P6305Activation of invariant natural killer T cells ameliorates doxorubicin-induced cardiomyopathy

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Sada ◽  
S Matsushima ◽  
S Ikeda ◽  
K Okabe ◽  
A Ishikita ◽  
...  
Keyword(s):  
Natural Killer ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Active Form ◽  
Left Ventricular ◽  
Specific Marker ◽  
Inkt Cells ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Background Invariant natural killer T (iNKT) cells orchestrate tissue inflammation via regulating various cytokine productions, especially strongly upregulating interferon (IFN)-γ. Activation of iNKT cells have been previously reported to exert protective effects against post-infarcted cardiac remodeling and cardiac ischemia/reperfusion injury. However, the role of iNKT cells has not been determined in doxorubicin (DOX)-induced cardiomyopathy. Purpose The purpose of this study was to examine whether the activation of iNKT cells by α-galactosylceramide (αGC), which specifically activates iNKT cells, could affect DOX-induced cardiomyopathy, and if so, to elucidate its downstream target. Methods C57BL/6J mice were received the intraperitoneal injection of either αGC (0.1μg/g, n=11) or vehicle (n=13). After 1 week, these mice were treated with a low dose of DOX (18mg/kg via intravenous 3 injections over 1 week), and were followed during 14 days. Results DOX mice (DOX+vehicle) showed left ventricular (LV) dysfunction and dilatation, which were significantly ameliorated in DOX mice receiving αGC (DOX+αGC) (LV fractional shortening: 27.4±4.31 vs. 31.5±4.62%, p<0.05, LV end-diastolic diameter: 3.70±0.16 vs. 3.32±0.23mm, p<0.05), with no significant changes in arterial pressure, body weight, and food consumption, 14 days after DOX injection. DOX+vehicle demonstrated a significant decrease in myocardial gene expression of Vα14Jα18, a specific marker of iNKT cells, and IFN-γ compared with control mice. Vα14Jα18 expression levels were higher in DOX+αGC than DOX+vehicle by 9.2 folds (p<0.05). Consistent with this change, IFN-γ was higher in DOX+αGC than DOX+vehicle by 4.4 folds (p<0.05), whereas interleukin (IL)-1, IL-4, IL-6, IL-10, IL-17, IL-23, and tumor necrosis factor (TNF)-α were not altered in both groups. Phosphorylation of Akt, its active form, in the heart was significantly increased in DOX+αGC compared with DOX+vehicle by 1.8 folds (p<0.05). Conclusions Activation of iNKT cells by αGC play a protective role against DOX-induced cardiac dysfunction, which was associated with enhancing expression of IFN-γ and activating Akt. Therapies designed to activate iNKT cells might be beneficial to protect the heart from DOX injury.

Abstract 11982: Circulating Invariant Natural Killer T Cells are Decreased in Patients With Chronic Heart Failure

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Akimichi Saito ◽  
Naoki Ishimori ◽  
Mikito Nishikawa ◽  
Shintaro Kinugawa ◽  
Hiroyuki Tsutsui
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Natural Killer ◽  
Left Ventricular ◽  
Idiopathic Dilated Cardiomyopathy ◽  
Inkt Cells ◽  
Lv Ejection Fraction ◽  
Invariant Natural Killer ◽  
Natural Killer T

Objective: Inflammatory mediators play a crucial role in the development of chronic heart failure (HF). Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes, which recognize glycolipid antigens and secrete a large amount of T helper (Th) 1/Th2 cytokines on activation, function as immunomodulatory cells in the various pathological processes. We have demonstrated that iNKT cells have a protective role against the development of left ventricular (LV) remodeling and failure after myocardial infarction in mice. However, it remains unclear whether iNKT cells are involved in the development of HF in humans. Methods and Results: Nine HF patients (NYHA II or III, LV ejection fraction 26.3±3.0%) and 8 healthy controls were studied. The mean age and male gender were comparable between HF and controls (51.2±5.1 vs. 45.1±4.5 years and 77.8 vs. 75.0%). The causes of HF were idiopathic dilated cardiomyopathy in 3, ischemic in 2, and others in 4 patients. Plasma BNP was significantly higher in HF than in controls (739.4±207.2 vs. 19.8±6.5 pg/mL, P <0.01). The number of circulating iNKT cells, identified by the positive-staining of Vα24-Jα18 T Cell Receptor by flow-cytometric analysis, was significantly lower in HF (747±85 vs. 1058±271 counts/mL, P <0.01). Its ratio to the total lymphocyte was also significantly lower (0.111±0.004 vs. 0.146±0.035%, P <0.01). Plasma interleukin-6 and high-sensitivity CRP were significantly higher in HF (3.99±0.86 vs. 0.78±0.14 pg/mL and 0.28±0.10 vs. 0.06±0.02 mg/dL, respectively, both P <0.01). LV ejection fraction ( r =0.72, P <0.05) and plasma log BNP ( r =-0.70, P <0.05) were significantly correlated to the ratio of iNKT cells among HF patients. Conclusions: Circulating iNKT cells were decreased in HF patients, suggesting that they have a potential role in the development of human HF.

scholarly journals Vitamin D, invariant natural killer T-cells and experimental autoimmune disease

2011 ◽  
Vol 71 (1) ◽  
pp. 62-66 ◽  
Author(s):  
Margherita T. Cantorna ◽  
Jun Zhao ◽  
Linlin Yang
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Immune System ◽  
Vitamin D Deficiency ◽  
Natural Killer ◽  
Active Form ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Experimental Autoimmune ◽  
Natural Killer T

Vitamin D is an important regulator of the immune system in general and multiple sclerosis in particular. Experimentally (i), invariant natural killer T (iNKT) cells have been shown to be important suppressors of autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE; an animal model of multiple sclerosis). Conversely, in experimental allergic asthma iNKT cells are required for disease induction and are therefore pathogenic. The active form of vitamin D (calcitriol) suppresses EAE. The development of EAE symptoms is accelerated in vitamin D deficiency. Interestingly experimental asthma is less severe in vitamin D deficiency although there is no effect of calcitriol on disease severity. The data suggest that an important target of vitamin D in EAE and asthma are the iNKT cells. Vitamin D and/or vitamin D receptor deficiency results in the impaired development of iNKT cells. Vitamin D is critical very early during development of the immune system. Low levels of vitamin D in utero resulted in significantly reduced numbers of iNKT cells that failed to recover when calcitriol was used to supplement neonatal or adult mice. The data suggest that one of the consequences of early vitamin D deficiency is a reduction in the numbers of iNKT cells that develop. The iNKT cells are required for the beneficial effects of calcitriol in EAE. The important role of vitamin D on iNKT cells could impact the development of human immune-mediated diseases including multiple sclerosis and asthma.

Relevance of sexual dimorphism to regulatory T cells: estradiol promotes IFN-γ production by invariant natural killer T cells

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2415-2420 ◽  
Author(s):  
Pierre Gourdy ◽  
Luiza M. Araujo ◽  
Ren Zhu ◽  
Barbara Garmy-Susini ◽  
Séverine Diem ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Interleukin 4 ◽  
Response To Treatment ◽  
Inkt Cells ◽  
Gender Dimorphism ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Mechanisms accounting for gender dimorphism during immune responses are still poorly understood. Since invariant natural killer T (iNKT) cells exert important regulatory functions through their capacity to produce both T helper 1 (Th1) and Th2 cytokines, we addressed the question of whether these activities could be modulated by sexual hormones. We found that in vivo challenge with the specific ligand of iNKT cells, α-galactosylceramide (α-GalCer), induced significantly higher concentrations of interferon γ (IFN-γ) in the serum of female than in that of male mice, while interleukin 4 (IL-4) production was not modified. In support of a crucial role of ovarian hormones in this phenomenon, a significant decrease of serum IFN-γ concentrations occurred in ovariectomized females, in response to treatment with α-GalCer, while orchidectomy affected neither IFN-γ nor IL-4 serum concentrations in males. The implication of estrogens in this selective enhancement of IFN-γ production by iNKT cells was demonstrated by (1) the increased α-GalCer–induced IFN-γ synthesis by iNKT cells upon both in vitro and in vivo exposure to estradiol and (2) the abolition of the sex-linked difference in α-GalCer–induced IFN-γ release in estrogen receptor α-deficient mice. These results provide the first evidence that estrogens influence iNKT cells leading to this gender dimorphism in their cytokine production profile.

scholarly journals Combination of NKT14m and Low Dose IL-12 Promotes Invariant Natural Killer T Cell IFN-γ Production and Tumor Control

2020 ◽  
Vol 21 (14) ◽  
pp. 5085
Author(s):  
Peng Guan ◽  
Robert Schaub ◽  
Kim E. Nichols ◽  
Rupali Das
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Low Dose ◽  
Inkt Cell ◽  
Tumor Control ◽  
Inkt Cells ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d+ tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions.

P1623Activation of invariant natural killer T cells by alpha-galactosylceramide ameliorates doxorubicin-induced cardiotoxicity in mice

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y Obata ◽  
N Ishimori ◽  
A Saito ◽  
S Kinugawa ◽  
I Nakano ◽  
...  
Keyword(s):  
Body Weight ◽  
Natural Killer ◽  
Intraperitoneal Injection ◽  
Antineoplastic Agent ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Inkt Cells ◽  
Anti Inflammatory ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Objective Doxorubicin (DOX) is an effective antineoplastic agent commonly used to treat many types of cancer but its clinical use is limited because of cardiotoxicity, which might proceed to irreversible cardiac dysfunction in a dose-dependent manner. The precise mechanism of DOX-induced cardiotoxicity is still not fully elucidated but it has been reported that cardiac inflammation is involved in the cardiotoxicity. Invariant natural killer T (iNKT) cells, a unique subset of T lymphocytes that recognize glycolipid antigens and secrete a large amount of Th1 and Th2 cytokines on activation, have been shown to play crucial roles in the regulation of immune responses. However, it remains unclear whether iNKT cells are involved in DOX-induced cardiotoxicity. Methods and results Male C57BL/6J mice were administered DOX (20mg/kg body weight single intraperitoneal injection; n=28) or vehicle (Vehicle; n=6). DOX-administered mice were further divided into 2 groups; α-galactosylceramide (αGC, 0.1μg/g body weight twice intraperitoneal injection; DOX-αGC; n=14), which specifically activates iNKT cells, or phosphate-buffered saline alone (PBS; DOX-PBS; n=14) 4 days before and 3 days after DOX administration. Survival rate at 14 days after DOX/Vehicle administration was significantly lower in DOX-PBS than in Vehicle (71% vs. 100%, P<0.05), and this decrease was completely attenuated in DOX-αGC (100%, P<0.05 vs. DOX-PBS). Echocardiography at 14 days after DOX/Vehicle administration revealed that left ventricular (LV) fractional shortening was significantly reduced in DOX-PBS compared to Vehicle (49.3±0.8% vs. 59.2±1.7%, P<0.05), and this decrease was completely attenuated in DOX-αGC (57.7±1.3%, P<0.05 vs. DOX-PBS) without affecting LV end-diastolic diameter. Picro-sirius red staining revealed that the ratio of fibrosis area to the cardiac tissue was markedly higher in DOX-PBS than in Vehicle (4.3±0.5% vs. 2.2±0.1%, P<0.05), and this increase was completely attenuated in DOX-αGC (2.8±0.1%, P<0.05 vs. DOX-PBS). Real-time PCR analysis revealed that mRNA expression of anti-inflammatory Th2 cytokine IL-4 was enhanced by 7.9-folds in DOX-αGC compared to DOX-PBS, though the difference did not reach statistically significance (P=0.09). Conclusions Activation of iNKT cells by αGC ameliorates DOX-induced cardiotoxicity in mice via up-regulation of anti-inflammatory IL-4 and reducing cardiac fibrosis. iNKT cell activation may be a novel therapeutic strategy against DOX-induced cardiotoxicity. Acknowledgement/Funding Japan Agency for Medical Research and Development (18lm0203001j0002) and JSPS KAKENHI (18K15834)

scholarly journals Natural Killer T Cell–derived IL-17 Mediates Lung Ischemia–Reperfusion Injury

2011 ◽  
Vol 183 (11) ◽  
pp. 1539-1549 ◽  
Author(s):  
Ashish K. Sharma ◽  
Damien J. LaPar ◽  
Yunge Zhao ◽  
Li Li ◽  
Christine L. Lau ◽  
...  
Keyword(s):  
T Cell ◽  
Reperfusion Injury ◽  
Natural Killer ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Natural Killer T Cell ◽  
Killer T Cell ◽  
Natural Killer T

Evaluating The Frequency Of Invariant Natural Killer T (iNKT) Cells In Nasal Polyps

2008 ◽  
Vol 121 (2) ◽  
pp. S263-S263
Author(s):  
M FEREIDOUNI ◽  
R FARIDHOSSEINI ◽  
M MAHMOUDI ◽  
M BAKHSHAEI ◽  
L ALHARTHI
Keyword(s):  
Natural Killer ◽  
Nasal Polyps ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

scholarly journals Invariant natural killer T cells are functionally impaired in patients with systemic sclerosis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Ann-Christin Pecher ◽  
Felix Kettemann ◽  
Elisa Asteriti ◽  
Hannes Schmid ◽  
Silke Duerr-Stoerzer ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Natural Killer ◽  
Immunosuppressive Drugs ◽  
Healthy Controls ◽  
Inkt Cells ◽  
Novel Approach ◽  
Functionally Impaired ◽  
Transfer Strategies ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Background Systemic sclerosis (SSc) is a potentially fatal autoimmune disease that leads to extensive fibrosis of the skin and internal organs. Invariant natural killer T (iNKT) cells are potent immunoregulatory T lymphocytes being able to orchestrate dysregulated immune responses. The purpose of this study was to evaluate numbers and function of iNKT cells in patients with SSc and to analyze their correlation with disease parameters. Methods Human iNKT cells from 88 patients with SSc and 33 healthy controls were analyzed by flow cytometry. Their proliferative capacity and cytokine production were investigated following activation with CD1d ligand α-galactosylceramide (α-GalCer). Results We observed an absolute and relative decrease of iNKT cells in patients with SSc compared with healthy controls. Interestingly, the subtype of SSc, disease severity, or treatment with immunosuppressive drugs did not affect iNKT cell numbers. However, T helper (Th) cell immune polarization was biased towards a Th17 immunophenotype in SSc patients. Moreover, iNKT cells from patients with SSc showed a significantly decreased expansion capacity upon stimulation with α-GalCer. Conclusion iNKT cells are deficient and functionally impaired in patients with SSc. Therefore, adoptive transfer strategies using culture-expanded iNKT cells could be a novel approach to treat SSc patients.

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