Browsing by Subject "Lymph nodes"

Now showing 1 - 6 of 6
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    Lymph node and peri-lymph node stroma : phenotype and interaction with T-cells
    (2014-07-11) Stoffel, Nicholas J.; Touloukian, Christopher E.; Broxmeyer, Hal E.; Srour, Edward F.; Ingram Jr., David A.
    The non-hematopoietic, stationary stromal cells located inside and surrounding skin-draining lymph nodes play a key role in regulating immune responses. We studied distinct populations of lymph node stromal cells from both human subjects and animal models in order to describe their phenotype and function. In the mouse model, we studied two distinct populations: an endothelial cell population expressing Ly51 and MHC-II, and an epithelial cell population expressing the epithelial adhesion molecule EpCAM. Analysis of intra-nodal and extra-nodal lymph node (CD45-) stromal cells through flow cytometry and qPCR provides a general phenotypic profile of the distinct populations. My research focused on the EpCAM+ epithelial cell population located in the fat pad surrounding the skin draining lymph nodes. The EpCAM+ population has been characterized by surface marker phenotype, anatomic location, and gene expression profile. This population demonstrates the ability to inhibit the activation and proliferation of both CD4 and CD8 T cells. This population may play a role in suppressing overactive inflammation and auto-reactive T cells that escaped thymic deletion. The other major arm of my project consisted of identifying a novel endothelial cell population in human lymph nodes. Freshly resected lymph nodes were processed into single cell suspensions and selected for non-hematopoietic CD45- stromal cells. The unique endothelial population expressing CD34 HLA-DR was then characterized and analyzed for anatomic position, surface marker expression, and gene profiles. Overall, these studies emphasize the importance of stationary lymph node stromal cells to our functioning immune systems, and may have clinical relevance to autoimmune diseases, inflammation, and bone marrow transplantation.
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    Lysosomal Acid Lipase Deficiency Controls T- and B-Regulatory Cell Homeostasis in the Lymph Nodes of Mice with Human Cancer Xenotransplants
    (Elsevier, 2021) Ding, Xinchun; Zhao, Ting; Lee, Chih-Chun; Yan, Cong; Du, Hong; Pathology and Laboratory Medicine, School of Medicine
    Utilization of proper preclinical models accelerates development of immunotherapeutics and the study of the interplay between human malignant cells and immune cells. Lysosomal acid lipase (LAL) is a critical lipid hydrolase that generates free fatty acids and cholesterol. Ablation of LAL suppresses immune rejection and allows growth of human lung cancer cells in lal-/- mice. In the lal-/- lymph nodes, the percentages of both T- and B-regulatory cells (Tregs and Bregs, respectively) are increased, with elevated expression of programmed death-ligand 1 and IL-10, and decreased expression of interferon-γ. Levels of enzymes in the glucose and glutamine metabolic pathways are elevated in Tregs and Bregs of the lal-/- lymph nodes. Pharmacologic inhibitor of pyruvate dehydrogenase, which controls the transition from glycolysis to the citric acid cycle, effectively reduces Treg and Breg elevation in the lal-/- lymph nodes. Blocking the mammalian target of rapamycin or reactivating peroxisome proliferator-activated receptor γ, an LAL downstream effector, reduces lal-/- Treg and Breg elevation and PD-L1 expression in lal-/- Tregs and Bregs, and improves human cancer cell rejection. Treatment with PD-L1 antibody also reduces Treg and Breg elevation in the lal-/- lymph nodes and improves human cancer cell rejection. These observations conclude that LAL-regulated lipid metabolism is essential to maintain antitumor immunity.
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    OGR1/GPR68 Modulates the Severity of Experimental Autoimmune Encephalomyelitis and Regulates Nitric Oxide Production by Macrophages.
    (PLOS, 2016) D’Souza, Cheryl A.; Zhao, Fei Linda; Li, Xujian; Xu, Yan; Dunn, Shannon E.; Zhang, Li; Department of Obstetrics & Gynecology, IU School of Medicine
    Ovarian cancer G protein-coupled receptor 1 (OGR1) is a proton-sensing molecule that can detect decreases in extracellular pH that occur during inflammation. Although OGR1 has been shown to have pro-inflammatory functions in various diseases, its role in autoimmunity has not been examined. We therefore sought to determine whether OGR1 has a role in the development of T cell autoimmunity by contrasting the development of experimental autoimmune encephalomyelitis between wild type and OGR1-knockout mice. OGR1-knockout mice showed a drastically attenuated clinical course of disease that was associated with a profound reduction in the expansion of myelin oligodendrocyte glycoprotein 35-55-reactive T helper 1 (Th1) and Th17 cells in the periphery and a reduced accumulation of Th1 and Th17 effectors in the central nervous system. We determined that these impaired T cell responses in OGR1-knockout mice associated with a reduced frequency and number of dendritic cells in draining lymph nodes during EAE and a higher production of nitric oxide by macrophages. Our studies suggest that OGR1 plays a key role in regulating T cell responses during autoimmunity.
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    Quality of Life Following Receipt of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node–Positive and High-Risk Lymph Node–Negative Breast Cancer
    (American Medical Association, 2022-02-01) Rosenberg, Shoshana M.; O'Neill, Anne; Sepucha, Karen; Miller, Kathy D.; Dang, Chau T.; Northfelt, Donald W.; Sledge, George W.; Schneider, Bryan P.; Partridge, Ann H.; Medicine, School of Medicine
    Importance: Breast cancer treatment can impact not only short-term health but may also affect longer-term quality of life (QOL). Objective: To describe and evaluate factors associated with diminished QOL following completion of active treatment. Design, setting, and participants: This was a secondary analysis of a randomized clinical trial included patients with lymph node-positive or high-risk lymph node-negative breast cancer who had undergone definitive surgery and were enrolled in ECOG-ACRIN E5103, a multisite phase 3 trial. A survey was administered 18 months after enrollment to patients enrolled between January and June 2010. Final analysis of the data took place from March to December 2021. Interventions: Patients received adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo. Main outcomes and measures: QOL and health status assessed with the EuroQol 5-Dimension 3-Levels (EQ-5D-3L), EQ-visual analog scale (EQ-VAS), and the Functional Assessment of Cancer Therapy-Breast Cancer, with arm subscale (FACT-B+4). Groups were compared by Fisher exact test, Wilcoxon rank sum, or Kruskal-Wallis test. Multivariable linear regression was used to assess factors independently associated with FACT-B scores. Results: Data at 18 months were available from 455 of 519 patients (87.7%) enrolled in the trial. Median (range) age at enrollment was 52 (25-76) years. No differences in QOL (median [range] FACT-B scores: group A, 123 [67-146]; group B, 114 [54-148]; group C, 117 [42-148]; P = .23) or health status (median [range] EQ-5D-3L index scores: group A, 0.83 [0.28-1.00]; group B, 0.83 [0.20-1.00]; group C, 0.83 [0.17-1.00], P = .80; median EQ-VAS: group A, 85 [20-100]; group B, 85 [0-100]; group C, 85 [0-100]; P = .79) were observed across treatment groups; results for subsequent analyses were therefore reported irrespective of primary treatment. Overall, half of patients (258 of 444 [58%]) reported at least some pain or discomfort; 170 (38%) reported symptoms of anxiety or depression. In multivariable analyses, mastectomy with radiation (vs breast conserving surgery) and Asian, Black, or American Indian or Alaska Native race (vs White race) were associated with lower QOL (mastectomy with radiation: coefficient: -5.5; 95% CI, -10.1 to -0.9; Asian, Black, or American Indian or Alaska Native race: coefficient: -7.3; 95% CI, -13.2, -1.4). Conclusions and relevance: In this study, the addition of bevacizumab to chemotherapy was not negatively associated with QOL at 18 months. A substantial proportion of participants reported problems related to pain or discomfort and anxiety or depression, demonstrating persistent consequences for physical and psychosocial well-being in this heavily treated population. Many problems reported are amenable to intervention, underscoring the need for timely referral to supportive resources, especially for women of color and those who have more extensive local therapy.
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    Racial Differences in Response to Neoadjuvant Chemotherapy: Impact on Breast and Axillary Surgical Management
    (Springer, 2021) Relation, Theresa; Obeng-Gyasi, Samilia; Bhattacharyya, Oindrila; Li, Yaming; Eskander, Mariam F.; Tsung, Allan; Oppong, Bridget A.; Economics, School of Liberal Arts
    Background: Neoadjuvant chemotherapy (NAC), an increasingly used method for breast cancer patients, has the potential to downstage patient tumors and thereby have an impact on surgical options for treatment of the breast and axilla. Previous studies have identified racial disparities in tumor heterogeneity, nodal recurrence, and NAC completion. This report compares the effects of NAC response among non-Hispanic white women and black women in relation to surgical treatment of the breast and axilla. Methods: A retrospective review of 85,303 women with stages 1 to 3 breast cancer in the National Cancer Database who received NAC between 1 January 2010 and 31 December 2016 was conducted. Differences in sociodemographic and clinical variables between black patients and white patients with breast cancer were tested. Results: The study identified 68,880 non-Hispanic white and 16,423 non-Hispanic black women who received NAC. The average age at diagnosis was 54.8 years for the white women versus 52.5 years for the black women. A higher proportion of black women had stage 3 disease, more poorly differentiated tumors, and triple-negative subtype. The black women had lower rates of complete pathologic response, more breast-conservation surgery, and higher rates of axillary lymph node dissection, but fewer sentinel lymph node biopsies. Axillary management for the women who were downstaged showed more use of axillary lymph node dissection for black women compared with sentinel lymph node biopsy. Conclusions: The black patients were younger at diagnosis, had more advanced disease, and were more likely to have breast-conservation surgery. De-escalating axillary surgery is being adopted increasingly but used disproportionately for white women.
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    Regulation of the germinal center reaction by T helper cells and T regulatory cells
    (2016-04-11) Wu, Hao; Dent, Alexander L.; Kaplan, Mark H.; Turner, Matthew J.; Zhou, Baohua
    Germinal Centers (GCs) are transient lymphoid structures that arise in lymphoid organs in response to T cell-dependent antigen. Within the GC, follicular T helper (TFH) cells promote GC B cell differentiation and in turn the proper antibody production to protect us from invading pathogens. We wished to study the regulation of this process by transcription factors STAT3 and Bcl6. STAT3 is important for both TFH cell differentiation and IL-4 production by Th2 cells. IL-4 is a major functional cytokine produced by TFH cells. To dissect the role of STAT3 in IL-4 production by TFH cells, we generated T cell-specific conditional STAT3 knockout mice (STAT3KO). Compared to WT mice, TFH cell differentiation in STAT3KO mice was partially impaired, both in spleen following sheep red blood cells (SRBC) immunization and in Peyer's patches (PPs). In STAT3KO mice, the numbers of splenic GC B cells were markedly decreased, whereas PP GC B cells developed at normal numbers and IgG1 class switching was greatly increased. Unexpectedly, we found that STAT3 intrinsically suppressed the expression of IL-4 and Bcl6 in TFH cells. Mechanistically, in vitro repression of IL-4 expression in CD4 T cells by Bcl6 required STAT3 function. Apart from TFH cells, the GC reaction is also controlled by regulatory follicular T helper (TFR) cells, a subset of Treg cells. To study the mechanism of how TFR cells regulate the GC reaction, we generated mice specifically lacking TFR cells by specifically deleting Bcl6 in Treg cells. Following immunization, these "Bcl6FC" mice developed normal TFH and GC B cell populations. However, Bcl6FC mice produced altered antigen-specific antibody responses, with reduced titers of IgG and increased IgA. Bcl6FC mice also developed IgG antibodies with significantly decreased avidity to antigen in an HIV-1 gp120 "prime-boost" vaccine model. Additionally, TFH cells from Bcl6FC mice produced higher levels of Interferon-γ, IL-10 and IL-21. Loss of TFR cells therefore leads to highly abnormal TFH and GC B cell responses. Overall, our studies have uncovered unexpected regulatory roles of STAT3 in TFH cell function as well as the novel regulatory roles of TFR cells on cytokine production by TFH cells and on antibody production.