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Item Abstract 27: Physiologic Oxygen Expansion Enhances Lymphocyte and Neutrophil Recovery Following Transplantation(Oxford University Press, 2024-08-21) Gutch, Sarah; Ropa, Jim; Beasley, Lindsay; Whitacre, Grace; Van't Hof, Wouter; Capitano, Maegan; Medical and Molecular Genetics, School of MedicineIntroduction: Expeditious recovery of lymphocytes after hematopoietic cell transplantation is a major determinant of patient outcome. There are few efficient clinical therapies to enhance lymphocyte recovery, indicating a clear unmet need. Ex vivo expansion of cord blood (CB) units is an approved therapy to increase numbers of hematopoietic stem and progenitor cells, but impact on lymphocyte recovery remains uncertain. Moreover, culture in physioxic (physiological oxygen) conditions results in increased lymphoid-biased RNA levels. Objectives: We hypothesize that ex vivo expansion in physioxic conditions will increase lymphoid-biased cells and increase lymphocyte counts post-transplantation (PT). The objective of this study is to increase lymphocyte numbers following transplantation without sacrificing reconstitution of potent hematopoietic cells. Methods: Three independent transplants were conducted. 1) Murine lineage- bone marrow (BM) was expanded for 7 days then transplanted into lethally irradiated mice with/without additional common lymphoid progenitors (CLPs). 2) Murine lineage- BM was expanded in 1%, 3%, 5%, 14%, and 21% O2 for 7 days and transplanted into lethally irradiated mice. 3) Human CD34+ CB cells were expanded for 7 days in 1%, 3%, 5%, 14%, and 21% O2 and transplanted into NSG mice. Unexpanded BM or CB cells were used as controls. Results: Additional CLPs did not contribute to lymphocyte recovery. Mice transplanted with expanded BM had increased lymphocyte counts compared to transplantations with unexpanded BM at weeks 2 and 5 PT via complete blood count (CBC) and increased B-cell reconstitution in the spleen, BM, and peripheral blood (PB) at weeks 2, 5, and 8 PT. LSK (Lin- SCA1+ cKIT+) and neutrophil frequencies were increased at 3% O2 in the BM and 5% O2 in the PB, respectively. Compared to 21% O2, CB cells expanded at 1%, 3%, 5%, 14% O2 had increased neutrophil and lymphocyte frequencies in the PB at weeks 2 and 10, respectively, and demonstrated greater recovery than unexpanded at week 2. Discussion: Expansion increases lymphocyte counts via CBC and immunophenotyping. Physioxic expansion increases numbers of potent hematopoietic cell subpopulations and frequencies of specific lymphocyte compartments in multiple organs. Thus, expansion under physioxia is a viable strategy to enhance recovery of lymphocytes PT.Item B Quiet: Autoantigen-Specific Strategies to Silence Raucous B Lymphocytes and Halt Cross-Talk with T Cells in Type 1 Diabetes(MDPI, 2021-01-06) Felton, Jamie L.; Conway, Holly; Bonami, Rachel H.; Pediatrics, School of MedicineIslet autoantibodies are the primary biomarkers used to predict type 1 diabetes (T1D) disease risk. They signal immune tolerance breach by islet autoantigen-specific B lymphocytes. T-B lymphocyte interactions that lead to expansion of pathogenic T cells underlie T1D development. Promising strategies to broadly prevent this T-B crosstalk include T cell elimination (anti-CD3, teplizumab), B cell elimination (anti-CD20, rituximab), and disruption of T cell costimulation/activation (CTLA-4/Fc fusion, abatacept). However, global disruption or depletion of immune cell subsets is associated with significant risk, particularly in children. Therefore, antigen-specific therapy is an area of active investigation for T1D prevention. We provide an overview of strategies to eliminate antigen-specific B lymphocytes as a means to limit pathogenic T cell expansion to prevent beta cell attack in T1D. Such approaches could be used to prevent T1D in at-risk individuals. Patients with established T1D would also benefit from such targeted therapies if endogenous beta cell function can be recovered or islet transplant becomes clinically feasible for T1D treatment.Item Bmi1 maintains the self-renewal property of innate-like B lymphocytes(American Association of Immunologists, 2020-06-15) Kobayashi, Michihiro; Lin, Yang; Mishra, Akansha; Shelly, Chris; Gao, Rui; Reeh, Colton W; Wang, Paul Zhiping; Xi, Rongwen; Liu, Yunlong; Wenzel, Pamela; Ghosn, Eliver; Liu, Yan; Yoshimoto, Momoko; Pediatrics, School of MedicineThe self-renewal ability is a unique property of fetal-derived innate-like B-1a lymphocytes, which survive and function without being replenished by bone marrow (BM) progenitors. However, the mechanism by which IgM-secreting mature B-1a lymphocytes self-renew is poorly understood. In this study, we showed that Bmi1 was critically involved in this process. Although Bmi1 is considered essential for lymphopoiesis, the number of mature conventional B cells was not altered when Bmi1 was deleted in the B cell lineage. In contrast, the number of peritoneal B-1a cells was significantly reduced. Peritoneal cell transfer assays revealed diminished self-renewal ability of Bmi1-deleted B-1a cells, which was restored by additional deletion of Ink4-Arf, the well-known target of Bmi1 Fetal liver cells with B cell-specific Bmi1 deletion failed to repopulate peritoneal B-1a cells, but not other B-2 lymphocytes after transplantation assays, suggesting that Bmi1 may be involved in the developmental process of B-1 progenitors to mature B-1a cells. Although Bmi1 deletion has also been shown to alter the microenvironment for hematopoietic stem cells, fat-associated lymphoid clusters, the reported niche for B-1a cells, were not impaired in Bmi1 -/- mice. RNA expression profiling suggested lysine demethylase 5B (Kdm5b) as another possible target of Bmi1, which was elevated in Bmi1-/- B-1a cells in a stress setting and might repress B-1a cell proliferation. Our work has indicated that Bmi1 plays pivotal roles in self-renewal and maintenance of fetal-derived B-1a cells.Item Clinical Predictors of Functional Cure in Children 1–6 Years-old with Chronic Hepatitis B(Xia & He, 2022) Pan, Jing; Wang, Haiyan; Yao, Tiantian; Liao, Xuejiao; Cheng, Hao; Liangpunsakul, Suthat; Wang, Yan; Zhang, Min; Zhang, Zheng; Medicine, School of MedicineBackground and aims: Hepatitis B surface antigen (HBsAg) clearance is significantly more common in children with chronic hepatitis B (CHB) than in adults; however, the possible influencing factors related to HBsAg loss have yet to be found. This study aimed to explore the efficacy of long-term interferon (IFN)α therapy in treating children with CHB and analyzed the factors influencing functional cure after treatment. Methods: A total of 236 children aged 1-6 years and diagnosed with CHB via liver biopsy were included in the study, all receiving IFNα treatment (IFNα-2b monotherapy, IFNα-2b followed by lamivudine [LAM] or IFNα-2b combined with LAM) and followed up for 144 weeks. A comprehensive analysis was conducted on clinical data, including biochemical items, serum markers of hepatitis B virus (HBV) and immunological indexes, and logistic regression analysis was used to screen the influencing factors related to HBsAg loss. Results: The cumulative loss rates of HBsAg were 79.5%, 62.1% and 42.1% at 144 weeks after the start of treatment in the 1-3 years-old group, 3-5 years-old group and 5-7 years-old group, respectively (p<0.05). IFNα-2b combined with LAM treatment displayed the highest HBsAg loss rates compared with monotherapy and sequential treatment (p=0.011). Younger baseline age and lower HBsAg levels were independent factors for the prediction of HBsAg loss (p<0.05). The baseline PreS1 and hepatitis B core antibody levels in the HBsAg loss group were lower than those in the HBsAg non-loss group. In addition, the PreS1 level was positively corelated with the level of HBsAg, HBV DNA and liver inflammation. Conclusions: Long-term treatment with IFNα was effective in achieving HBsAg loss in CHB children aged 1-6 years-old. Age less than 3 years-old and lower HBsAg levels are independent predictors of functional cure in children with CHB.Item Contribution of Th17 cells to tissue injury in hypertension(Wolters Kluwer, 2021) Basile, David P.; Abais-Battad, Justine M.; Mattson, David L.; Anatomy, Cell Biology and Physiology, School of MedicinePurpose of review: Hypertension has been demonstrated to be a chief contributor to morbidity and mortality throughout the world. Although the cause of hypertension is multifactorial, emerging evidence, obtained in experimental studies, as well as observational studies in humans, points to the role of inflammation and immunity. Many aspects of immune function have now been implicated in hypertension and end-organ injury; this review will focus upon the recently-described role of Th17 cells in this pathophysiological response. Recent findings: Studies in animal models and human genetic studies point to a role in the adaptive immune system as playing a contributory role in hypertension and renal tissue damage. Th17 cells, which produce the cytokine IL17, are strongly pro-inflammatory cells, which may contribute to tissue damage if expressed in chronic disease conditions. The activity of these cells may be enhanced by physiological factors associated with hypertension such as dietary salt or Ang II. This activity may culminate in the increased sodium retaining activity and exacerbation of inflammation and renal fibrosis via multiple cellular mechanisms. Summary: Th17 cells are a distinct component of the adaptive immune system that may strongly enhance pathways leading to increased sodium reabsorption, elevated vascular tone and end-organ damage. Moreover, this pathway may lend itself towards specific targeting for treatment of kidney disease and hypertension.Item Effects of indomethacin on lymphocyte populations in rabbit lymphoid tissues and peripheral blood(1991) Ennis, Keith EdwardItem Exploring the Tumor-Suppressing Potential of PSCA in Pancreatic Ductal Adenocarcinoma(MDPI, 2023-10-10) Li, Kexin; Huo, Qingji; Minami, Kazumasa; Tamari, Keisuke; Ogawa, Kazuhiko; Na, Sungsoo; Fishel, Melissa L.; Li, Bai-Yan; Yokota, Hiroki; Biomedical Engineering, School of Engineering and TechnologyPancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with low survival rates. We explored an innovative therapeutic approach by leveraging prognostic oncogenic markers. Instead of inhibiting these marker genes, we harnessed their tumor-modifying potential in the extracellular domain. Surprisingly, many of the proteins highly expressed in PDAC, which is linked to poor survival, exhibited tumor-suppressing qualities in the extracellular environment. For instance, prostate stem cell antigens (PSCA), associated with reduced survival, acted as tumor suppressors when introduced extracellularly. We performed in vitro assays to assess the proliferation and migration and evaluated the tumor-modifying capacity of extracellular factors from peripheral blood mononuclear cells (PBMCs) in PDAC tissues. Molecular docking analysis, immunoprecipitation, Western blotting, and RNA interference were employed to study the regulatory mechanism. Extracellular PSCA recombinant protein notably curtailed the viability, motility, and transwell invasion of PDAC cells. Its anti-PDAC effects were partially mediated by Mesothelin (MSLN), another highly expressed tumor-associated antigen in PDAC. The anti-tumor effects of extracellular PSCA complemented those of chemotherapeutic agents like Irinotecan, 5-Fluorouracil, and Oxaliplatin. PSCA expression increased in a conditioned medium derived from PBMCs and T lymphocytes. This study unveils the paradoxical anti-PDAC potential of PSCA, hinting at the dual roles of oncoproteins like PSCA in PDAC suppression.Item Field size effects on the risk and severity of treatment-induced lymphopenia in patients undergoing radiation therapy for solid tumors(Elsevier, 2018-10-23) Ellsworth, Susannah G.; Radiation Oncology, School of MedicinePurpose: Radiation-induced lymphopenia (RIL) is the result of direct toxicity to circulating lymphocytes as they traverse the irradiated field, occurs in 40% to 70% of patients who undergo conventional external beam radiation therapy, and is associated with worse outcomes in multiple solid tumors. As immunotherapy strategies evolve, a better understanding of radiation's effects on the immune system is needed in order to develop rational methods of combining RT with immunotherapy. Methods and materials: This paper is a review of the available literature on the clinical significance and dosimetric predictors of radiation-induced toxicity to the immune system. Results: An association between severe RIL and inferior survival has been described in multiple solid tumors, including glioma, lung cancer, and pancreatic cancer. RIL risk is correlated with field size, dose per fraction, and fraction number. SBRT and proton therapy techniques are associated with lower RIL risk. Conclusions: The immune system should be considered an organ at risk during RT, and absolute lymphocyte count is an important biomarker of RT-induced immunotoxicity. Radiation dose and technique affect the risk and severity of RIL. Further research is needed to accurately characterize RT-induced immunotoxicity and develop strategies to prevent or mitigate this clinically significant side effect.Item Inhibition of the mitogen-induced proliferation of human lymphocytes by chlamydia trachomatis(1990) Halvorson, Mark JohnItem Initial analysis of peripheral lymphocytic extracellular signal related kinase activation in autism(Elsevier, 2017-01) Erickson, Craig A.; Ray, Balmiki; Wink, Logan K.; Bayon, Baindu L.; Pedapat, Ernest V.; Shaffer, Rebecca; Schaefer, Tori L.; Lahiri, Debomoy K.; Psychiatry, School of MedicineBACKGROUND: Dysregulation of extracellular signal-related kinase (ERK) activity has been potentially implicated in the pathophysiology of autistic disorder (autism). ERK is part of a central intracellular signaling cascade responsible for a myriad of cellular functions. ERK is expressed in peripheral blood lymphocytes, and measurement of activated (phosphorylated) lymphocytic ERK is commonly executed in many areas of medicine. We sought to conduct the first study of ERK activation in humans with autism by utilizing a lymphocytic ERK activation assay. We hypothesized that ERK activation would be enhanced in peripheral blood lymphocytes from persons with autism compared to those of neurotypical control subjects. METHOD: We conducted an initial study of peripheral lymphocyte ERK activation in 45 subjects with autism and 26 age- and gender-matched control subjects (total n = 71). ERK activation was measured using a lymphocyte counting method (primary outcome expressed as lymphocytes staining positive for cytosolic phosphorylated ERK divided by total cells counted) and additional Western blot analysis of whole cell phosphorylated ERK adjusted for total ERK present in the lymphocyte lysate sample. RESULTS: Cytosolic/nuclear localization of pERK activated cells were increased by almost two-fold in the autism subject group compared to matched neurotypical control subjects (cell count ratio of 0.064 ± 0.044 versus 0.034 ± 0.031; p = 0.002). Elevated phosphorylated ERK levels in whole cell lysates also showed increased activated ERK in the autism group compared to controls (n = 54 total) in Western blot analysis. CONCLUSIONS: The results of this first in human ERK activation study are consistent with enhanced peripheral lymphocytic ERK activation in autism, as well as suggesting that cellular compartmentalization of activated ERK may be altered in this disorder. Future work will be required to explore the impact of concomitant medication use and other subject characteristics such as level of cognitive functioning on ERK activation.