Browsing by Subject "immune response"
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Item Combining Theoretical and Experimental Techniques to Study Murine Heart Transplant Rejection(Frontiers Media SA, 2016) Arciero, Julia C.; Maturo, Andrew; Arun, Anirudh; Oh, Byoung Chol; Brandacher, Gerald; Raimondi, Giorgio; Department of Mathematical Sciences, School of ScienceThe quality of life of organ transplant recipients is compromised by complications associated with life-long immunosuppression, such as hypertension, diabetes, opportunistic infections, and cancer. Moreover, the absence of established tolerance to the transplanted tissues causes limited long-term graft survival rates. Thus, there is a great medical need to understand the complex immune system interactions that lead to transplant rejection so that novel and effective strategies of intervention that redirect the system toward transplant acceptance (while preserving overall immune competence) can be identified. This study implements a systems biology approach in which an experimentally based mathematical model is used to predict how alterations in the immune response influence the rejection of mouse heart transplants. Five stages of conventional mouse heart transplantation are modeled using a system of 13 ordinary differential equations that tracks populations of both innate and adaptive immunity as well as proxies for pro- and anti-inflammatory factors within the graft and a representative draining lymph node. The model correctly reproduces known experimental outcomes, such as indefinite survival of the graft in the absence of CD4(+) T cells and quick rejection in the absence of CD8(+) T cells. The model predicts that decreasing the translocation rate of effector cells from the lymph node to the graft delays transplant rejection. Increasing the starting number of quiescent regulatory T cells in the model yields a significant but somewhat limited protective effect on graft survival. Surprisingly, the model shows that a delayed appearance of alloreactive T cells has an impact on graft survival that does not correlate linearly with the time delay. This computational model represents one of the first comprehensive approaches toward simulating the many interacting components of the immune system. Despite some limitations, the model provides important suggestions of experimental investigations that could improve the understanding of rejection. Overall, the systems biology approach used here is a first step in predicting treatments and interventions that can induce transplant tolerance while preserving the capacity of the immune system to protect against legitimate pathogens.Item Glucocorticoid Induced Leucine Zipper in Lipopolysaccharide Induced Neuroinflammation(Frontiers, 2019) Witek, Emily; Hickman, Debra; Lahiri, Debomoy K.; Srinivasan, Mythily; Oral Pathology, Medicine and Radiology, School of DentistryGlucocorticoids (GC) are steroid hormones secreted as the end-product of the neuroendocrine stress cascade. Both absence and elevated GC mediate neurotoxic responses, suggesting that a narrow window ranging from physiological to slightly high GC mediate protective responses. The beneficial effects of GC are attributed to the transactivation of regulatory proteins and inhibition mediated by glucocorticoid receptor interactions with other co-factors. The glucocorticoid induced leucine zipper (GILZ) is a gene strongly upregulated by GC and mediates many of the anti-inflammatory and anti-proliferative effects of GC. Although GILZ is constitutively expressed in many tissues including the brain, the expression has been shown to occur with varying dynamics suggesting that the local milieu modulates its expression with consequent effects on cellular responses. Here we investigated the expression profile of GILZ in lipopolysaccharide mediated neuroinflammation model of Alzheimer’s disease. Our data suggest that the GILZ expression is downregulated in neuroinflammation correlating inversely with the pro-inflammatory cytokines and innate immune responses.Item IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice(Elsevier, 2022-12-07) Butterfield, John S. S.; Yamada, Kentaro; Bertolini, Thais B.; Syed, Farooq; Kumar, Sandeep R. P.; Li, Xin; Arisa, Sreevani; Piñeros, Annie R.; Tapia, Alejandro; Rogers, Christopher A.; Li, Ning; Rana, Jyoti; Biswas, Moanaro; Terhorst, Cox; Kaufman, Randal J.; de Jong, Ype P.; Herzog, Roland W.; Pediatrics, School of MedicineHepatic adeno-associated viral (AAV) gene transfer has the potential to cure the X-linked bleeding disorder hemophilia A. However, declining therapeutic coagulation factor VIII (FVIII) expression has plagued clinical trials. To assess the mechanistic underpinnings of this loss of FVIII expression, we developed a hemophilia A mouse model that shares key features observed in clinical trials. Following liver-directed AAV8 gene transfer in the presence of rapamycin, initial FVIII protein expression declines over time in the absence of antibody formation. Surprisingly, loss of FVIII protein production occurs despite persistence of transgene and mRNA, suggesting a translational shutdown rather than a loss of transduced hepatocytes. Some of the animals develop ER stress, which may be linked to hepatic inflammatory cytokine expression. FVIII protein expression is preserved by interleukin-15/interleukin-15 receptor blockade, which suppresses CD8+ T and natural killer cell responses. Interestingly, mice with initial FVIII levels >100% of normal had diminishing expression while still under immune suppression. Taken together, our findings of interanimal variability of the response, and the ability of the immune system to shut down transgene expression without utilizing cytolytic or antibody-mediated mechanisms, illustrate the challenges associated with FVIII gene transfer. Our protocols based upon cytokine blockade should help to maintain efficient FVIII expression.Item The national blueprint for future basic and translational research to understand factor VIII immunogenicity: NHLBI State of the Science Workshop on factor VIII inhibitors(Wiley, 2019-07) Meeks, Shannon L.; Herzog, Roland W.; Pediatrics, School of MedicineIntroduction Inhibitor formation against coagulation factor VIII (FVIII) is an unresolved serious problem in replacement therapy for the X‐linked bleeding disorder haemophilia A. Although FVIII inhibitors have been extensively studied, much of the basic mechanism of this immune response remains to be uncovered. Aim Within the NHLBI State of the Science Workshop on Factor VIII Inhibitors, Working Group 3 identified three scientific priorities for basic and translational research on FVIII inhibitor formation. Methods A larger list of potential areas of research was initially developed as a basis for subsequent prioritization. Each scientific goal was further evaluated based on required effort, potential impact, approach, methods, technologies and models. Results The three priorities include the following: activation signals and immune regulation that shape the response to FVIII (including innate immunity, microbiome, adaptive immunity and regulatory T cell studies in humans); utility of animal models and non‐animal approaches (in silico, genetic, single‐cell/sorted population “omics,” in vitro) to help predict inhibitor formation and identify novel therapeutics; and impact of the source of FVIII, its structure and von Willebrand factor on immunogenicity and tolerance. Conclusions Early interactions between FVIII and the immune system, biomarker development and studies in different patient groups (previously treated or untreated, with or without inhibitor formation, patients undergoing immune tolerance induction or gene therapy) deserve particular emphasis. Finally, linking basic to clinical studies, development of a repository for biospecimens and opportunities for interdisciplinary research training are important components to solving the urgent problem of inhibitor formation.Item Predicting Experimental Sepsis Survival with a Mathematical Model of Acute Inflammation(Frontiers, 2021-11) Barber, Jared; Carpenter, Amy; Torsey, Allison; Borgard, Tyler; Namas, Rami A.; Vodovotz, Yoram; Arciero, Julia; Mathematical Sciences, School of ScienceSepsis is characterized by an overactive, dysregulated inflammatory response that drives organ dysfunction and often results in death. Mathematical modeling has emerged as an essential tool for understanding the underlying complex biological processes. A system of four ordinary differential equations (ODEs) was developed to simulate the dynamics of bacteria, the pro- and anti-inflammatory responses, and tissue damage (whose molecular correlate is damage-associated molecular pattern [DAMP] molecules and which integrates inputs from the other variables, feeds back to drive further inflammation, and serves as a proxy for whole-organism health status). The ODE model was calibrated to experimental data from E. coli infection in genetically identical rats and was validated with mortality data for these animals. The model demonstrated recovery, aseptic death, or septic death outcomes for a simulated infection while varying the initial inoculum, pathogen growth rate, strength of the local immune response, and activation of the pro-inflammatory response in the system. In general, more septic outcomes were encountered when the initial inoculum of bacteria was increased, the pathogen growth rate was increased, or the host immune response was decreased. The model demonstrated that small changes in parameter values, such as those governing the pathogen or the immune response, could explain the experimentally observed variability in mortality rates among septic rats. A local sensitivity analysis was conducted to understand the magnitude of such parameter effects on system dynamics. Despite successful predictions of mortality, simulated trajectories of bacteria, inflammatory responses, and damage were closely clustered during the initial stages of infection, suggesting that uncertainty in initial conditions could lead to difficulty in predicting outcomes of sepsis by using inflammation biomarker levels.Item SLAMF6 in health and disease: Implications for therapeutic targeting(Elsevier, 2018) Yigit, Burcu; Wang, Ninghai; Herzog, Roland W.; Terhorst, Cox; Pediatrics, School of MedicineItem Temporospatial Analysis and New Players in the Immunology of Amyotrophic Lateral Sclerosis(MDPI, 2018-02-23) Iyer, Abhirami K.; Jones, Kathryn J.; Sanders, Virginia M.; Walker, Chandler L.; Biomedical and Applied Sciences, School of DentistryAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive loss of lower and upper motor neurons (MN) leading to muscle weakness, paralysis and eventually death. Although a highly varied etiology results in ALS, it broadly manifests itself as sporadic and familial forms that have evident similarities in clinical symptoms and disease progression. There is a tremendous amount of knowledge on molecular mechanisms leading to loss of MNs and neuromuscular junctions (NMJ) as major determinants of disease onset, severity and progression in ALS. Specifically, two main opposing hypotheses, the dying forward and dying back phenomena, exist to account for NMJ denervation. The former hypothesis proposes that the earliest degeneration occurs at the central MNs and proceeds to the NMJ, whereas in the latter, the peripheral NMJ is the site of precipitating degeneration progressing backwards to the MN cell body. A large body of literature strongly indicates a role for the immune system in disease onset and progression via regulatory involvement at the level of both the central and peripheral nervous systems (CNS and PNS). In this review, we discuss the earliest reported immune responses with an emphasis on newly identified immune players in mutant superoxide dismutase 1 (mSOD1) transgenic mice, the gold standard mouse model for ALS.