (Van Staveren et al. 2018). VCAM-1/VLA-4 pathway has been proved to be associated with inflammatory and autoimmune diseases by recruiting leukocytes to tissues (Mitroulis et al. 2015; Yusuf-Makagiansar et al. 2002). For example, VCAM-1/VLA-4 pathway seems to be critical for the infiltration in rheumatoid arthritis (RA)(Klimiuk et al. 2002; Wang et al. 2015). In addition, it has been demonstrated that VLA-4/VCAM-1 pathway is important in mediating leukocyte adherence to the inflamed endothelium in the central nervous system of multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE) model (Rice et al. 2005; Wan et al. 2018).
Roles of the bone marrow niche in hematopoiesis, leukemogenesis, and chemotherapy resistance in acute myeloid leukemia
Published in Hematology, 2018
The adherence of AML cells to the bone marrow microenvironment via VLA-4 leads to CAM-DR. VLA-4 is an integrin dimer, α4β1, which is located on leukemic cells. Fibronectin (FN) is a major component of the extracellular matrix and is secreted by various cells. The VLA-4–FN interaction plays an instrumental role in chemokine-mediated homing and mobilization [36] and is closely related to MRD. Matsunaga et al. [37] found that AML cells coated with FN had lower apoptosis rates and higher survival rates than those cultured with BSA in vitro. AML patients who are VLA-4 negative have much higher overall survival rates than those with high VLA-4 expression. The negative prognostic value of VLA-4 in AML might imply that physical contact between fibronectin and VLA-4-positive AML cells reduces chemotherapy sensitivity and provides a sanctuary for MRD, ultimately resulting in a shorter survival time. With anti–VLA-4–specific antibodies, cells from VLA-4–positive AML patients co-cultured with stromal cells or FN tend to be more sensitive to chemotherapy than those without VLA-4 antibodies. Poulos et al. [38] have demonstrated that ECs establish a fertile niche, activation of ECs by VEGF-A leads to the expansion of AML cells and increases the number of EC-adherent leukemia cells partly via VLA-4/VCAM-1 interaction. Furthermore, ECs stimulated by VEGF-A conferred chemotherapeutic protection on AML cells. In contrast, the inhibition of VEGFR2 led to a profound increase in chemosensitivity.
EGFL7 – a potential therapeutic target for multiple sclerosis?
Published in Expert Opinion on Therapeutic Targets, 2018
Timo Uphaus, Frauke Zipp, Catherine Larochelle
In the MS therapeutic arsenal, two main treatment strategies to overcome neuroinflammation can be distinguished: 1) to modulate/suppress aberrantly activated pro-inflammatory peripheral immune cell subsets, causing various degrees of systemic immunosuppression, or 2) to inhibit the entry of immune cells into the CNS, resulting in a more selective but potentially life-threatening CNS immunosuppression. Natalizumab, a humanized monoclonal antibody against the very late antigen 4 (VLA4), is the only approved medication belonging to the second category. Indeed, natalizumab prevents the interaction among integrin VLA4, broadly expressed on immune cells, and its cognate ligand VCAM-1, expressed on CNS endothelial cells. This translates into a robust clinical and radiological amelioration of MS disease activity, but is associated with a significant risk of severe CNS infection in a large number of MS subjects, thus limiting its use [15]. No treatment strategies specifically targeting the ECM are currently approved, although the antibiotic minocycline may exert part of its beneficial effects in MS and EAE through a reduction of MMP activity in relation to induction of tissue inhibitors of MMPs [16,17]. As EGFL7 can enhance neuronal differentiation [13,18] in addition to its promotion of endothelial survival and barrier properties, it represents a promising candidate for a first ECM-based intervention to prevent lesion formation and promote CNS homeostasis in neuroinflammatory conditions, without the risks associated with significant peripheral or CNS immunosuppression.