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Human T lymphotropic virus type 1 (HTLV-1)
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Other therapeutic interventions have tried to modulate the immune response in HAM/TSP. Cyclosporin A, methotrexate, azathioprine, pentoxifylline, and danazol have all been used in small clinical studies [30]. Given the non-specific effects on the immune system, these medications have unique side effect profiles to review when considering use in treatment. Targeted immune interventions include anti-IL2 receptor monoclonal antibody (anti-Tac, anti-CD25, or daclizumab). In a five dose, 15-week trial of anti-Tac in nine HAM/TSP patients, the number of CD4+ CD25+ cells were reduced, proviral load was reduced, and no patient had clinical progression of disease [43]. Another pro-inflammatory cytokine pathway upregulated in HAM/TSP is the IL-15 pathway and it has been targeted by anti-IL15 receptor monoclonal antibody (Hu Mik β1) currently underway [44]. Anti-CCR4 antibody, mogamulizumab has been used in treatment of ATL patients and a clinical trial with HAM/TSP patients is currently underway [45].
Chemokines and Chemokine Receptor Interactions and Functions
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Philip L. Shields, David H. Adams
CCR5 (the receptor for MIP-1α, MIP-1β and RANTES)and CXCR3 (the receptor for IP-10, Mig and I-TAC) show increased expression on human peripheral blood memory CD45RO+ T cells (50). CCR5 and CXCR4 appear to denote an effector phenotype as these cells are predominantly CCR7 negative (49). Tissue infiltrating T cells in rheumatoid synovium which are predominantly of a memory phenotype have also been shown to express high levels of CXCR3 and CCR5 (51). CCR4 marks memory T cells, but its expression appears to be even more specific; skin homing memory T cells express high levels of this receptor, whereas gut homing memory T cells express low levels. CCR4 may, therefore, direct tissue specific T cell migration (48).
Pathophysiology of asthma
Published in Louis-Philippe Boulet, Applied Respiratory Pathophysiology, 2017
Th2 cells expressing the receptor for chemokine CCR4 have been involved in the chronic allergic inflammatory process and the severity of the disease, but the mechanisms involved are also to be determined. Furthermore, with time, inflammation can lead to chronic changes such as collagen/proteoglycan deposition under the subepithelial basement membrane or smooth muscle hypertrophy. Such changes seem to be involved with the chronicity of asthma.
CCL22-based peptide vaccines induce anti-cancer immunity by modulating tumor microenvironment
Published in OncoImmunology, 2022
Inés Lecoq, Katharina L. Kopp, Marion Chapellier, Panagiotis Mantas, Evelina Martinenaite, Maria Perez-Penco, Lars Rønn Olsen, Mai-Britt Zocca, Ayako Wakatsuki Pedersen, Mads Hald Andersen
The CCL22:CCR4 axis has been shown to function as an immune checkpoint; this axis is crucial for controlling T-cell immunity, particularly in the TME context, where a CCL22 deficiency was correlated with prolonged survival.43 Consequently, different approaches to disrupt this axis are currently under investigation. A CCR4 antagonist (mogamulizumab), was recently developed to disrupt CCL22:CCR4-mediated Treg recruitment to the tumor.44 Anti-CCR4 antibodies showed promising results in vivo. These antibodies effectively inhibited chemotactic Treg recruitment to the tumor in a CCL22-dependent manner, which led to the restoration of anti-tumor immunity in a humanized murine model.17 Furthermore, those findings were reproduced in a clinical setting, and in 2018, mogamulizumab was approved by the FDA for the treatment of cutaneous T-cell lymphoma. Subsequently, a phase Ia trial tested a combination therapy of mogalinumab and nivolumab (anti-PDL1) in multicancer solid tumors and found that effector Tregs were depleted in peripheral blood and in the TME.45 In some cases, the Treg depletion induced by mogamulizumab was associated with serious autoimmune side effects.46,47 Its application in combination with checkpoint inhibitors was tested in a phase I48 and a phaseI/II49 study. However, the combination did not results in a potent antitumor efficacy in patients with advanced solid tumors therefore, leaving an open door for other approaches aiming at targeting Treg recruitment through the CCL22:CCR4 axis.
MiRNA-6089 inhibits rheumatoid arthritis fibroblast-like synoviocytes proliferation and induces apoptosis by targeting CCR4
Published in Archives of Physiology and Biochemistry, 2022
Suxian Lin, Shengnan Wang, Zhiyong Zhang, Yang Lu, Meilv Yang, Ping Chen, Lianguo Chen, Mudan Wang
Recently, several studies showed that CCR4 is highly expressed on circulating Tregs (Watanabe et al. 2019). Tregs is recruited at tumour sites in many cancers, such as breast cancer and colorectal cancer (Sasidharan Nair et al. 2020). The anti-CCR4 antibody, alone or in combination with other immune modulators may potentially be used in the treatment of a human solid cancer with high levels of CCR4 expression in tumour-infiltrating leukocytes and abnormal plasma CCR4 ligand levels (Berlato et al. 2017). Importantly, CCR4 has been widely implicated in the pathogenesis of inflammatory diseases such as asthma and atopic dermatitis due to its expression on Th2 cells (Anderson et al. 2020). In our study, we found an increased mRNA level of CCR4 in synovial tissues, and the overexpression CCR4 reversed the effects of miR-6089 on proliferation and apoptosis in RA-FLSs. Our results showed that miR-6089 performed its inhibitory role in the development of RA-FLSs, at least in part, by targeting CCR4.
New nonchemotherapy treatment options for cutaneous T-cell lymphomas
Published in Expert Review of Anticancer Therapy, 2021
Mogamulizumab is another targeted agent directed against a chemokine receptor, CCR4, which is expressed on MF/SS cells as well as on normal T-regs. This unconjugated antibody requires intact immune function for its activity as it depends on ADCC to eradicate tumor cells. A secondary mechanism may be its effects on T-regs in the tumor microenvironment. Mogamulizumab has shown significant activity in the circulating blood compartment with more modest activity in patients with skin only disease and is a treatment of choice for patients with B1 or B2 blood involvement. Skin flare has occurred but is managed with topical and systemic corticosteroids. Similarly, IPH4102 is an unconjugated antibody dependent on ADCC for efficacy which has shown activity in Sézary syndrome and is under further investigation. Because of their acceptable toxicity profiles, these antibodies may be useful for long-term maintenance or in conjunction with skin directed approaches. Studies with alternate dosing schedules of mogamulizumab are underway.