Papers by Annabelle Julius
Cancer Immunology, Immunotherapy, 2010
We reported that murine tumor lysate-pulsed dendritic cells (TP-DC) could elicit tumor-specific C... more We reported that murine tumor lysate-pulsed dendritic cells (TP-DC) could elicit tumor-specific CD4 + and CD8 + T cells in vitro and in vivo. In some limited cases, TP-DC treatments in vivo could also result in regression of established subcutaneous tumors and lung metastases. By gene array analysis, we reported a high level of expression of a novel member of the cell surface class A scavenger receptor family, MARCO, by murine TP-DC compared to unpulsed DC. MARCO is thought to play an important role in the immune response by mediating binding and phagocytosis, but also in the formation of lamellipodia-like structures and dendritic processes. We have now examined the biologic and therapeutic implications of MARCO expressed by TP-DC. In vitro exposure of TP-DC to a monoclonal anti-MARCO antibody resulted in a morphologic change of rounding with disappearance of dendritic-like processes. TP-DC remained viable after anti-MARCO antibody treatment; had little, if any, change in production of IL-10, IL-12p70 and TNF-alpha; but demonstrated enhanced migratory capacity in a microchemotaxis assay. The use of a selective inhibitor showed MARCO expression to be linked to the p38 mitogen-activated protein kinase (MAPK) pathway. In vivo, anti-MARCO antibody treated TP-DC showed better trafficking from the skin injection site to lymph node, enhanced generation of tumor-reactive IFN-gamma producing T cells, and improved therapeutic efficacy against B16 melanoma. These results, coupled with our finding that human monocyte-derived DC also express MARCO, could have important implications to human clinical DC vaccine trials.
The Journal of Immunology
We recently reported that bone marrow-derived dendritic cells (DCs) from old C57BL/6 mice are les... more We recently reported that bone marrow-derived dendritic cells (DCs) from old C57BL/6 mice are less effective than their young counterpart in inducing the regression of pre-established B16-OVA melanomas. However, the mechanisms for this are unclear. DCs migration to lymphoid organs is essential to effective DC anti-tumor activity and is regulated by interactions between CCR7 and its ligands CCL21 and CCL19. We therefore examined the effect of aging on DC migration, CCR7 expression and function. Young (3–6 months) and old (18–20 months) DCs were labeled with CFSE and CMPTX, and their in vivo migration quantified by fluorescent microscopy. Half as many aged DCs were present in the popliteal lymph nodes (p<0.025). DCs from aged mice express 50% less CCR7 compared to young DCs (p< 0.0005). Surprisingly, the reduced gene expression did not result in any significant change in CCR7 surface expression on DCs. Nevertheless, the reduced CCR7 gene expression correlated with the impaired i...
The Journal of Immunology
Dendritic cells (DCs) play an important role in many immune-mediated processes in aging. One of t... more Dendritic cells (DCs) play an important role in many immune-mediated processes in aging. One of their major functions is the phagocytic clearance of pathogens and tumor cells. Currently, very little is known about the role of aging in determining DC phagocytic function. Using murine CD11c+ bone marrow-derived DCs from young (3-6 months) and old (21-23 months) C57BL/6 mice, we compared the phagocytic function of DCs. We found that old DCs have decrease capacity to internalize exogenous FITC-dextran compared with young DCs. Similarly, old DCs displayed a decrease in the global uptake of E. coli bacteria per cells (398 ± 32.6 fluorescence units) when compared to young DCs (598.7 ± 13.7). This impaired phagocytic activity in old DCs was further confirmed by quantifying the number of bacteria ingested per cell by confocal microscopy. Intriguingly, aging does not affect the ability of DCs to ingest zymosan or Gram positive bacteria such as S. Aureus, suggesting a decrease in the expressio...
<b>Copyright information:</b>Taken from "The effect of aging and caloric restric... more <b>Copyright information:</b>Taken from "The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression"http://www.immunityageing.com/content/4/1/8Immunity &amp; ageing : I &amp; A 2007;4():8-8.Published online 14 Nov 2007PMCID:PMC2200663. Intracellular proteins were isolated from groups of 4–6 young and old C57Bl/6 mice. (A) Western blot analysis of CCR4 using proteins from 4 groups of young (Y1–Y4) and old (O1–O4) CD8+ T cells (total 20 young and 20 old mice). (B) Western blot analysis of CCR5 on CR8+ T cells isolated from 5 groups of young (Y1–Y5) and Old (O1–O5) mice (total 25 young and 25 old mice). (C) Histogram showing the composite results of the relative CCR4 and CCR5 protein level of old CD8+ T cells compared to young CD8+ T cells. Pairwise comparison was done for each individual sample preparation (Y1 versus O1, Y2 versus O2 etc., with the young group arbitrarily assigned the value of 1). The results are corrected for gel loading using β-actin as controls. The results are presented as mean ± SD.
<b>Copyright information:</b>Taken from "The effect of aging and caloric restric... more <b>Copyright information:</b>Taken from "The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression"http://www.immunityageing.com/content/4/1/8Immunity &amp; ageing : I &amp; A 2007;4():8-8.Published online 14 Nov 2007PMCID:PMC2200663. The indicated concentrations of the chemokine were placed in the lower chamber of a Costar Transwell system. Equal number of freshly isolated young (3–4 months) or old (18–20 months) CD8+ T cells was then placed in the upper chamber of the insert, and the number of cells in the upper and lower chambers counted 5 hours later using a Coulter counter. The results are expressed as percent transmigration and represent the mean ± SD of triplicate determinations. P ≤ 0.05 is considered significant. The results are representative of 3 independent experiments.
OncoTarget, Mar 17, 2017
Recombinant human erythropoietin (EPO) is standard treatment for anemia in cancer patients. Recen... more Recombinant human erythropoietin (EPO) is standard treatment for anemia in cancer patients. Recent clinical trials suggest that EPO may accelerate tumor progression and increase mortality. However, the evidence supporting a growthpromoting effect of EPO has remained controversial. Employing an in vivo model of B16 murine melanoma, we observed that administration of EPO to tumor bearing C57BL/6 mice resulted in pronounced acceleration of melanoma growth. Our in vitro studies demonstrate that B16 murine melanoma cells express EPOR, both at the protein and mRNA levels. Interestingly, expression of EPOR was retained in the established tumors. EPO stimulation of B16 cells enhanced proliferation and protein synthesis rates, and correlated with activation of the receptor associated Janus kinase 2 (Jak2) as well as phosphorylation of extracellular signal-regulated kinase (Erk) 1/2 and Akt kinases. Treatment with EPO and Jak-2 antagonists significantly inhibited EPO-mediated B16 cell proliferation. Moreover, EPO dose-dependently induced the phosphorylation and activation of the translation initiation factor eIF4E as well as the phosphorylation of its repressor, the eIF4E binding protein 4E-BP1. Finally, using eIF4E small interfering RNA (siRNA), we observed that EPO-mediated stimulation of B16 cell proliferation is eIF4E-dependent. Our results indicate that EPO exerts a powerful stimulatory effect on cell proliferation and de novo protein synthesis in melanoma cells through activation of the initiation factor eIF4E.
<b>Copyright information:</b>Taken from "The effect of aging and caloric restric... more <b>Copyright information:</b>Taken from "The effect of aging and caloric restriction on murine CD8+ T cell chemokine receptor gene expression"http://www.immunityageing.com/content/4/1/8Immunity &amp; ageing : I &amp; A 2007;4():8-8.Published online 14 Nov 2007PMCID:PMC2200663. Ribonuclease protection assays (RPAs) were done using RNA from freshly isolated splenic CD8+ T cells from young (3–4 months), old (18–20 months), and caloric restricted old (18–20 months) mice in groups of 5 animals. Density of the bands was quantified using a phosphoimager. (A) Histogram showing the composite data of 4 experiments (total 20 animals in each condition). The results represent the mean ± SEM of the relative CD8+ T cell chemokine receptor gene expression level of old and old caloric restricted mice compared to those from the young cohort (arbitrarily defined as equal to 1). (B) CCR7 expression was also determined using a custom CCR7 RPA probe. The left panel is a representative autoradiograph (lane 1 = young CD8+ T cells; lane 2 = old CD8+ T cells; lane 3 = caloric restricted old CD8+ T cells). The right panel represents the composite data of 3 RPAs with a total of 15 animals in each group. Results are presented as mean ± SEM. CR = caloric restricted. Gel loading is corrected with L32 expression.
Dendritic Cells in Cancer, 2009
Page 1. Chapter 12 Changes in Dendritic Cells in Cancer and Aging Annabelle Grolleau-Julius and R... more Page 1. Chapter 12 Changes in Dendritic Cells in Cancer and Aging Annabelle Grolleau-Julius and Raymond L. Yung ... Scand J Immunol 55:453457. Tesar, BM, Walker, WE, Unternaehrer, J., Joshi, NS, Chandele, A., Haynes, L., Kaech, S. and Goldstein, DR 2006. ...
Journal of Leukocyte Biology, 2010
Review of the current understanding of age-dependent changes in leukocyte function and their cont... more Review of the current understanding of age-dependent changes in leukocyte function and their contribution to aging-related disease processes. Aging is associated with a progressive dysregulation of immune responses. Whether these changes are solely responsible for the observed increased mortality and morbidity amongst the elderly is uncertain. Recent advances have highlighted the age-associated changes that occur beyond T and B lymphocytes. Additionally, multiple human and animal studies have identified a relationship between chronic low-grade inflammation and geriatric syndromes, such as frailty, suggesting that the phenomenon of “inflamm-aging” may provide a rationale for the increased vulnerability to chronic inflammatory diseases in older adults. In the present review, we broadly summarize our current understanding of age-dependent changes in leukocyte function and their contribution to aging-related disease processes.
The Journal of Immunology, 2005
Estrogen has been implicated in the observed female bias in autoimmune diseases. However, the mec... more Estrogen has been implicated in the observed female bias in autoimmune diseases. However, the mechanisms behind this gender dimorphism are poorly defined. We have previously reported that in vivo T cell trafficking is gender- and estrogen-dependent. Chemokine receptors are critical determinants of T cell homing and immune response. In this study, we show that the female gender is associated with increased CD4+ T cell CCR1-CCR5 gene and protein expression in mice. The increased CCR expression correlates with enhanced in vitro chemotaxis response to MIP-1β (CCL4). In vivo treatment of young oophorectomized and postmenopausal female mice with 17β-estradiol also increased CD4+ T cell CCR expression. Finally, 17β-estradiol enhances tyrosine phosphorylation in T cells stimulated with MIP-1α in a time-dependent manner. Our results indicate an important role of estrogen in determining T cell chemokine response that may help explain the increased susceptibility and severity of autoimmune dis...
The Journal of Immunology, 2011
Age-related adiposity has been linked to chronic inflammatory diseases in late life. To date, the... more Age-related adiposity has been linked to chronic inflammatory diseases in late life. To date, the studies on adipose tissue leukocytes and aging have not taken into account the heterogeneity of adipose tissue macrophages (ATMs), nor have they examined how age impacts other leukocytes such as T cells in fat. Therefore, we have performed a detailed examination of ATM subtypes in young and old mice using state of the art techniques. Our results demonstrate qualitative changes in ATMs with aging that generate a decrease in resident type 2 (M2) ATMs. The profile of ATMs in old fat shifts toward a proinflammatory environment with increased numbers of CD206−CD11c− (double-negative) ATMs. The mechanism of this aging-induced shift in the phenotypic profile of ATMs was found to be related to a decrease in peroxisome proliferator-activated receptor-γ expression in ATMs and alterations in chemokine/chemokine receptor expression profiles. Furthermore, we have revealed a profound and unexpected e...
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2006
Background. Despite recognition that weight loss is a problem in elderly persons with probable Al... more Background. Despite recognition that weight loss is a problem in elderly persons with probable Alzheimer's disease (AD), increasing their food intake remains a challenge. To effectively enhance intake, interventions must work with individuals' changing needs and intake patterns. Previously, the authors reported greater food consumption at breakfast, a high-carbohydrate meal, compared with dinner, and shifts toward carbohydrate preference at dinner in those with increased behavioral difficulties, low body mass index, or both. Methods. Thirty-four nursing home residents with probable AD who ate independently participated in a randomized, crossover, nonblinded study of two nutrition interventions. The intervention described here included replacing 12 nonconsecutive ''traditional'' dinners with meals high in carbohydrate but comparable to traditional dinners in protein. Measures included weighed food intake, body weight, cognitive function (as assessed using the Severe Impairment Battery and Global Deterioration Scale), behavioral disturbances (as assessed using the Neuropsychiatric Inventory-Nursing Home Version), and behavioral function (as assessed using the London Psychogeriatric Rating Scale). Results. Group mean dinner and 24-hour energy intake increased during the intervention phase compared with baseline, protein intake was unaffected, and carbohydrate intake increased. Increased dinner intake, attributable to intervention foods, was achieved in 20 of 32 of participants who completed the study and was associated with increased carbohydrate preference, poorer memory, and increased aberrant motor behavior. Those with low body mass indices were the most resistant to the intervention. Conclusions. Providing a high-carbohydrate meal for dinner increases food intake in seniors at later stages of the disease who are experiencing cognitive and behavioral difficulties, possibly as a result of a shift in preference for highcarbohydrate foods.
Immunity & Ageing, 2007
Background: The mechanism explaining the increased disease susceptibility in aging is not well un... more Background: The mechanism explaining the increased disease susceptibility in aging is not well understood. CD8+ T cells are crucial in anti-viral and anti-tumor responses. Although the chemokine system plays a critical role in CD8+ T cell function, very little is known about the relationship between aging and the T cell chemokine system. Results: In this study we have examined the effect of aging on murine CD8+ T cell chemokine receptor gene expression. Freshly isolated splenic CD8+ T cells from old C57BL/6 mice were found to have higher CCR1, CCR2, CCR4, CCR5 and CXCR5, and lower CCR7 gene expression compared to their younger cohort. Anti-CD3/anti-CD28 stimulation elicited a similar robust chemokine receptor response from young and old CD8+ T cells. Western blot analyses confirmed elevated protein level of CCR4 and CCR5 in aged CD8+ T cells. Increases in T cell CCR1 and CCR5 expression also correlate to increased in vitro chemotaxis response to macrophageinflammatory protein-1 α(MIP-1α). Finally, caloric restriction selectively prevents the loss of CD8+ T cell CCR7 gene expression in aging to the level that is seen in young CD8+ T cells. Conclusion: These findings are consistent with the notion that aging exists in a state of low grade pro-inflammatory environment. In addition, our results provide a potential mechanism for the reported aging-associated impaired T cell lymphoid homing and allograft response, and reduced survival in sepsis.
Cancer Research, 2008
We recently reported that bone marrow–derived dendritic cells (DC) from aged miced are less effec... more We recently reported that bone marrow–derived dendritic cells (DC) from aged miced are less effective than their young counterparts in inducing the regression of B16-ovalbumin (OVA) melanomas. To examine the underlying mechanisms, we investigated the effect of aging on DC tumor antigen presentation and migration. Although aging does not affect the ability of DCs to present OVA peptide(257–264), DCs from aged mice are less efficient than those from young mice in stimulating OVA-specific T cells in vitro. Phenotypic analysis revealed a selective decrease in DC-specific/intracellular adhesion molecule type-3–grabbing nonintegrin (DC-SIGN) level in aged DCs. Adoptive transfer experiments showed defective in vivo DC trafficking in aging. This correlates with impaired in vitro migration and defective CCR7 signaling in response to CCL21 in aged DCs. Interestingly, vaccination of young mice using old OVA peptide(257–264)–pulsed DCs (OVA PP-DC) resulted in impaired activation of OVA-specific...
Cancer Immunology, Immunotherapy, 2008
Effective cancer immunotherapy depends on the body's ability to generate tumor antigen-presenting... more Effective cancer immunotherapy depends on the body's ability to generate tumor antigen-presenting cells and tumor-reactive effector lymphocytes. As the most potent antigen presenting cells (APCs), dendritic cells (DCs) are capable of sensitizing T cells to new and recall antigens. Clinical trials of antigen-pulsed autologous DCs have been conducted in patients with a number of hematological and solid cancers, including malignant melanoma, lymphoma, myeloma, and non-small cell lung cancer. These studies suggest that antigen-loaded DC vaccination is a potentially safe and effective cancer therapy. However, the clinical results have been variable. Since the elderly are preferentially affected by diseases targeted by DC-directed immunotherapy, it is quite striking that few studies to date have focused on the effect of aging on DC function, a key aspect of optimal immunotherapy design in an aging population. In the present paper, we will discuss the consequences of aging on murine bone marrow-derived DC function and their use in cancer immunotherapy.
Autoimmunity, 2008
The decline in immunocompetence with age is accompanied by the increase in the incidence of autoi... more The decline in immunocompetence with age is accompanied by the increase in the incidence of autoimmune diseases. Aging of the immune system, or immunosenescence, is characterized by a decline of both T and B cell function, and paradoxically the presence of low grade chronic inflammation. There is growing evidence that epigenetics, the study of inherited changes in gene expression that are not encoded by the DNA sequence itself, changes with aging. Interestingly, emerging evidence suggests a key role for epigenetics in human pathologies, including inflammatory and neoplastic disorders. Here we will review the potential mechanisms that contribute to the increase in autoimmune responses in aging. In particular, we will discuss how epigenetic alterations, especially DNA methylation and histone acetylation, are accumulated during aging and how these events contribute to autoimmunity risk.
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Papers by Annabelle Julius