scholarly journals P03.13 Age-induced changes in anti-tumor immunity alter the tumor immune infiltrate and reduce response to immune-oncology treatments

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A27.2-A27
Author(s):  
S Sitnikova ◽  
M Morrow ◽  
V Valge-Archer ◽  
RW Wilkinson ◽  
MJ Robinson ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Expression Profiles ◽  
Receptor Expression ◽  
Altered Expression ◽  
Aged Mice ◽  
Oncology Research ◽  
Age Related ◽  
Part Time ◽  
Young Mice

BackgroundImmuno-Oncology research relies heavily on murine syngeneic tumor models. However, whilst the median age for a cancer diagnosis is 65 years or older, for practical purposes the majority of preclinical studies are conducted in young mice, despite the fact that ageing has been shown to have a significant impact on the immune response.Materials and MethodsUsing aged mice bearing CT26 tumors, we analysed how aging impacts the immune composition of the tumor, spleen and tumor-draining lymph nodes by flow cytometry.ResultsWe found many age-related changes between aged (60–72 weeks old) and young (6–8 weeks old) mice, such as a reduction in the naïve T cell population and a decreased CD8/Treg ratio in aged animals. Profiling of co-inhibitory and co-stimulatory receptor expression levels on immune cells in aged versus young mice also identified altered expression profiles in both the periphery and tumor. We hypothesised that these differences may contribute to impaired anti-cancer immune responses in aged mice. To investigate this, we compared the anti-tumor efficacy of immune checkpoint blockade (PD-L1 and CTLA-4) and T-cell costimulation (OX-40) in aged versus young mice. Our data demonstrate that aged mice retained their capacity to generate effective anti-tumor immune responses, albeit often attenuated when compared to the responses observed in young mice.ConclusionsThese differences highlight the potential importance of age-related immunological changes in assessing and refining the translational insights gained from preclinical mouse models.Disclosure InformationS. Sitnikova: A. Employment (full or part-time); Significant; AstraZeneca. M. Morrow: A. Employment (full or part-time); Significant; AstraZeneca. V. Valge-Archer: A. Employment (full or part-time); Significant; AstraZeneca. R.W. Wilkinson: A. Employment (full or part-time); Significant; AstraZeneca. M.J. Robinson: A. Employment (full or part-time); Significant; AstraZeneca. S.J. Dovedi: A. Employment (full or part-time); Significant; AstraZeneca.

scholarly journals SARS-CoV-2 rapidly adapts in aged BALB/c mice and induces typical pneumonia

2021 ◽  
Author(s):  
Yufei Zhang ◽  
Kun Huang ◽  
Ting Wang ◽  
Fei Deng ◽  
Wenxiao Gong ◽  
...  
Keyword(s):  
Immune Responses ◽  
Antiviral Agents ◽  
Clinical Manifestations ◽  
Antibody Responses ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Aged Mice ◽  
Age Related ◽  
Human Infections ◽  
Young Mice

Age is a risk factor for coronavirus disease 2019 (COVID-19) associated morbidity and mortality in humans; hence, in this study, we compared the course of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) infection in young and aged BALB/c mice. We found that SARS-CoV-2 isolates replicated in the respiratory tracts of 12-month-old (aged) mice and caused pathological features of pneumonia upon intranasal infection. In contrast, rapid viral clearance was observed 5 days following infection in 2-month-old (young) mice with no evidence of pathological changes in the lungs. Infection with SARS-CoV-2 elicited significantly upregulated production of cytokines, especially interleukin 6 and interferon gamma, in aged mice; whereas this response was much weaker in young mice. Subsequent challenge of infected aged BALB/c mice with SARS-CoV-2 resulted in neutralized antibody responses, a significantly reduced viral burden in the lungs, and inflammation mitigation. Deep sequencing showed a panel of mutations potentially associated with the enhanced infection in aged BALB/c mice, such as the Q498H mutations which are located at the receptor binding domain (RBD) of the spike (S) protein. We further found that the isolates can not only multiply in the respiratory tract of mice but also cause disease in aged mice. Overall, viral replication and rapid adaption in aged BALB/c mice were associated with pneumonia, confirming that the age-related susceptibility to SARS-CoV-2 in mice resembled that in humans. Importance Aged BALB/c model are in use as a model of disease caused by SARS-CoV-2. Our research demonstrated SARS-CoV-2 can rapidly adapt in aged BALB/c mice through causing mutations at the RBD of the S protein. Moreover, SARS-CoV-2-infected aged BALB/c mice indicated that alveolar damage, interstitial pneumonia, and inflammatory immune responses were similar to the clinical manifestations of human infections. Therefore, our aged BALB/c challenge model will be useful for further understanding the pathogenesis of SARS-CoV-2 and for testing vaccines and antiviral agents.

scholarly journals Aging dampens the intestinal innate immune response during Clostridioides difficile infection and is associated with altered intestinal eosinophil mobilization

2020 ◽  
Author(s):  
Lisa Abernathy-Close ◽  
Michael G. Dieterle ◽  
Kimberly C. Vendrov ◽  
Ingrid L. Bergin ◽  
Vincent B. Young
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Disease Severity ◽  
Advanced Age ◽  
Simultaneous Increase ◽  
Aged Mice ◽  
Age Related ◽  
Cellular Immune ◽  
The Impact ◽  
Young Mice

ABSTRACTClostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the impact of aging on the cellular immune response associated with C. difficile infection in the setting of advanced age remains to be well described. This study explores the effect of age on cellular immune responses in C. difficile infection as well as disease severity. Young adult mice (2-3 months old) and aged mice (22-28 months old) were rendered susceptible to C. difficile infection with cefoperazone and then infected with C. difficile strains of varying disease-causing potential. Aged mice infected with C. difficile develop more severe clinical disease, compared to young mice. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the cecum and colon of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice. Interestingly, while C. difficile infection in young mice was associated with a robust increase in cecal and colonic eosinophils, there was a complete lack of an intestinal eosinophil response in aged counterparts accompanied by a simultaneous increase in blood eosinophils with severe disease. These findings demonstrate that age-related alterations in immune responses are associated with significantly worse C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.

scholarly journals Bcl-2-dependent autophagy disruption during aging impairs amino acid utilization that is restored by hochuekkito

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Miwa Nahata ◽  
Sachiko Mogami ◽  
Hitomi Sekine ◽  
Seiichi Iizuka ◽  
Naoto Okubo ◽  
...  
Keyword(s):  
Amino Acid ◽  
Energy Homeostasis ◽  
Mitochondrial Dynamics ◽  
Negative Regulator ◽  
Aged Mice ◽  
Glucose Levels ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Daily Food ◽  
Young Mice

AbstractChronic undernutrition contributes to the increase in frailty observed among elderly adults, which is a pressing issue in the sector of health care for older people worldwide. Autophagy, an intracellular recycling system, is closely associated with age-related pathologies. Therefore, decreased autophagy in aging could be involved in the disruption of energy homeostasis that occurs during undernutrition; however, the physiological mechanisms underlying this process remain unknown. Here, we showed that 70% daily food restriction (FR) induced fatal hypoglycemia in 23–26-month-old (aged) mice, which exhibited significantly lower hepatic autophagy than 9-week-old (young) mice. The liver expressions of Bcl-2, an autophagy-negative regulator, and Beclin1–Bcl-2 binding, were increased in aged mice compared with young mice. The autophagy inducer Tat-Beclin1 D11, not the mTOR inhibitor rapamycin, decreased the plasma levels of the glucogenic amino acid and restored the blood glucose levels in aged FR mice. Decreased liver gluconeogenesis, body temperature, physical activity, amino acid metabolism, and hepatic mitochondrial dynamics were observed in the aged FR mice. These changes were restored by treatment with hochuekkito that is a herbal formula containing several autophagy-activating ingredients. Our results indicate that Bcl-2 upregulation in the liver during the aging process disturbs autophagy activation, which increases the vulnerability to undernutrition. The promotion of liver autophagy may offer clinical therapeutic benefits to frail elderly patients.

scholarly journals Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice

2021 ◽  
Vol 118 (23) ◽  
pp. e2103730118
Author(s):  
Yuka Nakajima ◽  
Kenji Chamoto ◽  
Takuma Oura ◽  
Tasuku Honjo
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Critical Role ◽  
Cell Subset ◽  
Effector Memory ◽  
T Cell Subset ◽  
Aged Mice ◽  
Age Related

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism–related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1–deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

scholarly journals IL-10–producing Tfh cells accumulate with age and link inflammation with age-related immune suppression

2020 ◽  
Vol 6 (31) ◽  
pp. eabb0806 ◽  
Author(s):  
Maha Almanan ◽  
Jana Raynor ◽  
Ireti Ogunsulire ◽  
Anna Malyshkina ◽  
Shibabrata Mukherjee ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Suppression ◽  
Serum Levels ◽  
Normal Serum ◽  
Antibody Responses ◽  
Regulatory Cells ◽  
Aged Mice ◽  
Follicular Helper ◽  
Forkhead Box ◽  
Age Related

Aging results in profound immune dysfunction, resulting in the decline of vaccine responsiveness previously attributed to irreversible defects in the immune system. In addition to increased interleukin-6 (IL-6), we found aged mice exhibit increased systemic IL-10 that requires forkhead box P3–negative (FoxP3−), but not FoxP3+, CD4+T cells. Most IL-10–producing cells manifested a T follicular helper (Tfh) phenotype and required the Tfh cytokines IL-6 and IL-21 for their accrual, so we refer to them as Tfh10 cells. IL-21 was also required to maintain normal serum levels of IL-6 and IL-10. Notably, antigen-specific Tfh10 cells arose after immunization of aged mice, and neutralization of IL-10 receptor signaling significantly restored Tfh-dependent antibody responses, whereas depletion of FoxP3+ regulatory and follicular regulatory cells did not. Thus, these data demonstrate that immune suppression with age is reversible and implicate Tfh10 cells as an intriguing link between “inflammaging” and impaired immune responses with age.

scholarly journals Sex differences in T cell immune responses, gut permeability and outcome after ischemic stroke in aged mice

2020 ◽  
Vol 87 ◽  
pp. 556-567 ◽  
Author(s):  
Hilda Ahnstedt ◽  
Anthony Patrizz ◽  
Anjali Chauhan ◽  
Meaghan Roy-O'Reilly ◽  
Joseph W. Furr ◽  
...  
Keyword(s):  
Sex Differences ◽  
Ischemic Stroke ◽  
T Cell ◽  
Immune Responses ◽  
Gut Permeability ◽  
Aged Mice ◽  
T Cell Immune Responses

scholarly journals Aging Dampens the Intestinal Innate Immune Response during Severe Clostridioides difficile Infection and Is Associated with Altered Cytokine Levels and Granulocyte Mobilization

2020 ◽  
Vol 88 (6) ◽  
Author(s):  
Lisa Abernathy-Close ◽  
Michael G. Dieterle ◽  
Kimberly C. Vendrov ◽  
Ingrid L. Bergin ◽  
Krishna Rao ◽  
...  
Keyword(s):  
Immune Responses ◽  
Disease Severity ◽  
Immune Cell ◽  
White Blood Cells ◽  
Host Susceptibility ◽  
Simultaneous Increase ◽  
Content Type ◽  
Aged Mice ◽  
Clostridioides Difficile ◽  
Age Related

ABSTRACT Clostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the specific impact of aging on immune responses during C. difficile infection remains to be well described. This study explores the effect of age on cellular and cytokine immune responses during C. difficile infection. Young mice (2 to 3 months old) and aged mice (22 to 28 months old) were rendered susceptible to C. difficile infection with the antibiotic cefoperazone and then infected with C. difficile strains with varied disease-causing potentials. We observe that the host age and the infecting C. difficile strain influenced the severity of disease associated with infection. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the ceca and colons of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice, with a corresponding decrease in circulating CXCL1, an important neutrophil recruiter and activator. Interestingly, this lack of intestinal granulocyte response in aged mice during severe C. difficile infection was accompanied by a simultaneous increase in circulating white blood cells, granulocytes, and interleukin 17A (IL-17A). These findings demonstrate that age-related alterations in neutrophils and eosinophils and systemic cytokine and chemokine responses are associated with severe C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.

Inhibition of in vitro spontaneous apoptosis by IL-7 correlates with Bcl-2 up-regulation, cortical/mature immunophenotype, and better early cytoreduction of childhood T-cell acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 96 (1) ◽  
pp. 297-306 ◽  
Author(s):  
Leonid Karawajew ◽  
Velia Ruppert ◽  
Christian Wuchter ◽  
Annett Kösser ◽  
Martin Schrappe ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Receptor Expression ◽  
Spontaneous Apoptosis ◽  
Expression Levels ◽  
Apoptosis Inhibition ◽  
Cell Acute Lymphoblastic Leukemia

Abstract In normal T-cell development, IL-7 plays a nonredundant role as an antiapoptic factor by regulating Bcl-2 expression in pro-T cells. In the current study, we addressed the roles of IL-7 and related cytokines as apoptosis-modulating factors in precursor T-cell acute lymphoblastic leukemia (T-ALL). To this end, leukemic blasts from pediatric patients with T-ALL were prospectively investigated as to their responsiveness to IL-7, IL-4, and IL-2 (in terms of modulation of spontaneous apoptosis, assessed by flow cytometry), cytokine receptor expression profiles, and expression levels of Bcl-2 and Bax proteins. IL-7, in contrast to IL-4 and IL-2, was highly efficient in apoptosis inhibition , and this effect correlated with the expression levels of IL-7R chain and with the up-regulation of Bcl-2 protein expression (P< .0001). Subclassification of T-ALL samples (n = 130) according to their in vitro IL-7 responses revealed that IL-7 refractory samples were more frequently positive for CD34 (P< .0001) and the myeloid-associated antigen CD33 (P= .01), whereas IL-7 responsiveness was associated with an expression of more mature differentiation-associated T-cell antigens (CD1a, surface CD3, CD4/8; P < .05). Furthermore, the extent of apoptosis inhibition by IL-7 in vitro quantitatively correlated with early cytoreduction as determined by the prednisone peripheral blood response on day 8 and cytoreduction in the marrow on day 15 (n = 87;P < .05). Multivariate analysis of the apoptosis-related parameters investigated, including spontaneous apoptosis, its inhibition by IL-7, and expression levels of Bcl-2 and Bax, showed that only IL-7 responsiveness has an independent impact on early cytoreduction (P < .05), thus indicating a potential prognostic relevance of IL-7 sensitivity in T-ALL.

scholarly journals Protective Effects of Curcumin and Broccoli Seed Extract Against Age-Related Bone Loss in Mice

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 46-46
Author(s):  
Jing Li ◽  
Dong Zhang ◽  
Yiping Ren ◽  
Zhongdong Qiao ◽  
Doug Stevenson ◽  
...  
Keyword(s):  
Bone Loss ◽  
Seed Extract ◽  
Control Group ◽  
Protective Effects ◽  
Trabecular Thickness ◽  
Time Points ◽  
Aged Mice ◽  
Funding Sources ◽  
Age Related ◽  
Young Mice

Abstract Objectives Age-related bone loss occurs in both men and women, and is the leading cause of elderly disability. An age-related bone loss model was established in mice to investigate the protective effects of curcumin and broccoli seed extract. Methods 20 young (6-month-old) male C57BL/6 J mice after administration with vehicle once daily were sacrificed at four time points: day 0, 30, 60 and 90. 8 out of the 109 aged (18-month-old) male C57BL/6 J mice were sacrificed at the beginning and used as control. The rest of these aged mice were then randomly divided into four groups: one group served as control (vehicle), the other three groups were administrated with curcumin (CMN) and/or broccoli seed extract (BSE) by oral gavage. Mice in each group were sacrificed at four time points: day 0, 30, 60 and 90. L2 vertebrae of mice were fixed with paraformaldehyde and scanned with a Scanco Medical μCT40 scanner. Quantitative analyses of bone volume (BV), tissue volume (TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) and trabecular spacing (Tb.Sp) were performed with the Scanco Medical's software. Results BV/TV of the young mice group were significantly higher compared to the aged mice group at all four time points. Similarly, Tb.N and Tb.Th were also higher in the young mice group compared to the aged mice group. In contrast, Tb.Sp was lower in the young mice group. When comparing different groups in the aged mice, we found that mice administered with CMN had a higher BV/TV value compared to the mice in the control group at all three time points. Such a difference is significant by day 30. The mice administered with combined CMN and BSE also showed significant increase in BV/TV on day 30. For Tb.N, both mice administered with either CMN or BSE had higher values at all three time points. But no obvious difference in Tb.N was found for mice administered with combined CMN and BSE. For Tb.Th, both mice administered with CMN and with combined CMN and BSE had higher values compared to the control. For Tb.Sp, both mice administered with either CMN or BSE had lower values compared to the control. Conclusions This study showed that curcumin could slow down bone loss in the mouse model. There is no obvious positive effect with broccoli seed extract or with curcumin and broccoli seed extract combined. The curcumin used in this study may shed light on the alleviation of bone loss in humans. Funding Sources Nu Skin Enterprises.

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