Cutting Edge: Dexamethasone Potentiates the Responses of Both Regulatory T Cells and B-1 Cells to Antigen Immunization in the ApoE−/− Mouse Model of Atherosclerosis

Chen, Aoshuang; Geng, Yajun; Ke, Hanzhong; Constant, Laura; Yan, Zhaoqi; Pan, Yue; Lee, Patricia; Tan, Isaiah; Williams, Kurt; George, Samantha E.; Munirathinam, Gnanasekar; Reardon, Catherine A.; Getz, Godfrey S.; Wang, Bin; Zheng, Guoxing

doi:10.4049/jimmunol.1302469

Cited by 13 publications

(16 citation statements)

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“…The IgM response was specific to the immunizing Ag as the same mice showed no increase in IgM against HP1 (Fig. 4B), an HSP60-derived dual epitope 29 , which was not used in the immunization. Moreover, these mice showed preferential increases in HMW4-reactive B-1 (over B-2) cells (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…To that end, we first searched for MHC II-restricted T cell epitopes in HGMB1, using a combination of bioinformatics 26–28 and T cell proliferation assays, as we described 29 . We identified one epitope named HMW4 (HMGB1 98-112, PSAFFLFCSEYRPKI), which overlaps partially with two dendritic cell activating peptides Hp91 (HMGB1 89-107 ) and Hp106 (HMGB1 105-122 ) and a TLR4-binding peptide C106 (HMGB1 89-108 ) reported previously 30, 31 .…”

Section: Resultsmentioning

confidence: 99%

“…While T and B cells are classically considered to recognize different parts of an Ag, we showed recently 29 that the HSP60-derived epitope HP1 can be recognized by both T and B cells (we termed such epitopes as “dual epitopes”). To determine whether HMW4 is also a “dual epitope,” we tested its ability to specifically block the binding of the anti-HMGB1 Ig and IgM to plate-bound HMGB1 in ELISA.…”

Section: Resultsmentioning

confidence: 99%

“…The other strategy was immunizing the mice with HMW4 in the presence of the immunosuppressant dexamethasone (Dex) serving as a tolerogenic adjuvant, a strategy we developed and termed as “suppressed immunization” (“SI”) 29, 34 , which would diminish the anti-HMW4 responses in an Ag-specific way 29, 34 . In contrast to the CI-treated mice, SI-treated mice showed an increase in anti-HMW4 IgM, but not in anti-HMW4 IgG (Fig.…”

Section: Resultsmentioning

confidence: 99%

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The western-type diet induces anti-HMGB1 autoimmunity in Apoe −/− mice

Pan

Yan

et al. 2016

Atherosclerosis

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Background and aims-Anti-HMGB1 autoimmunity plays a role in systemic lupus erythematosus (SLE). Because SLE increases atherosclerosis, we asked whether the same autoimmunity might play a role in atherogenesis.Methods-We looked for the induction of HMGB1-specific B and T cell responses by a westerntype diet (WTD) in the Apoe −/− mouse model of atherosclerosis. We also determined whether modifying the responses modulates atherosclerosis.Results-In the plasma of male Apoe −/− mice fed WTD, the level of anti-HMGB1 antibodies (Abs) was detected at ~50 μg/ml, which was ~6 times higher than that in either Apoe −/− mice fed a normal chow or Apoe +/+ mice fed WTD (p ≤ 0.0005). The Abs were directed largely toward a novel, dominant epitope of HMGB1 named HMW4; accordingly, compared with chow-fed mice, WTD-fed Apoe −/− mice had more activated HMW4-reactive B and T cells (p = 0.005 and p = 0.01, respectively). Compared with mock-immunized mice, Apoe −/− mice immunized with HMW4 along with an immunogenic adjuvant showed proportional increases in anti-HMW4 IgG and IgM Abs, HMW4-reactive B-1 and B-2 cells, and HMW4-reactive Treg and Teff cells, which was associated with ~30% increase in aortic arch lesions (p ≤ 0.01) by two methods. In contrast, Apoe −/− mice immunized with HMW4 using a tolerogenic adjuvant showed preferential increases in anti-HMW4 IgM (over IgG) Abs, in HMW4-reactive B-1 (over B-2) cells, and in HMW4-specific Treg (over Teff) cells, which was associated with ~40% decrease in aortic arch lesions (p ≤ 0.03).

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

The western-type diet induces anti-HMGB1 autoimmunity in Apoe −/− mice

Pan

Yan

et al. 2016

Atherosclerosis

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“…Whereas these pathways can impact a wide range of cellular functions, the role of dexamethasone in atherosclerosis is unclear even though it is predominantly described as anti-inflammatory 136,137 . In addition, PPARG activation and the PPARG agonist rosiglitazone have been shown to be atheroprotective [138][139][140][141][142][143] .…”

Section: Smc Specificmentioning

confidence: 99%

"Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions"

Durgin

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Atherosclerotic plaque rupture or erosion with subsequent embolic events is a major cause of sudden death from myocardial infarction or stroke [1][2][3][4][5][6] . Plaque stability is classically characterized by a fibrous cap rich in ACTA2 + presumed smooth muscle cells (SMC) and collagen with a paucity of CD68 + presumed macrophages [7][8][9][10] . The dogma in the field is that SMC produce collagens that in turn provide tensile strength and stability to atherosclerotic plaques. This has largely been supported by evidence that SMC can produce collagens in vitro [11][12][13] . However, there is no direct evidence in vivo that SMC produce collagens as: 1) collagens are secreted molecules making it challenging to identify their cell source in vivo; and 2) recent lineage tracing studies by our lab [14][15][16] and others [17][18][19][20] have shown that marker genes used to identify cell type within lesions are nonspecific. For example, SMC marker genes (e.g. ACTA2) can be expressed by myeloid-derived cells and endothelial cells and SMC can express marker genes of macrophages (e.g. CD68 and LGALS3) [14][15][16][17][18][19][20] . Therefore major unanswered questions remained in the field as to whether SMC are the primary source of collagens in vivo and if SMC produced collagens in turn impact plaque development.We are interested in type XV collagen alpha 1 (COL15A1) as we identified Combined, these results provide the first direct evidence that a SMC-derived collagen, COL15A1, is critical in lesion development. IV DedicationI dedicate this to my grandfather, Arthur Labuz. You were the heart of my family and a testament to hard work, perseverance, and inner strength. I hope I have inherited an ounce of these qualities from you and have made you proud.V Acknowledgements

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Targeted IL‐4 therapy synergizes with dexamethasone to induce a state of tolerance by promoting Treg cells and macrophages in mice with arthritis

et al. 2016

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F8-IL-4 is a recently developed immunocytokine that delivers IL-4 to sites of inflammationby targeting the neovasculature. We previously reported that F8-IL-4, in combination with dexamethasone (DXM), provides a durable therapy in mice with collagen-induced arthritis (CIA). Therefore, the objective of this study was to identify the mechanism by which IL-4 and DXM combination therapy provides long-lasting disease remission. F8-IL-4 alone attenuated inflammation in CIA and this was associated with increased T H 2 and decreased T H 17 cell numbers in the joints. Similarly, DXM alone had an antiinflammatory effect associated with lower T H 17 cell numbers. In both cases, these therapeutic benefits were reversed once treatment was stopped. On the other hand, combination therapy with F8-IL-4 plus DXM led to a synergistic increase in the percentage of regulatory T (Treg) cells and antiinflammatory macrophages in the arthritic joint and spleen as well as IL-10 levels in serum and spleen. The net result of this was a more pronounced attenuation of inflammation and, more importantly, protection from arthritis relapse post therapy retraction. In conclusion, F8-IL-4 plus DXM is a durable treatment for arthritis that acts by promoting Treg cells in a synergistic manner, and by producing a sustained increase in antiinflammatory macrophages.Keywords: Arthritis r Dexamethasone r IL-4 r Macrophages r Tolerance Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionRheumatoid arthritis (RA) is a chronic autoimmune disease affecting joints, in which the delicate balance between pro-and antiinflammatory cells and their cytokines is perturbed. This is illustrated by the fact that targeting proinflammatory cytokines (TNF-α, IL-1β, and IL-6) in RA patients and in mouse models of Correspondence: Dr. Joanna Z. Kawalkowska e-mail: joanna.kawalkowska@kennedy.ox.ac.uk RA, as well as boosting levels of antiinflammatory cytokines (IL-10 and IL-4) leads to a reduction in disease severity [1][2][3]. IL-4 is an antiinflammatory cytokine, which has been under investigation for the treatment of autoimmune arthritis since the late 1990s. IL-4 downregulates the production of proinflammatory cytokines such as IL-1, TNF-α, and IL-6, which have been implicated in the pathogenesis of RA [4,5]. The ex vivo delivery of IL-4 has been shown to be effective in attenuating inflammation in mouse models of arthritis [2,6,7]. Furthermore, IL-4 has been identified in mice with arthritis during disease remission [8], which suggests that this cytokine also plays a role in the resolution of disease. Sustained treatment-free remission in patients with autoimmune diseases has long been the unattainable holy grail of autoimmune disease treatment. Tolerizing strategies with dexamethasone (DXM) and immunogenic peptides have shown great promise in mouse models of diabetes [22]. We showed previously that F8-IL-4 attenuates collagen-induced arthritis (CIA) in DBA/1 mice, a preclinical model for RA [23]. ...

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Cutting Edge: Dexamethasone Potentiates the Responses of Both Regulatory T Cells and B-1 Cells to Antigen Immunization in the ApoE−/− Mouse Model of Atherosclerosis

Cited by 13 publications

References 20 publications

The western-type diet induces anti-HMGB1 autoimmunity in Apoe −/− mice

The western-type diet induces anti-HMGB1 autoimmunity in Apoe −/− mice

"Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions"

Targeted IL‐4 therapy synergizes with dexamethasone to induce a state of tolerance by promoting Treg cells and macrophages in mice with arthritis

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