scholarly journals Electroacupuncture Attenuates Ovalbumin-Induced Allergic Asthma via Modulating CD4+CD25+Regulatory T Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Youngjoo Kwon ◽  
Sung-Hwa Sohn ◽  
Gihyun Lee ◽  
Youngeun Kim ◽  
Hyejung Lee ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Allergic Asthma ◽  
Experimental Model ◽  
Inflammatory Cell ◽  
Treated Group ◽  
Treg Depletion ◽  
Beneficial Effects ◽  
Inflammatory Processes ◽  
Histopathologic Analysis

A mouse pulmonary hypersensitivity experimental model that mimics human asthma was developed, and electroacupuncture (EA) treatment was shown to reduce allergic inflammatory processes. In addition, we also assessed whether the beneficial effects of EA on allergic asthma could be correlated with CD4+CD25+Foxp3+regulatory T cells (Treg). Cellular profiles and histopathologic analysis demonstrated that peribronchial and perivascular inflammatory cell infiltrates were significantly decreased in the EA-treated groups when compared to the OVA and anti-CD25 Ab-injected (Treg depletion) groups. Furthermore, total BAL cells were reduced in the EA groups when compared to other groups. Interestingly, the population of CD4+CD25+Foxp3+Tregs in pneumonocytes increased in EA-treated group when compared to OVA and Treg depletion groups. These results imply that EA stimulation at ST 36 may affect CD4+CD25+Foxp3+Treg in an OVA-induced experimental model and may enhance Treg function by suppressing other T cells and limiting the immune response.

scholarly journals 231 Molecular insights on safety and anti-tumor activity of a non-irAE-inducing anti-CTLA-4 monoclonal antibody ONC-392

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A246-A246
Author(s):  
Yang Liu ◽  
Yan Zhang ◽  
Xuexiang Du ◽  
Mingyue Liu ◽  
Xianfeng Fang ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Surface ◽  
Cancer Immunotherapy ◽  
Immune Tolerance ◽  
Ph Sensitive ◽  
Clinical Testing ◽  
Wild Type ◽  
Treg Depletion ◽  
Anti Tumor Activity

BackgroundAnti-CTLA-4 antibodies have brought about limited clinical benefit because severe toxicity limits dosing levels and/or duration. We used CTLA-4 knockin mice to screen for antibodies with higher anti-tumor activity but lower autoimmunity. We have revealed that the key for better safety and preclinical efficacy is preservation of CTLA-4 for immune tolerance and intratumorial Treg depletion. Our work established that, independent of blocking activities, mAbs that preserve CTLA-4 recycling maintain the physiological immune tolerance checkpoint function while allowing more efficient and selective elimination of tumor-infiltrating regulatory T cells, resulting in highest efficacy and lowest toxicity and was thus developed for clinical testing of all antibodies tested.1–6 The antibody with best safety and efficacy profile, ONC-392 was developed for clinical testing. The first-in human studies showed that ONC-392 is safe and well tolerated. Remarkably, no irAE has been reported among patients who has received repeated dosing of 3.0 mg/kg and 10.0 mg/kg of ONC-392. The molecular and cellular characterization of ONC-392 will be presented.MethodsIn vitro binding and disassociation assay were determined between pH 4.0–7.0. The intracellular traffic of both antibodies and CTLA-4 molecules were visualized by confocal microscopy. The binding to human and mouse FcgRI, IIA, IIB, and III (A), FcRn as well as mouse FcgRIV were evaluated by surface plasmon resonance (SPR). Depletion of regulatory T cells in tumor and lymphoid tissues were determined by flow cytometry.ResultsONC-392 is a pH-sensitive antibody that preserves CTLA-4 recycling. By preserving cell surface CTLA-4, Onco-392 preserves immune tolerance. Preserving CTLA-4 on tumor-infiltrating Treg contribute to more effective immunotherapy. In addition to its unique feature of pH sensitive binding, OncoC4 also have several important features in Fc. ONC-392 shown comparable binding to human FcgRI and IIIA as wild-type IgG1s. As expected from the mutations introduced, ONC-392 show about 6 fold higher affinity for FcRn than wild-type IgG1. Interestingly, ONC-392 has shown 7–10-fold reduction to FcgRIIB, which is generally considered to be a negative signaling FcR. ONC-392 binding to mouse FcgRI-IV was lower that WT IgG1.ConclusionsUnlike other clinical anti-CTLA-4 antibodies, ONC-392 preserves CTLA-4 recycling and thus Treg function in the peripheral tissues. The higher cell surface CTLA-4 allows more efficient Treg depletion in the tumor microenvironment. In addition, despite reduced binding to mouse activating Fc?RI, III/IV, ONC-392 was more effective in intratumor Treg depletion in the mice. Therefore, lacking negative signaling from Fc?RIIB may also contribute to its anti-tumor activity.Trial RegistrationNCT04140526ReferencesDu X, et al. Uncoupling therapeutic from immunotherapy-related adverse effects for safer andeffective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res 2018;28:433–447.Du X, et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018;28:416–432.Liu Y, Zheng P. How does an anti-CTLA-4 antibody promote cancer immunity? Trends Immunol 2018;39:953–956.Zhang Y, et al. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res 2019;29:609–627.Liu Y, Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci 2020;41(1):4–12.Zhang P, et al. Mechanism- and immune landscape-based ranking of therapeutic responsiveness of 22 major human cancers to next generation anti-CTLA-4 antibodies. Cancers 2020;12:284.

scholarly journals Lung Tissue Damage Associated with Allergic Asthma in BALB/c Mice Could Be Controlled with a Single Injection of Mesenchymal Stem Cells from Human Bone Marrow up to 14 d After Transplantation

2020 ◽  
Vol 29 ◽  
pp. 096368972091325 ◽  
Author(s):  
Lidiane Maria Boldrini-Leite ◽  
Pedro Vicente Michelotto ◽  
Sérgio Adriane Bezerra de Moura ◽  
Luiz Guilherme Achcar Capriglione ◽  
Fernanda Cristina Mendes Barussi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Allergic Asthma ◽  
Experimental Model ◽  
Total Protein ◽  
Inflammatory Process ◽  
Single Injection ◽  
Airway Remodeling ◽  
Treated Group ◽  
Human Bone ◽  
Human Bone Marrow

Mesenchymal stem cell (MSC) research has demonstrated the potential of these cells to modulate lung inflammatory processes and tissue repair; however, the underlying mechanisms and treatment durability remain unknown. Here, we investigated the therapeutic potential of human bone marrow-derived MSCs in the inflammatory process and pulmonary remodeling of asthmatic BALB/c mice up to 14 d after transplantation. Our study used ovalbumin to induce allergic asthma in male BALB/c mice. MSCs were injected intratracheally in the asthma groups. Bronchoalveolar lavage fluid (BALF) was collected, and cytology was performed to measure the total protein, hydrogen peroxide (H2O2), and proinflammatory (IL-5, IL-13, and IL-17A) and anti-inflammatory (IL-10) interleukin (IL) levels. The lungs were removed for the histopathological evaluation. On day zero, the eosinophil and lymphochte percentages, total protein concentrations, and IL-13 and IL-17A levels in the BALF were significantly increased in the asthma group, proving the efficacy of the experimental model of allergic asthma. On day 7, the MSC-treated group exhibited significant reductions in the eosinophil, lymphocyte, total protein, H2O2, IL-5, IL-13, and IL-17A levels in the BALF, while the IL-10 levels were significantly increased. On day 14, the total cell numbers and lymphocyte, total protein, IL-13, and IL-17A levels in the BALF in the MSC-treated group were significantly decreased. A significant decrease in airway remodeling was observed on days 7 and 14 in almost all bronchioles, which showed reduced inflammatory infiltration, collagen deposition, muscle and epithelial thickening, and mucus production. These results demonstrate that treatment with a single injection of MSCs reduces the pathophysiological events occurring in an experimental model of allergic asthma by controlling the inflammatory process up to 14 d after transplantation.

scholarly journals Kidney GATA3+ regulatory T cells play roles in the convalescence stage after antibody-mediated renal injury

2020 ◽  
Author(s):  
Ryota Sakai ◽  
Minako Ito ◽  
Kyoko Komai ◽  
Mana Iizuka-Koga ◽  
Kazuhiko Matsuo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Disease Control ◽  
Renal Injury ◽  
Disease Onset ◽  
Renal Tissue ◽  
Tissue Destruction ◽  
Treg Depletion ◽  
Pparγ Agonist

Abstract FoxP3+ regulatory T cells (Tregs) play crucial roles in peripheral immune tolerance. In addition, Tregs that reside or accumulate in nonlymphoid tissues, called tissue Tregs, exhibit tissue-specific functions and contribute to the maintenance of tissue homeostasis and repair. In an experimental mouse model of crescentic glomerulonephritis induced by an anti-glomerular basement membrane antibody, Tregs started to accumulate in the kidney on day 10 of disease onset and remained at high levels (~30–35% of CD4+ T cells) during the late stage (days 21–90), which correlated with stable disease control. Treg depletion on day 21 resulted in the relapse of renal dysfunction and an increase in Th1 cells, suggesting that Tregs are essential for disease control during the convalescence stage. The Tregs that accumulated in the kidney showed tissue Treg phenotypes, including high expression of GATA3, ST2 (the IL33 receptor subunit), amphiregulin (Areg), and PPARγ. Although T-bet+ Tregs and RORγt+ Tregs were observed in the kidney, GATA3+ Tregs were predominant during the convalescence stage, and a PPARγ agonist enhanced the accumulation of GATA3+ Tregs in the kidney. To understand the function of specific genes in kidney Tregs, we developed a novel T cell transfer system to T cell-deficient mice. This experiment demonstrates that ST2, Areg, and CCR4 in Tregs play important roles in the accumulation of GATA3+ Tregs in the kidney and in the amelioration of renal injury. Our data suggest that GATA3 is important for the recruitment of Tregs into the kidney, which is necessary for convalescence after renal tissue destruction.

Regulatory T cells and allergic asthma

2001 ◽  
Vol 3 (11) ◽  
pp. 899-904 ◽  
Author(s):  
Hans Yssel ◽  
Sandrine Lécart ◽  
Jérôme Pène
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Allergic Asthma
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