The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis

Chen, Jiajie; Xie, Lin; Toyama, Sayaka; Hünig, Thomas; Takahara, Shiro; Li, Xiaokang; Liu, Zhong

doi:10.1016/j.intimp.2010.11.034

Cited by 20 publications

(24 citation statements)

References 49 publications

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“…Perhaps counterintuitively, superagonistic anti-CD28 antibodies that potently stimulate T cell activation (55) have been observed to restore immune tolerance in several autoimmune and transplantation models (56)(57)(58). This presents something of a conundrum as to whether enhancing Treg (superagonists) or blocking effector cells (antagonists) is the better strategy.…”

Section: Anti-cd28 Specific Antibodiesmentioning

confidence: 99%

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Gardner

Jeffery

Sansom

2014

American Journal of Transplantation

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T cell activation is a key event in the adaptive immune system and vital in the generation of protective cellular and humoral immunity. Activation is required to generate CD4 effector T cell responses and provide help for B cell and cytotoxic T cell responses. While defective T responses to foreign antigen result in infectious pathology, over-reactive T cell responses against self-antigens result in autoimmunity and, in a transplantation setting, tissue rejection. Understanding how T cell activation is normally regulated is critical to therapeutic intervention and the CD28/CTLA-4 (CD152) pathway represents the initial activation checkpoint in molecular terms. In particular, while the CTLA-4 pathway is well established as an essential regulator of self-reactivity, its mechanism of action is still uncertain. Such mechanistic issues are important given its central position in T cell activation and the increasing number of therapeutic modalities aimed at manipulating the CD28/CTLA-4 pathway. Here, we provide an updated view of CTLA-4 biology, reviewing the established features of the system and highlighting its interplay with CD28. We then discuss how recent progress in our understanding of this pathway affects our interpretations following intervention. A Functional Overview of the CD28/CTLA-4 Pathway CD28 is expressed on the surface of the majority of na€ ıve CD4 and CD8 T cells and is the major costimulatory molecule in initial T cell activation. Together with engagement of the T cell receptor CD28 ligation results in the augmentation of many aspects of T cell-mediated immunity (1-3). Consequently, mice deficient in CD28 show an array of immune defects including impaired T cell activation, a lack of T cell help for B cells and poor memory T cell responses, all highlighting the importance of CD28 costimulation in the generation of effective T cell responses and immune memory.The immune stimulatory features of the CD28 pathway are triggered by engagement of two well-described ligands found on antigen-presenting cells (4). The two ligands CD80 (B7/BB1 or B7-1) and CD86 (B7-2) were, until recently, thought to be the sole ligands for CD28 and CTLA-4; however, there are recent reports that human (but not mouse) CD28 and CTLA-4, can also bind to the ICOS ligand (5). In addition, the PD-1 ligand, PD-L1 can also interact with CD80 (6). The significance of these novel interactions is still emerging and will not be discussed further here. Importantly, the expression of CD80 and CD86 is up-regulated in response to inflammatory stimuli including Toll-like receptor stimulation. As such, up-regulation of ligands is seen as a key link between innate ''danger'' signals and the triggering of an effective adaptive immune response (7). Despite structural and affinity differences (8) which would suggest functional differences, to date, the current view is that CD80 and CD86 have largely redundant or overlapping functions as represented in Figure 1 (9,10).In addition to binding to CD28, both CD80 and CD86 also bind to the inhibitory p...

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Section: Anti-cd28 Specific Antibodiesmentioning

confidence: 99%

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Gardner

Jeffery

Sansom

2014

American Journal of Transplantation

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“…As described previously (Xie et al 2009;Chen et al 2011), the total tissue RNA was extracted from frozen spinal cords using Sepasol-RNA I Super (Nacalai Tesque, Kyoto, Japan) according to the manufacturer's protocol. The quality of total RNA was checked by the ratio of 260/280 nm.…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

[11C]DAC-PET for Noninvasively Monitoring Neuroinflammation and Immunosuppressive Therapy Efficacy in Rat Experimental Autoimmune Encephalomyelitis Model

Xie

Yamasaki

Ichimaru

et al. 2011

J Neuroimmune Pharmacol

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Neuroimaging measures have potential for monitoring neuroinflammation to guide treatment before the occurrence of significant functional impairment or irreversible neuronal damage in multiple sclerosis (MS). N-Benzyl-N-methyl-2-(7-[(11)C]methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([(11)C]DAC), a new developed positron emission tomography (PET) probe for translocator protein 18 kDa (TSPO), has been adopted to evaluate the neuroinflammation and treatment effects of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. [(11)C]DAC-PET enabled visualization of neuroinflammation lesion of EAE by tracing TSPO expression in the spinal cords; the maximal uptake value reached in day 11 and 20 EAE rats with profound inflammatory cell infiltration compared with control, day 0 and 60 EAE rats. Biodistribution studies and in vitro autoradiography confirmed these in vivo imaging results. Doubling immunohistochemical studies showed the infiltration and expansion of CD4+ T cells and CD11b+ microglia; CD68+ macrophages were responsible for the increased TSPO levels visualized by [(11)C]DAC-PET. Furthermore, mRNA level analysis of the cytokines by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) revealed that TSPO+/CD4 T cells, TSPO+ microglia and TSPO+ macrophages in EAE spinal cords were activated and secreted multiple proinflammation cytokines to mediate inflammation lesions of EAE. EAE rats treated with an immunosuppressive agent: 2-amino-2-[2-(4-octylphenyl)ethyl] propane-1,3-diolhydrochloride (FTY720), which exhibited an absence of inflammatory cell infiltrates, displaying a faint radioactive signal compared with the high accumulation of untreated EAE rats. These results indicated that [(11)C] DAC-PET imaging is a sensitive tool for noninvasively monitoring the neuroinflammation response and evaluating therapeutic interventions in EAE.

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“…We hypothesized that, similarly to CD4 Treg frequencies in the MLNs and spleens of mice with colitis were lower than those in mice without colitis [13] . The target organs and mouse species assessed, as well as the concentrations of DSS, evaluation timing and evaluation methodology used may explain the differences in these results.…”

Section: Foxp3mentioning

confidence: 99%

“…This induced colitis is similar in appearance to human UC both clinically and histologically [10,11] . Several reports have evaluated Treg dynamics during active DSS colitis tolerance [12,13] ; however, few reports have assessed Breg dynamics during active DSS colitis.…”

Section: Introductionmentioning

confidence: 99%

Oral tolerance is inducible during active dextran sulfate sodium-induced colitis

Ino

Kohda

Takeshima

et al. 2016

WJGPT

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AIM:To investigate whether oral tolerance is inducible during the active phase of dextran sulfate sodium (DSS)-induced colitis. METHODS:Colitis was induced in 6-to 8-wk-old female BALB/c mice by the administration of 2% DSS. To induce oral tolerance, mice that received water with DSS [DSS (+)] and mice that received autoclaved water [DSS (-) Hiroshi Takahashi, Division of Gastroenterology, Department of Internal Medicine, Showa University, Yokohama 227-8501, JapanAuthor contributions: Ino S, Kohda C and Takeshima K performed the majority of experiments and analyzed the data; Norose T, Yamochi T and Takimoto M contributed pathological analysis; Kohda C, Ishikawa H, Takahashi H and Tanaka K designed and coordinated the research; Ino S and Kohda C wrote the paper.Institutional review board statement: All procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee of Showa University (Permit Number: 04127) and complied with the Guide for the Care and Use of Laboratory Animals (7 th and 8 th edition, ILAR-NRC). In our facility, the Animal Care and Use Committee of Showa University also functions as an Institutional Review Board for animal experiments.Institutional animal care and use committee statement: All procedures involving experimental animals were approved by the Institutional Animal Care and Use Committee of Showa University (Permit Number: 04127) and complied with the Guide for the Care and Use of Laboratory Animals (7 th and 8 th edition, ILAR-NRC). Conflict-of-interest statement:To the best of our knowledge, no conflict of interest exists.Data sharing statement: A technical appendix, statistical code, and dataset are available from the corresponding author at kohda@med.showa-u.ac.jp. All participants provided informed consent for data sharing. ORIGINAL ARTICLE Foxp3+ cell and B10 cell frequencies were evaluated using flow cytometry. Cytokine mRNA expression profiles were evaluated by reverse transcription real-time polymerase chain reaction. RESULTS:Regardless of the presence of DSS colitis, OVA-specific immunoglobulin E concentrations were significantly reduced in mice that were i.g. administered OVA compared to mice that were i.g. administered PBS[DSS (+): 4.4 (4.2-9.5) ng/mL vs 83.9 (66.1-123.2) ng/mL, P < 0.01; DSS (-): 27.7 (0.1-54.5) ng/mL vs 116.5 (80.6-213.6) ng/mL, P < 0.01]. These results demonstrated that oral tolerance was induced in both the presence and absence of colitis. In the spleen and mesenteric lymph nodes (MLN), the frequencies of CD4 + CD25 + Foxp3 + cells and B10 cells, both of which are associated with oral tolerance, did not significantly change. In the spleen, interferon-γ mRNA expression significantly decreased in mice with colitis [DSS (+): 0.42 (0.31-0.53) vs DSS (-): 1.00 (0.84-1.39), P < 0.01]. The expression levels of other cytokines did not significantly change. CONCLUSION:Oral tolerance is inducible during active DSS colitis. The stability of regulatory cell populations in the spleen and MLN in colitis might correla...

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The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis

Cited by 20 publications

References 49 publications

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

[11C]DAC-PET for Noninvasively Monitoring Neuroinflammation and Immunosuppressive Therapy Efficacy in Rat Experimental Autoimmune Encephalomyelitis Model

Oral tolerance is inducible during active dextran sulfate sodium-induced colitis

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