470 results on '"Brusko, Todd M."'
Search Results
2. DHCR7 Expression Predicts Poor Outcomes and Mortality From Sepsis
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Guirgis, Faheem W, Jacob, Vinitha, Wu, Dongyuan, Henson, Morgan, Daly-Crews, Kimberly, Hopson, Charlotte, Black, Lauren Page, DeVos, Elizabeth L, Sulaiman, Dawoud, Labilloy, Guillaume, Brusko, Todd M, Shavit, Jordan A, Bertrand, Andrew, Feldhammer, Matthew, Baskovich, Brett, Graim, Kiley, Datta, Susmita, and Reddy, Srinivasa T
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Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Hematology ,Infectious Diseases ,Biotechnology ,Sepsis ,Detection ,screening and diagnosis ,Aetiology ,2.1 Biological and endogenous factors ,4.2 Evaluation of markers and technologies ,Inflammatory and immune system ,Infection ,Good Health and Well Being ,genetics ,lipids ,sepsis ,transcriptomics ,zebrafish ,Clinical sciences - Abstract
This is a study of lipid metabolic gene expression patterns to discover precision medicine for sepsis.ObjectivesSepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 d). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets.Design setting and particitpantsSecondary analysis of samples from prospectively enrolled sepsis patients (first 24 hr) and a zebrafish endotoxemia model for drug discovery. Patients were enrolled from the emergency department or ICU at an urban teaching hospital. Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing and reverse transcriptase polymerase chain reaction. A lipopolysaccharide zebrafish endotoxemia model was used for confirmation of human transcriptomic findings and drug discovery.Main outcomes and measuresThe derivation cohort included 96 patients and controls (12 early death, 13 CCI, 51 rapid recovery, and 20 controls) and the validation cohort had 52 patients (6 early death, 8 CCI, and 38 rapid recovery).ResultsThe cholesterol metabolism gene 7-dehydrocholesterol reductase (DHCR7) was significantly up-regulated in both derivation and validation cohorts in poor outcome sepsis compared with rapid recovery patients and in 90-day nonsurvivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed up-regulation of dhcr7 and several of the same lipid genes up-regulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1, and ldlra) compared with controls. We then tested six lipid-based drugs in the zebrafish endotoxemia model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from lipopolysaccharide death in a model with 100% lethality.ConclusionsDHCR7, an important cholesterol metabolism gene, was up-regulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.
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- 2023
3. Induction of bronchus-associated lymphoid tissue is an early life adaptation for promoting human B cell immunity
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Matsumoto, Rei, Gray, Joshua, Rybkina, Ksenia, Oppenheimer, Hanna, Levy, Lior, Friedman, Lilach M., Khamaisi, Muhammad, Meng, Wenzhao, Rosenfeld, Aaron M., Guyer, Rebecca S., Bradley, Marissa C., Chen, David, Atkinson, Mark A., Brusko, Todd M., Brusko, Maigan, Connors, Thomas J., Luning Prak, Eline T., Hershberg, Uri, Sims, Peter A., Hertz, Tomer, and Farber, Donna L.
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- 2023
- Full Text
- View/download PDF
4. A genomic data archive from the Network for Pancreatic Organ donors with Diabetes
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Perry, Daniel J., Shapiro, Melanie R., Chamberlain, Sonya W., Kusmartseva, Irina, Chamala, Srikar, Balzano-Nogueira, Leandro, Yang, Mingder, Brant, Jason O., Brusko, Maigan, Williams, MacKenzie D., McGrail, Kieran M., McNichols, James, Peters, Leeana D., Posgai, Amanda L., Kaddis, John S., Mathews, Clayton E., Wasserfall, Clive H., Webb-Robertson, Bobbie-Jo M., Campbell-Thompson, Martha, Schatz, Desmond, Evans-Molina, Carmella, Pugliese, Alberto, Concannon, Patrick, Anderson, Mark S., German, Michael S., Chamberlain, Chester E., Atkinson, Mark A., and Brusko, Todd M.
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- 2023
- Full Text
- View/download PDF
5. A hypolipoprotein sepsis phenotype indicates reduced lipoprotein antioxidant capacity, increased endothelial dysfunction and organ failure, and worse clinical outcomes
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Guirgis, Faheem W, Black, Lauren Page, Henson, Morgan, Labilloy, Guillaume, Smotherman, Carmen, Hopson, Charlotte, Tfirn, Ian, DeVos, Elizabeth L, Leeuwenburgh, Christiaan, Moldawer, Lyle, Datta, Susmita, Brusko, Todd M, Hester, Alexis, Bertrand, Andrew, Grijalva, Victor, Arango-Esterhay, Alexander, Moore, Frederick A, and Reddy, Srinivasa T
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Biomedical and Clinical Sciences ,Clinical Sciences ,Atherosclerosis ,Cardiovascular ,Sepsis ,Hematology ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Infection ,Good Health and Well Being ,Aged ,Antioxidants ,Biomarkers ,Cohort Studies ,Female ,Humans ,Hypolipoproteinemias ,Intensive Care Units ,Lipoproteins ,Longitudinal Studies ,Male ,Middle Aged ,Multiple Organ Failure ,Organ Dysfunction Scores ,Outcome Assessment ,Health Care ,Phenotype ,Prospective Studies ,Protective Factors ,Inflammation ,Lipids ,Lipoprotein ,Quality of life ,Shock ,Medical and Health Sciences ,Emergency & Critical Care Medicine ,Biomedical and clinical sciences ,Health sciences - Abstract
ObjectiveApproximately one-third of sepsis patients experience poor outcomes including chronic critical illness (CCI, intensive care unit (ICU) stay > 14 days) or early death (in-hospital death within 14 days). We sought to characterize lipoprotein predictive ability for poor outcomes and contribution to sepsis heterogeneity.DesignProspective cohort study with independent replication cohort.SettingEmergency department and surgical ICU at two hospitals.PatientsSepsis patients presenting within 24 h.MethodsMeasures included cholesterol levels (total cholesterol, high density lipoprotein cholesterol [HDL-C], low density lipoprotein cholesterol [LDL-C]), triglycerides, paraoxonase-1 (PON-1), and apolipoprotein A-I (Apo A-I) in the first 24 h. Inflammatory and endothelial markers, and sequential organ failure assessment (SOFA) scores were also measured. LASSO selection assessed predictive ability for outcomes. Unsupervised clustering was used to investigate the contribution of lipid variation to sepsis heterogeneity.Measurements and main results172 patients were enrolled. Most (~ 67%, 114/172) rapidly recovered, while ~ 23% (41/172) developed CCI, and ~ 10% (17/172) had early death. ApoA-I, LDL-C, mechanical ventilation, vasopressor use, and Charlson Comorbidity Score were significant predictors of CCI/early death in LASSO models. Unsupervised clustering yielded two discernible phenotypes. The Hypolipoprotein phenotype was characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1), higher SOFA scores, and worse clinical outcomes (45% rapid recovery, 40% CCI, 16% early death; 28-day mortality, 21%). The Normolipoprotein cluster patients had higher cholesterol levels, less endothelial dysfunction, lower SOFA scores and better outcomes (79% rapid recovery, 15% CCI, 6% early death; 28-day mortality, 15%). Phenotypes were validated in an independent replication cohort (N = 86) with greater sepsis severity, which similarly demonstrated lower HDL-C, ApoA-I, and higher ICAM-1 in the Hypolipoprotein cluster and worse outcomes (46% rapid recovery, 23% CCI, 31% early death; 28-day mortality, 42%). Normolipoprotein patients in the replication cohort had better outcomes (55% rapid recovery, 32% CCI, 13% early death; 28-day mortality, 28%) Top features for cluster discrimination were HDL-C, ApoA-I, total SOFA score, total cholesterol level, and ICAM-1.ConclusionsLipoproteins predicted poor sepsis outcomes. A Hypolipoprotein sepsis phenotype was identified and characterized by lower lipoprotein levels, increased endothelial dysfunction (ICAM-1) and organ failure, and worse clinical outcomes.
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- 2021
6. Low-Dose ATG/GCSF in Established Type 1 Diabetes: A Five-Year Follow-up Report.
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Lin, Andrea, Mack, Jasmine A, Bruggeman, Brittany, Jacobsen, Laura M, Posgai, Amanda L, Wasserfall, Clive H, Brusko, Todd M, Atkinson, Mark A, Gitelman, Stephen E, Gottlieb, Peter A, Gurka, Matthew J, Mathews, Clayton E, Schatz, Desmond A, and Haller, Michael J
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Diabetes ,Clinical Research ,Clinical Trials and Supportive Activities ,Metabolic and endocrine ,Antilymphocyte Serum ,Area Under Curve ,C-Peptide ,Diabetes Mellitus ,Type 1 ,Granulocyte Colony-Stimulating Factor ,Humans ,Pilot Projects ,Medical and Health Sciences ,Endocrinology & Metabolism - Abstract
Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes (n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data (n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo (P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders (n = 9) and nonresponders (n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA1c over 5 years (mean [95% CI] adjusted change 0.29% [-0.69%, 1.27%]), but the study was not powered for comparisons against nonresponders 1.75% (-0.57%, 4.06%) or placebo recipients 1.44% (0.21%, 2.66%). These data underscore the importance of long-term follow-up in previous and ongoing phase 2 trials of low-dose ATG in recent-onset type 1 diabetes.
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- 2021
7. Site-specific development and progressive maturation of human tissue-resident memory T cells over infancy and childhood
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Connors, Thomas J., Matsumoto, Rei, Verma, Shivali, Szabo, Peter A., Guyer, Rebecca, Gray, Joshua, Wang, Zicheng, Thapa, Puspa, Dogra, Pranay, Poon, Maya M.L., Rybkina, Ksenia, Bradley, Marissa C., Idzikowski, Emma, McNichols, James, Kubota, Masaru, Pethe, Kalpana, Shen, Yufeng, Atkinson, Mark A., Brusko, Maigan, Brusko, Todd M., Yates, Andrew J., Sims, Peter A., and Farber, Donna L.
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- 2023
- Full Text
- View/download PDF
8. Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes.
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Battaglia, Manuela, Ahmed, Simi, Anderson, Mark S, Atkinson, Mark A, Becker, Dorothy, Bingley, Polly J, Bosi, Emanuele, Brusko, Todd M, DiMeglio, Linda A, Evans-Molina, Carmella, Gitelman, Stephen E, Greenbaum, Carla J, Gottlieb, Peter A, Herold, Kevan C, Hessner, Martin J, Knip, Mikael, Jacobsen, Laura, Krischer, Jeffrey P, Long, S Alice, Lundgren, Markus, McKinney, Eoin F, Morgan, Noel G, Oram, Richard A, Pastinen, Tomi, Peters, Michael C, Petrelli, Alessandra, Qian, Xiaoning, Redondo, Maria J, Roep, Bart O, Schatz, Desmond, Skibinski, David, and Peakman, Mark
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Humans ,Diabetes Mellitus ,Type 1 ,Disease Progression ,Insulin ,Blood Glucose ,Phenotype ,Precision Medicine ,Biological Variation ,Population ,Clinical Trials and Supportive Activities ,Autoimmune Disease ,Diabetes ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Good Health and Well Being ,Medical and Health Sciences ,Endocrinology & Metabolism - Abstract
The clinical diagnosis of new-onset type 1 diabetes has, for many years, been considered relatively straightforward. Recently, however, there is increasing awareness that within this single clinical phenotype exists considerable heterogeneity: disease onset spans the complete age range; genetic susceptibility is complex; rates of progression differ markedly, as does insulin secretory capacity; and complication rates, glycemic control, and therapeutic intervention efficacy vary widely. Mechanistic and immunopathological studies typically show considerable patchiness across subjects, undermining conclusions regarding disease pathways. Without better understanding, type 1 diabetes heterogeneity represents a major barrier both to deciphering pathogenesis and to the translational effort of designing, conducting, and interpreting clinical trials of disease-modifying agents. This realization comes during a period of unprecedented change in clinical medicine, with increasing emphasis on greater individualization and precision. For complex disorders such as type 1 diabetes, the option of maintaining the "single disease" approach appears untenable, as does the notion of individualizing each single patient's care, obliging us to conceptualize type 1 diabetes less in terms of phenotypes (observable characteristics) and more in terms of disease endotypes (underlying biological mechanisms). Here, we provide our view on an approach to dissect heterogeneity in type 1 diabetes. Using lessons from other diseases and the data gathered to date, we aim to delineate a roadmap through which the field can incorporate the endotype concept into laboratory and clinical practice. We predict that such an effort will accelerate the implementation of precision medicine and has the potential for impact on our approach to translational research, trial design, and clinical management.
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- 2020
9. Human γδ T cells in diverse tissues exhibit site-specific maturation dynamics across the life span
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Gray, Joshua I., primary, Caron, Daniel P., additional, Wells, Steven B., additional, Guyer, Rebecca, additional, Szabo, Peter, additional, Rainbow, Daniel, additional, Ergen, Can, additional, Rybkina, Ksenia, additional, Bradley, Marissa C., additional, Matsumoto, Rei, additional, Pethe, Kalpana, additional, Kubota, Masaru, additional, Teichmann, Sarah, additional, Jones, Joanne, additional, Yosef, Nir, additional, Atkinson, Mark, additional, Brusko, Maigan, additional, Brusko, Todd M., additional, Connors, Thomas J., additional, Sims, Peter A., additional, and Farber, Donna L., additional
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- 2024
- Full Text
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10. Dual-Sized Microparticle System for Generating Suppressive Dendritic Cells Prevents and Reverses Type 1 Diabetes in the Nonobese Diabetic Mouse Model
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Lewis, Jamal S, Stewart, Joshua M, Marshall, Gregory P, Carstens, Matthew R, Zhang, Ying, Dolgova, Natalia V, Xia, Changqing, Brusko, Todd M, Wasserfall, Clive H, Clare-Salzler, Michael J, Atkinson, Mark A, and Keselowsky, Benjamin G
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Autoimmune Disease ,Prevention ,Immunization ,Diabetes ,Vaccine Related ,Metabolic and endocrine ,Inflammatory and immune system ,type 1 diabetes ,treatment ,PLGA ,microparticle ,biomaterial ,dendritic cell ,trafficking ,Biomedical Engineering - Abstract
Antigen specificity is a primary goal in developing curative therapies for autoimmune disease. Dendritic cells (DCs), as the most effective antigen presenting cells in the body, represent a key target to mediate restoration of antigen-specific immune regulation. Here, we describe an injectable, dual-sized microparticle (MP) approach that employs phagocytosable ∼1 μm and nonphagocytosable ∼30 μm MPs to deliver tolerance-promoting factors both intracellularly and extracellularly, as well as the type 1 diabetes autoantigen, insulin, to DCs for reprogramming of immune responses and remediation of autoimmunity. This poly(lactic-co-glycolic acid) (PLGA) MP system prevented diabetes onset in 60% of nonobese diabetic (NOD) mice when administered subcutaneously in 8 week old mice. Prevention of disease was dependent upon antigen inclusion and required encapsulation of factors in MPs. Moreover, administration of this "suppressive-vaccine" boosted pancreatic lymph node and splenic regulatory T cells (Tregs), upregulated PD-1 on CD4+ and CD8+ T cells, and reversed hyperglycemia for up to 100 days in recent-onset NOD mice. Our results demonstrate that a MP-based platform can reeducate the immune system in an antigen-specific manner, augment immunomodulation compared to soluble administration of drugs, and provide a promising alternative to systemic immunosuppression for autoimmunity.
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- 2019
11. A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells.
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Van Gool, Frédéric, Nguyen, Michelle LT, Mumbach, Maxwell R, Satpathy, Ansuman T, Rosenthal, Wendy L, Giacometti, Simone, Le, Duy T, Liu, Weihong, Brusko, Todd M, Anderson, Mark S, Rudensky, Alexander Y, Marson, Alexander, Chang, Howard Y, and Bluestone, Jeffrey A
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Th2 Cells ,Animals ,Mice ,Inbred C57BL ,Mice ,Knockout ,Humans ,Genetic Diseases ,X-Linked ,Polyendocrinopathies ,Autoimmune ,Cytokines ,Cell Differentiation ,Gene Expression Regulation ,Mutation ,Child ,Male ,T-Lymphocytes ,Regulatory ,Forkhead Transcription Factors ,Foxp3 ,GATA3 ,IPEX ,Th2-like Treg ,autoimmunity ,regulatory T cells ,Genetics ,Biotechnology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Underpinning research ,Aetiology ,Inflammatory and immune system ,Immunology - Abstract
Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells.
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- 2019
12. The immuneML ecosystem for machine learning analysis of adaptive immune receptor repertoires
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Pavlović, Milena, Scheffer, Lonneke, Motwani, Keshav, Kanduri, Chakravarthi, Kompova, Radmila, Vazov, Nikolay, Waagan, Knut, Bernal, Fabian L. M., Costa, Alexandre Almeida, Corrie, Brian, Akbar, Rahmad, Al Hajj, Ghadi S., Balaban, Gabriel, Brusko, Todd M., Chernigovskaya, Maria, Christley, Scott, Cowell, Lindsay G., Frank, Robert, Grytten, Ivar, Gundersen, Sveinung, Haff, Ingrid Hobæk, Hovig, Eivind, Hsieh, Ping-Han, Klambauer, Günter, Kuijjer, Marieke L., Lund-Andersen, Christin, Martini, Antonio, Minotto, Thomas, Pensar, Johan, Rand, Knut, Riccardi, Enrico, Robert, Philippe A., Rocha, Artur, Slabodkin, Andrei, Snapkov, Igor, Sollid, Ludvig M., Titov, Dmytro, Weber, Cédric R., Widrich, Michael, Yaari, Gur, Greiff, Victor, and Sandve, Geir Kjetil
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- 2021
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13. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization
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Fuchs, Anke, Gliwiński, Mateusz, Grageda, Nathali, Spiering, Rachel, Abbas, Abul K, Appel, Silke, Bacchetta, Rosa, Battaglia, Manuela, Berglund, David, Blazar, Bruce, Bluestone, Jeffrey A, Bornhäuser, Martin, Brinke, Anja ten, Brusko, Todd M, Cools, Nathalie, Cuturi, Maria Cristina, Geissler, Edward, Giannoukakis, Nick, Gołab, Karolina, Hafler, David A, van Ham, S Marieke, Hester, Joanna, Hippen, Keli, Di Ianni, Mauro, Ilic, Natasa, Isaacs, John, Issa, Fadi, Iwaszkiewicz-Grześ, Dorota, Jaeckel, Elmar, Joosten, Irma, Klatzmann, David, Koenen, Hans, van Kooten, Cees, Korsgren, Olle, Kretschmer, Karsten, Levings, Megan, Marek-Trzonkowska, Natalia Maria, Martinez-Llordella, Marc, Miljkovic, Djordje, Mills, Kingston HG, Miranda, Joana P, Piccirillo, Ciriaco A, Putnam, Amy L, Ritter, Thomas, Roncarolo, Maria Grazia, Sakaguchi, Shimon, Sánchez-Ramón, Silvia, Sawitzki, Birgit, Sofronic-Milosavljevic, Ljiljana, Sykes, Megan, Tang, Qizhi, Vives-Pi, Marta, Waldmann, Herman, Witkowski, Piotr, Wood, Kathryn J, Gregori, Silvia, Hilkens, Catharien MU, Lombardi, Giovanna, Lord, Phillip, Martinez-Caceres, Eva M, and Trzonkowski, Piotr
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Vaccine Related ,Autoimmune Disease ,Inflammatory and immune system ,minimum information model ,T regulatory cells ,immunotherapy ,good manufacturing practice ,cell therapy ,immune tolerance ,Immunology ,Medical Microbiology - Abstract
Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.
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- 2018
14. Data-driven selection of analysis decisions in single-cell RNA-seq trajectory inference
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Dong, Xiaoru, primary, Leary, Jack R, additional, Yang, Chuanhao, additional, Brusko, Maigan A, additional, Brusko, Todd M, additional, and Bacher, Rhonda, additional
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- 2024
- Full Text
- View/download PDF
15. The Post-Septic Peripheral Myeloid Compartment Reveals Unexpected Diversity in Myeloid-Derived Suppressor Cells
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Barrios, Evan L., primary, Leary, John, additional, Darden, Dijoia B., additional, Rincon, Jaimar C., additional, Willis, Micah, additional, Polcz, Valerie E., additional, Gillies, Gwendolyn S., additional, Munley, Jennifer A., additional, Dirain, Marvin L., additional, Ungaro, Ricardo, additional, Nacionales, Dina C., additional, Gauthier, Marie-Pierre L., additional, Larson, Shawn D., additional, Morel, Laurence, additional, Loftus, Tyler J., additional, Mohr, Alicia M., additional, Maile, Robert, additional, Kladde, Michael P., additional, Mathews, Clayton E., additional, Brusko, Maigan A., additional, Brusko, Todd M., additional, Moldawer, Lyle L., additional, Bacher, Rhonda, additional, and Efron, Philip A., additional
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- 2024
- Full Text
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16. Expansion of Human Tregs from Cryopreserved Umbilical Cord Blood for GMP-Compliant Autologous Adoptive Cell Transfer Therapy
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Seay, Howard R, Putnam, Amy L, Cserny, Judit, Posgai, Amanda L, Rosenau, Emma H, Wingard, John R, Girard, Kate F, Kraus, Morey, Lares, Angela P, Brown, Heather L, Brown, Katherine S, Balavage, Kristi T, Peters, Leeana D, Bushdorf, Ashley N, Atkinson, Mark A, Bluestone, Jeffrey A, Haller, Michael J, and Brusko, Todd M
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Biomedical and Clinical Sciences ,Immunology ,Stem Cell Research - Umbilical Cord Blood/ Placenta ,Stem Cell Research - Umbilical Cord Blood/ Placenta - Human ,Prevention ,Immunization ,Stem Cell Research - Nonembryonic - Human ,Vaccine Related ,Transplantation ,Autoimmune Disease ,Stem Cell Research ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,Inflammatory and immune system ,T cell receptor ,adoptive cell transfer ,autoimmunity ,cord blood ,good manufacturing practices ,regulatory T cell ,type 1 diabetes ,Medical biotechnology - Abstract
Umbilical cord blood is a traditional and convenient source of cells for hematopoietic stem cell transplantation. Thymic regulatory T cells (Tregs) are also present in cord blood, and there is growing interest in the use of autologous Tregs to provide a low-risk, fully human leukocyte antigen (HLA)-matched cell product for treating autoimmune diseases, such as type 1 diabetes. Here, we describe a good manufacturing practice (GMP)-compatible Treg expansion protocol using fluorescence-activated cell sorting, resulting in a mean 2,092-fold expansion of Tregs over a 16-day culture for a median yield of 1.26 × 109 Tregs from single-donor cryopreserved units. The resulting Tregs passed prior clinical trial release criteria for Treg purity and sterility, including additional rigorous assessments of FOXP3 and Helios expression and epigenetic analysis of the FOXP3 Treg-specific demethylated region (TSDR). Compared with expanded adult peripheral blood Tregs, expanded cord blood Tregs remained more naive, as assessed by continued expression of CD45RA, produced reduced IFN-γ following activation, and effectively inhibited responder T cell proliferation. Immunosequencing of the T cell receptor revealed a remarkably diverse receptor repertoire within cord blood Tregs that was maintained following in vitro expansion. These data support the feasibility of generating GMP-compliant Tregs from cord blood for adoptive cell transfer therapies and highlight potential advantages in terms of safety, phenotypic stability, autoantigen specificity, and tissue distribution.
- Published
- 2017
17. Avidity and Bystander Suppressive Capacity of Human Regulatory T Cells Expressing De Novo Autoreactive T-Cell Receptors in Type 1 Diabetes
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Yeh, Wen-I, Seay, Howard R, Newby, Brittney, Posgai, Amanda L, Moniz, Filipa Botelho, Michels, Aaron, Mathews, Clayton E, Bluestone, Jeffrey A, and Brusko, Todd M
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Biomedical and Clinical Sciences ,Immunology ,Autoimmune Disease ,Genetics ,Diabetes ,Biotechnology ,5.2 Cellular and gene therapies ,Development of treatments and therapeutic interventions ,Metabolic and endocrine ,Inflammatory and immune system ,type 1 diabetes ,regulatory T cells ,T cell receptor ,avidity ,suppression mechanisms ,adoptive cellular therapies ,antigen-specific T cells ,glutamic acid decarboxylase 65 ,Medical Microbiology ,Biochemistry and cell biology - Abstract
The ability to alter antigen specificity by T-cell receptor (TCR) or chimeric antigen receptor (CAR) gene transfer has facilitated personalized cellular immune therapies in cancer. Inversely, this approach can be harnessed in autoimmune settings to attenuate inflammation by redirecting the specificity of regulatory T cells (Tregs). Herein, we demonstrate efficient protocols for lentiviral gene transfer of TCRs that recognize type 1 diabetes-related autoantigens with the goal of tissue-targeted induction of antigen-specific tolerance to halt β-cell destruction. We generated human Tregs expressing a high-affinity GAD555-567-reactive TCR (clone R164), as well as the lower affinity clone 4.13 specific for the same peptide. We demonstrated that de novo Treg avatars potently suppress antigen-specific and bystander responder T-cell (Tresp) proliferation in vitro in a process that requires Treg activation (P
- Published
- 2017
18. Minimum Information about T Regulatory Cells: A Step toward Reproducibility and Standardization.
- Author
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Fuchs, Anke, Gliwiński, Mateusz, Grageda, Nathali, Spiering, Rachel, Abbas, Abul K, Appel, Silke, Bacchetta, Rosa, Battaglia, Manuela, Berglund, David, Blazar, Bruce, Bluestone, Jeffrey A, Bornhäuser, Martin, Ten Brinke, Anja, Brusko, Todd M, Cools, Nathalie, Cuturi, Maria Cristina, Geissler, Edward, Giannoukakis, Nick, Gołab, Karolina, Hafler, David A, van Ham, S Marieke, Hester, Joanna, Hippen, Keli, Di Ianni, Mauro, Ilic, Natasa, Isaacs, John, Issa, Fadi, Iwaszkiewicz-Grześ, Dorota, Jaeckel, Elmar, Joosten, Irma, Klatzmann, David, Koenen, Hans, van Kooten, Cees, Korsgren, Olle, Kretschmer, Karsten, Levings, Megan, Marek-Trzonkowska, Natalia Maria, Martinez-Llordella, Marc, Miljkovic, Djordje, Mills, Kingston HG, Miranda, Joana P, Piccirillo, Ciriaco A, Putnam, Amy L, Ritter, Thomas, Roncarolo, Maria Grazia, Sakaguchi, Shimon, Sánchez-Ramón, Silvia, Sawitzki, Birgit, Sofronic-Milosavljevic, Ljiljana, Sykes, Megan, Tang, Qizhi, Vives-Pi, Marta, Waldmann, Herman, Witkowski, Piotr, Wood, Kathryn J, Gregori, Silvia, Hilkens, Catharien MU, Lombardi, Giovanna, Lord, Phillip, Martinez-Caceres, Eva M, and Trzonkowski, Piotr
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T regulatory cells ,cell therapy ,good manufacturing practice ,immune tolerance ,immunotherapy ,minimum information model ,Autoimmune Disease ,Vaccine Related ,Inflammatory and Immune System ,Immunology ,Medical Microbiology - Abstract
Cellular therapies with CD4+ T regulatory cells (Tregs) hold promise of efficacious treatment for the variety of autoimmune and allergic diseases as well as posttransplant complications. Nevertheless, current manufacturing of Tregs as a cellular medicinal product varies between different laboratories, which in turn hampers precise comparisons of the results between the studies performed. While the number of clinical trials testing Tregs is already substantial, it seems to be crucial to provide some standardized characteristics of Treg products in order to minimize the problem. We have previously developed reporting guidelines called minimum information about tolerogenic antigen-presenting cells, which allows the comparison between different preparations of tolerance-inducing antigen-presenting cells. Having this experience, here we describe another minimum information about Tregs (MITREG). It is important to note that MITREG does not dictate how investigators should generate or characterize Tregs, but it does require investigators to report their Treg data in a consistent and transparent manner. We hope this will, therefore, be a useful tool facilitating standardized reporting on the manufacturing of Tregs, either for research purposes or for clinical application. This way MITREG might also be an important step toward more standardized and reproducible testing of the Tregs preparations in clinical applications.
- Published
- 2017
19. Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes
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Haller, Michael J, Gitelman, Stephen E, Gottlieb, Peter A, Michels, Aaron W, Perry, Daniel J, Schultz, Andrew R, Hulme, Maigan A, Shuster, Jonathan J, Zou, Baiming, Wasserfall, Clive H, Posgai, Amanda L, Mathews, Clayton E, Brusko, Todd M, Atkinson, Mark A, and Schatz, Desmond A
- Subjects
Prevention ,Diabetes ,Clinical Research ,Clinical Trials and Supportive Activities ,Metabolic and endocrine ,Good Health and Well Being ,Adolescent ,Adult ,Antilymphocyte Serum ,Area Under Curve ,C-Peptide ,CD4-Positive T-Lymphocytes ,CD56 Antigen ,CD8-Positive T-Lymphocytes ,Child ,Diabetes Mellitus ,Type 1 ,Female ,Forkhead Transcription Factors ,Granulocyte Colony-Stimulating Factor ,Humans ,Immunologic Factors ,Killer Cells ,Natural ,Male ,Middle Aged ,Monocytes ,Polyethylene Glycols ,Receptors ,CXCR3 ,Receptors ,IgG ,Recombinant Proteins ,T-Lymphocyte Subsets ,T-Lymphocytes ,Regulatory ,Young Adult ,Medical and Health Sciences ,Endocrinology & Metabolism - Abstract
Low-dose antithymocyte globulin (ATG) plus pegylated granulocyte colony-stimulating factor (G-CSF) preserves β-cell function for at least 12 months in type 1 diabetes. Herein, we describe metabolic and immunological parameters 24 months following treatment. Patients with established type 1 diabetes (duration 4-24 months) were randomized to ATG and pegylated G-CSF (ATG+G-CSF) (N = 17) or placebo (N = 8). Primary outcomes included C-peptide area under the curve (AUC) following a mixed-meal tolerance test (MMTT) and flow cytometry. "Responders" (12-month C-peptide ≥ baseline), "super responders" (24-month C-peptide ≥ baseline), and "nonresponders" (12-month C-peptide < baseline) were evaluated for biomarkers of outcome. At 24 months, MMTT-stimulated AUC C-peptide was not significantly different in ATG+G-CSF (0.49 nmol/L/min) versus placebo (0.29 nmol/L/min). Subjects treated with ATG+G-CSF demonstrated reduced CD4+ T cells and CD4+/CD8+ T-cell ratio and increased CD16+CD56hi natural killer cells (NK), CD4+ effector memory T cells (Tem), CD4+PD-1+ central memory T cells (Tcm), Tcm PD-1 expression, and neutrophils. FOXP3+Helios+ regulatory T cells (Treg) were elevated in ATG+G-CSF subjects at 6, 12, and 18 but not 24 months. Immunophenotyping identified differential HLA-DR expression on monocytes and NK and altered CXCR3 and PD-1 expression on T-cell subsets. As such, a group of metabolic and immunological responders was identified. A phase II study of ATG+G-CSF in patients with new-onset type 1 diabetes is ongoing and may support ATG+G-CSF as a prevention strategy in high-risk subjects.
- Published
- 2016
20. Immunophenotyping reveals distinct subgroups of lupus patients based on their activated T cell subsets
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Perry, Daniel J., Titov, Anton A., Sobel, Eric S., Brusko, Todd M., and Morel, Laurence
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- 2020
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21. A global view of T cell metabolism in systemic lupus erythematosus.
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Goetz, Andrew, Cagmat, Joy, Brusko, Maigan, Brusko, Todd M., Rushin, Anna, Merritt, Matthew, Garrett, Timothy, Morel, Laurence, and Dixit, Purushottam
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SYSTEMIC lupus erythematosus ,T cells ,CELL metabolism ,CELL physiology - Abstract
Impaired metabolism is recognized as an important contributor to pathogenicity of T cells in Systemic Lupus Erythematosus (SLE). Over the last two decades, we have acquired significant knowledge about the signaling and transcriptomic programs related to metabolic rewiring in healthy and SLE T cells. However, our understanding of metabolic network activity derives largely from studying metabolic pathways in isolation. Here, we argue that enzymatic activities are necessarily coupled through mass and energy balance constraints with in-built network-wide dependencies and compensation mechanisms. Therefore, metabolic rewiring of T cells in SLE must be understood in the context of the entire network, including changes in metabolic demands such as shifts in biomass composition and cytokine secretion rates as well as changes in uptake/excretion rates of multiple nutrients and waste products. As a way forward, we suggest cell physiology experiments and integration of orthogonal metabolic measurements through computational modeling towards a comprehensive understanding of T cell metabolism in lupus. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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22. Data-driven selection of analysis decisions in single-cell RNA-seq trajectory inference
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Dong, Xiaoru, primary, Leary, Jack R, additional, Yang, Chuanhao, additional, Brusko, Maigan A, additional, Brusko, Todd M, additional, and Bacher, Rhonda, additional
- Published
- 2023
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- View/download PDF
23. NADPH Oxidase 2–Derived Reactive Oxygen Species Promote CD8+ T Cell Effector Function
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Chen, Jing, primary, Liu, Chao, additional, Chernatynskaya, Anna V., additional, Newby, Brittney, additional, Brusko, Todd M., additional, Xu, Yuan, additional, Barra, Jessie M., additional, Morgan, Nadine, additional, Santarlas, Christopher, additional, Reeves, Westley H., additional, Tse, Hubert M., additional, Leiding, Jennifer W., additional, and Mathews, Clayton E., additional
- Published
- 2023
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24. Characterizing cell-type spatial relationships across length scales in spatially resolved omics data
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dos Santos Peixoto, Rafael, primary, Miller, Brendan F, additional, Brusko, Maigan A, additional, Atta, Lyla, additional, Anant, Manjari, additional, Atkinson, Mark A, additional, Brusko, Todd M, additional, Wasserfall, Clive H, additional, and Fan, Jean, additional
- Published
- 2023
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25. Teaching Type 1 Diabetes: Creating Stakeholder Engagement in Biomedical Careers Through Undergraduate Research Curriculum
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Walker, Ashby F., Atkinson, Mark A., Lee, Alexandra M., Aulisio, Gina, Brusko, Todd M., Haller, Michael J., and Schatz, Desmond A.
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- 2020
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26. Divergent Phenotypes of Human Regulatory T Cells Expressing the Receptors TIGIT and CD226
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Fuhrman, Christopher A, Yeh, Wen-I, Seay, Howard R, Saikumar Lakshmi, Priya, Chopra, Gaurav, Zhang, Lin, Perry, Daniel J, McClymont, Stephanie A, Yadav, Mahesh, Lopez, Maria-Cecilia, Baker, Henry V, Zhang, Ying, Li, Yizheng, Whitley, Maryann, von Schack, David, Atkinson, Mark A, Bluestone, Jeffrey A, and Brusko, Todd M
- Subjects
Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Adult ,Antigens ,Differentiation ,T-Lymphocyte ,CD4 Antigens ,Cell Differentiation ,Cell Lineage ,Forkhead Transcription Factors ,Gene Expression Profiling ,Humans ,Ikaros Transcription Factor ,Immunophenotyping ,Interleukin-10 ,Ligands ,Lymphocyte Activation ,Middle Aged ,Phenotype ,Primary Cell Culture ,Protein Binding ,Receptors ,Immunologic ,Receptors ,Virus ,T-Lymphocytes ,Regulatory ,Transcriptome ,Immunology - Abstract
Regulatory T cells (Tregs) play a central role in counteracting inflammation and autoimmunity. A more complete understanding of cellular heterogeneity and the potential for lineage plasticity in human Treg subsets may identify markers of disease pathogenesis and facilitate the development of optimized cellular therapeutics. To better elucidate human Treg subsets, we conducted direct transcriptional profiling of CD4(+)FOXP3(+)Helios(+) thymic-derived Tregs and CD4(+)FOXP3(+)Helios(-) T cells, followed by comparison with CD4(+)FOXP3(-)Helios(-) T conventional cells. These analyses revealed that the coinhibitory receptor T cell Ig and ITIM domain (TIGIT) was highly expressed on thymic-derived Tregs. TIGIT and the costimulatory factor CD226 bind the common ligand CD155. Thus, we analyzed the cellular distribution and suppressive activity of isolated subsets of CD4(+)CD25(+)CD127(lo/-) T cells expressing CD226 and/or TIGIT. We observed TIGIT is highly expressed and upregulated on Tregs after activation and in vitro expansion, and is associated with lineage stability and suppressive capacity. Conversely, the CD226(+)TIGIT(-) population was associated with reduced Treg purity and suppressive capacity after expansion, along with a marked increase in IL-10 and effector cytokine production. These studies provide additional markers to delineate functionally distinct Treg subsets that may help direct cellular therapies and provide important phenotypic markers for assessing the role of Tregs in health and disease.
- Published
- 2015
27. Anti-thymocyte globulin/G-CSF treatment preserves β cell function in patients with established type 1 diabetes
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Haller, Michael J, Gitelman, Stephen E, Gottlieb, Peter A, Michels, Aaron W, Rosenthal, Stephen M, Shuster, Jonathan J, Zou, Baiming, Brusko, Todd M, Hulme, Maigan A, Wasserfall, Clive H, Mathews, Clayton E, Atkinson, Mark A, and Schatz, Desmond A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,Clinical Research ,Clinical Trials and Supportive Activities ,Autoimmune Disease ,Diabetes ,Pediatric ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Metabolic and endocrine ,Adolescent ,Adult ,Antilymphocyte Serum ,C-Peptide ,Child ,Diabetes Mellitus ,Type 1 ,Drug Combinations ,Female ,Glycated Hemoglobin ,Granulocyte Colony-Stimulating Factor ,Humans ,Hypoglycemic Agents ,Insulin ,Insulin-Secreting Cells ,Male ,Middle Aged ,Polyethylene Glycols ,Single-Blind Method ,Treatment Outcome ,Young Adult ,Medical and Health Sciences ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundPrevious efforts to preserve β cell function in individuals with type 1 diabetes (T1D) have focused largely on the use of single immunomodulatory agents administered within 100 days of diagnosis. Based on human and preclinical studies, we hypothesized that a combination of low-dose anti-thymocyte globulin (ATG) and pegylated granulocyte CSF (G-CSF) would preserve β cell function in patients with established T1D (duration of T1D >4 months and
- Published
- 2015
28. Diabetes Study of Children of Diverse Ethnicity and Race: Study design.
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Redondo, Maria J., Harrall, Kylie K., Glueck, Deborah H., Tosur, Mustafa, Uysal, Serife, Muir, Andrew, Atkinson, Elizabeth G., Shapiro, Melanie R., Yu, Liping, Winter, William E., Weedon, Michael, Brusko, Todd M., Oram, Richard, Vehik, Kendra, Hagopian, William, Atkinson, Mark A., and Dabelea, Dana
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DIABETES in children ,GENETIC risk score ,RACE ,TYPE 1 diabetes ,EXPERIMENTAL design ,TYPE 2 diabetes - Abstract
Aims: Determining diabetes type in children has become increasingly difficult due to an overlap in typical characteristics between type 1 diabetes (T1D) and type 2 diabetes (T2D). The Diabetes Study in Children of Diverse Ethnicity and Race (DISCOVER) programme is a National Institutes of Health (NIH)‐supported multicenter, prospective, observational study that enrols children and adolescents with non‐secondary diabetes. The primary aim of the study was to develop improved models to differentiate between T1D and T2D in diverse youth. Materials and Methods: The proposed models will evaluate the utility of three existing T1D genetic risk scores in combination with data on islet autoantibodies and other parameters typically available at the time of diabetes onset. Low non‐fasting serum C‐peptide (<0.6 nmol/L) between 3 and 10 years after diabetes diagnosis will be considered a biomarker for T1D as it reflects the loss of insulin secretion ability. Participating centres are enrolling youth (<19 years old) either with established diabetes (duration 3–10 years) for a cross‐sectional evaluation or with recent onset diabetes (duration 3 weeks–15 months) for the longitudinal observation with annual visits for 3 years. Cross‐sectional data will be used to develop models. Longitudinal data will be used to externally validate the best‐fitting model. Results: The results are expected to improve the ability to classify diabetes type in a large and growing subset of children who have an unclear form of diabetes at diagnosis. Conclusions: Accurate and timely classification of diabetes type will help establish the correct clinical management early in the course of the disease. [ABSTRACT FROM AUTHOR]
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- 2024
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29. Low-Dose Antithymocyte Globulin: A Pragmatic Approach to Treating Stage 2 Type 1 Diabetes.
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Foster, Timothy P., Jacobsen, Laura M., Bruggeman, Brittany, Salmon, Chelsea, Hosford, Jennifer, Chen, Angela, Cintron, Miriam, Mathews, Clayton E., Wasserfall, Clive, Brusko, Maigan A., Brusko, Todd M., Atkinson, Mark A., Schatz, Desmond A., and Haller, Michael J.
- Subjects
TYPE 1 diabetes ,TYPE 2 diabetes ,CONTINUOUS glucose monitoring ,GLOBULINS - Abstract
OBJECTIVE: Low-dose antithymocyte globulin (ATG) (2.5 mg/kg) preserves C-peptide and reduces HbA
1c in new-onset stage 3 type 1 diabetes, yet efficacy in delaying progression from stage 2 to stage 3 has not been evaluated. RESEARCH DESIGN AND METHODS: Children (n = 6) aged 5–14 years with stage 2 type 1 diabetes received off-label, low-dose ATG. HbA1c , C-peptide, continuous glucose monitoring, insulin requirements, and side effects were followed for 18–48 months. RESULTS: Three subjects (50%) remained diabetes free after 1.5, 3, and 4 years of follow-up, while three developed stage 3 within 1–2 months after therapy. Eighteen months posttreatment, even disease progressors demonstrated near-normal HbA1c (5.1% [32 mmol/mol], 5.6% [38 mmol/mol], and 5.3% [34 mmol/mol]), time in range (93%, 88%, and 98%), low insulin requirements (0.17, 0.18, and 0.34 units/kg/day), and robust C-peptide 90 min after mixed meal (1.3 ng/dL, 2.3 ng/dL, and 1.4 ng/dL). CONCLUSIONS: These observations support additional prospective studies evaluating ATG in stage 2 type 1 diabetes. [ABSTRACT FROM AUTHOR]- Published
- 2024
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30. Human immune phenotyping reveals accelerated aging in type 1 diabetes
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Shapiro, Melanie R., primary, Dong, Xiaoru, additional, Perry, Daniel J., additional, McNichols, James M., additional, Thirawatananond, Puchong, additional, Posgai, Amanda L., additional, Peters, Leeana D., additional, Motwani, Keshav, additional, Musca, Richard S., additional, Muir, Andrew, additional, Concannon, Patrick, additional, Jacobsen, Laura M., additional, Mathews, Clayton E., additional, Wasserfall, Clive H., additional, Haller, Michael J., additional, Schatz, Desmond A., additional, Atkinson, Mark A., additional, Brusko, Maigan A., additional, Bacher, Rhonda, additional, and Brusko, Todd M., additional
- Published
- 2023
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- View/download PDF
31. Treg-specific CD226 Deletion Reduces Diabetes Incidence in NOD Mice by Improving Regulatory T Cell Stability
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Thirawatananond, Puchong, primary, Brown, Matthew E., additional, Sachs, Lindsey K., additional, Arnoletti, Juan M., additional, Yeh, Wen-I, additional, Posgai, Amanda L., additional, Shapiro, Melanie R., additional, Chen, Yi-Guang, additional, and Brusko, Todd M., additional
- Published
- 2023
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- View/download PDF
32. Responders to low-dose ATG induce CD4+ T cell exhaustion in type 1 diabetes
- Author
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Jacobsen, Laura M., primary, Diggins, Kirsten, additional, Blanchfield, Lori, additional, McNichols, James, additional, Perry, Daniel J., additional, Brant, Jason, additional, Dong, Xiaoru, additional, Bacher, Rhonda, additional, Gersuk, Vivian H., additional, Schatz, Desmond A., additional, Atkinson, Mark A., additional, Mathews, Clayton E., additional, Haller, Michael J., additional, Long, S. Alice, additional, Linsley, Peter S., additional, and Brusko, Todd M., additional
- Published
- 2023
- Full Text
- View/download PDF
33. Insulin-like Growth Factor-1 Synergizes with IL-2 to Induce Homeostatic Proliferation of Regulatory T Cells
- Author
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Shapiro, Melanie R., primary, Peters, Leeana D., additional, Brown, Matthew E., additional, Cabello-Kindelan, Cecilia, additional, Posgai, Amanda L., additional, Bayer, Allison L., additional, and Brusko, Todd M., additional
- Published
- 2023
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- View/download PDF
34. Single Cell RNA-SEQ of Human Myeloid Derived Suppressor Cells in Late Sepsis Reveals Multiple Subsets with Unique Transcriptional Responses: A Pilot Study
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Darden, Dijoia B., Bacher, Rhonda, Brusko, Maigan A., Knight, Parker, Hawkins, Russell B., Cox, Michael C., Dirain, Marvin L., Ungaro, Ricardo, Nacionales, Dina C., Rincon, Jaimar C., Gauthier, Marie-Pierre L., Kladde, Michael, Bihorac, Azra, Brusko, Todd M., Moore, Frederick A., Brakenridge, Scott C., Mohr, Alicia M., Moldawer, Lyle L., and Efron, Philip A.
- Published
- 2020
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35. Cross-reactive public TCR sequences undergo positive selection in the human thymic repertoire
- Author
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Khosravi-Maharlooei, Mohsen, Obradovic, Aleksandar, Misra, Aditya, Motwani, Keshav, Holzl, Markus, Seay, Howard R., DeWolf, Susan, Nauman, Grace, Danzl, Nichole, Li, Haowei, Ho, Siu- Hong, Winchester, Robert, Shen, Yufeng, Brusko, Todd M., and Sykes, Megan
- Subjects
B cells -- Analysis ,Natural selection -- Analysis ,Autoimmunity -- Analysis ,Hematopoietic stem cells -- Analysis ,Type 1 diabetes -- Analysis ,T cells -- Analysis ,Stem cell transplantation -- Analysis ,Stem cells ,Peptides ,Health care industry - Abstract
We studied human T cell repertoire formation using high-throughput T cell receptor [beta] (TCR[beta]) complementarity-determining region 3 (CDR3) sequencing in immunodeficient mice receiving human hematopoietic stem cells (HSCs) and human thymus grafts. Replicate humanized mice generated diverse and highly divergent repertoires. We observed repertoire narrowing and increased CDR3[beta] sharing during thymocyte selection. Whereas hydrophobicity analysis implicated self-peptides in positive selection of the overall repertoire, positive selection favored shorter shared sequences that had reduced hydrophobicity at positions 6 and 7 of CDR3[beta]s, suggesting weaker interactions with self-peptides than were observed with unshared sequences, possibly allowing escape from negative selection. Sharing was similar between autologous and allogeneic thymi and occurred between different cell subsets. Shared sequences were enriched for allo-cross-reactive CDR3[beta]s and for type 1 diabetes-associated autoreactive CDR3[beta]s. Single-cell TCR sequencing showed increased sharing of CDR3[alpha]s compared with CDR3[beta]s between mice. Our data collectively implicate preferential positive selection for shared human CDR3[beta]s that are highly cross-reactive. Although previous studies suggested a role for recombination bias in producing 'public' sequences in mice, our study is the first to our knowledge to demonstrate a role for thymic selection. Our results implicate positive selection for promiscuous TCR[beta] sequences that probably evade negative selection, given their low affinity for self-ligands, in the abundance of 'public' human TCR[beta] sequences., Introduction A functional TCR repertoire requires great diversity to recognize a wide range of pathogens. Extrapolations of early sequencing results on a few hundred T cell receptors (TCRs) led to [...]
- Published
- 2019
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36. Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells.
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Golovina, Tatiana N, Mikheeva, Tatiana, Brusko, Todd M, Blazar, Bruce R, Bluestone, Jeffrey A, and Riley, James L
- Subjects
T-Lymphocytes ,Humans ,Tretinoin ,Sirolimus ,Cytokines ,Cell Culture Techniques ,Coculture Techniques ,Cell Proliferation ,Drug Synergism ,T-Lymphocytes ,Regulatory ,Forkhead Transcription Factors ,Regulatory ,General Science & Technology - Abstract
Natural T regulatory cells (Tregs) are challenging to expand ex vivo, and this has severely hindered in vivo evaluation of their therapeutic potential. All trans retinoic acid (ATRA) plays an important role in mediating immune homeostasis in vivo, and we investigated whether ATRA could be used to promote the ex vivo expansion of Tregs purified from adult human peripheral blood. We found that ATRA helped maintain FOXP3 expression during the expansion process, but this effect was transient and serum-dependent. Furthermore, natural Tregs treated with rapamycin, but not with ATRA, suppressed cytokine production in co-cultured effector T cells. This suppressive activity correlated with the ability of expanded Tregs to induce FOXP3 expression in non-Treg cell populations. Examination of CD45RA+ and CD45RA- Treg subsets revealed that ATRA failed to maintain suppressive activity in either population, but interestingly, Tregs expanded in the presence of both rapamycin and ATRA displayed more suppressive activity and had a more favorable epigenetic status of the FOXP3 gene than Tregs expanded in the presence of rapamycin only. We conclude that while the use of ATRA as a single agent to expand Tregs for human therapy is not warranted, its use in combination with rapamycin may have benefit.
- Published
- 2011
37. Human antigen-specific regulatory T cells generated by T cell receptor gene transfer.
- Author
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Brusko, Todd M, Koya, Richard C, Zhu, Shirley, Lee, Michael R, Putnam, Amy L, McClymont, Stephanie A, Nishimura, Michael I, Han, Shuhong, Chang, Lung-Ji, Atkinson, Mark A, Ribas, Antoni, and Bluestone, Jeffrey A
- Subjects
CD4-Positive T-Lymphocytes ,Cells ,Cultured ,Animals ,Mice ,Inbred C57BL ,Humans ,Mice ,Lentivirus ,Receptors ,Antigen ,T-Cell ,Flow Cytometry ,Genetic Vectors ,Adult ,Female ,Male ,T-Lymphocytes ,Regulatory ,Young Adult ,Cells ,Cultured ,Inbred C57BL ,Receptors ,Antigen ,T-Cell ,T-Lymphocytes ,Regulatory ,General Science & Technology - Abstract
BackgroundTherapies directed at augmenting regulatory T cell (Treg) activities in vivo as a systemic treatment for autoimmune disorders and transplantation may be associated with significant off-target effects, including a generalized immunosuppression that may compromise beneficial immune responses to infections and cancer cells. Adoptive cellular therapies using purified expanded Tregs represents an attractive alternative to systemic treatments, with results from animal studies noting increased therapeutic potency of antigen-specific Tregs over polyclonal populations. However, current methodologies are limited in terms of the capacity to isolate and expand a sufficient quantity of endogenous antigen-specific Tregs for therapeutic intervention. Moreover, FOXP3+ Tregs fall largely within the CD4+ T cell subset and are thus routinely MHC class II-specific, whereas class I-specific Tregs may function optimally in vivo by facilitating direct tissue recognition.Methodology/principal findingsTo overcome these limitations, we have developed a novel means for generating large numbers of antigen-specific Tregs involving lentiviral T cell receptor (TCR) gene transfer into in vitro expanded polyclonal natural Treg populations. Tregs redirected with a high-avidity class I-specific TCR were capable of recognizing the melanoma antigen tyrosinase in the context of HLA-A*0201 and could be further enriched during the expansion process by antigen-specific reactivation with peptide loaded artificial antigen presenting cells. These in vitro expanded Tregs continued to express FOXP3 and functional TCRs, and maintained the capacity to suppress conventional T cell responses directed against tyrosinase, as well as bystander T cell responses. Using this methodology in a model tumor system, murine Tregs designed to express the tyrosinase TCR effectively blocked antigen-specific effector T cell (Teff) activity as determined by tumor cell growth and luciferase reporter-based imaging.Conclusions/significanceThese results support the feasibility of class I-restricted TCR transfer as a promising strategy to redirect the functional properties of Tregs and provide for a more efficacious adoptive cell therapy.
- Published
- 2010
38. Modeling cell-mediated immunity in human type 1 diabetes by engineering autoreactive CD8+ T cells
- Author
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Peters, Leeana D., primary, Yeh, Wen-I, additional, Arnoletti, Juan M., additional, Brown, Matthew E., additional, Posgai, Amanda L., additional, Mathews, Clayton E., additional, and Brusko, Todd M., additional
- Published
- 2023
- Full Text
- View/download PDF
39. Expansion of Human Regulatory T-Cells From Patients With Type 1 Diabetes
- Author
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Putnam, Amy L, Brusko, Todd M, Lee, Michael R, Liu, Weihong, Szot, Gregory L, Ghosh, Taumoha, Atkinson, Mark A, and Bluestone, Jeffrey A
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Clinical Research ,Autoimmune Disease ,Diabetes ,Inflammatory and immune system ,Adult ,Age of Onset ,Antigens ,CD ,CD4-Positive T-Lymphocytes ,Cell Division ,Cell Proliferation ,Cytokines ,Diabetes Mellitus ,Type 1 ,Female ,Flow Cytometry ,Forkhead Transcription Factors ,Humans ,Immunosuppression Therapy ,Ionomycin ,Male ,Phenotype ,Reference Values ,T-Lymphocytes ,Regulatory ,Tetradecanoylphorbol Acetate ,Young Adult ,Medical and Health Sciences ,Endocrinology & Metabolism ,Biomedical and clinical sciences - Abstract
ObjectiveRegulatory T-cells (Tregs) have catalyzed the field of immune regulation. However, translating Treg-based therapies from animal models of autoimmunity to human clinical trials requires robust methods for the isolation and expansion of these cells-a need forming the basis for these studies.Research design and methodsTregs from recent-onset type 1 diabetic patients and healthy control subjects were isolated by fluorescence-activated cell sorting and compared for their capacity to expand in vitro in response to anti-CD3-anti-CD28-coated microbeads and IL-2. Expanded cells were examined for suppressive function, lineage markers and FOXP3, and cytokine production.ResultsBoth CD4+CD127(lo/-) and CD4+CD127(lo/-)CD25+ T-cells could be expanded and used as Tregs. However, expansion of CD4+CD127(lo/-) cells required the addition of rapamycin to maintain lineage purity. In contrast, expansion of CD4+CD127(lo/-)CD25+ T-cells, especially the CD45RA+ subset, resulted in high yield, functional Tregs that maintained higher FOXP3 expression in the absence of rapamycin. Tregs from type 1 diabetic patients and control subjects expanded similarly and were equally capable of suppressing T-cell proliferation. Regulatory cytokines were produced by Tregs after culture; however, a portion of FOXP3+ cells were capable of producing interferon (IFN)-gamma after reactivation. IFN-gamma production was observed from both CD45RO+ and CD45RA+ Treg populations.ConclusionsThe results support the feasibility of isolating Tregs for in vitro expansion. Based on expansion capacity, FOXP3 stability, and functional properties, the CD4+CD127(lo/-)CD25+ T-cells represent a viable cell population for cellular therapy in this autoimmune disease.
- Published
- 2009
40. Oral therapy with colonization factor antigen I prevents development of type 1 diabetes in Non-obese Diabetic mice
- Author
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Nelson, Andrew S., Maddaloni, Massimo, Abbott, Jeffrey R., Hoffman, Carol, Akgul, Ali, Ohland, Christina, Gharaibeh, Raad Z., Jobin, Christian, Brusko, Todd M., and Pascual, David W.
- Published
- 2020
- Full Text
- View/download PDF
41. Data from Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment
- Author
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Delitto, Daniel, primary, Delitto, Andrea E., primary, DiVita, Bayli B., primary, Pham, Kien, primary, Han, Song, primary, Hartlage, Emily R., primary, Newby, Brittney N., primary, Gerber, Michael H., primary, Behrns, Kevin E., primary, Moldawer, Lyle L., primary, Thomas, Ryan M., primary, George, Thomas J., primary, Brusko, Todd M., primary, Mathews, Clayton E., primary, Liu, Chen, primary, Trevino, Jose G., primary, Hughes, Steven J., primary, and Wallet, Shannon M., primary
- Published
- 2023
- Full Text
- View/download PDF
42. Supplementary Figures 1 through 3 from Human Pancreatic Cancer Cells Induce a MyD88-Dependent Stromal Response to Promote a Tumor-Tolerant Immune Microenvironment
- Author
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Delitto, Daniel, primary, Delitto, Andrea E., primary, DiVita, Bayli B., primary, Pham, Kien, primary, Han, Song, primary, Hartlage, Emily R., primary, Newby, Brittney N., primary, Gerber, Michael H., primary, Behrns, Kevin E., primary, Moldawer, Lyle L., primary, Thomas, Ryan M., primary, George, Thomas J., primary, Brusko, Todd M., primary, Mathews, Clayton E., primary, Liu, Chen, primary, Trevino, Jose G., primary, Hughes, Steven J., primary, and Wallet, Shannon M., primary
- Published
- 2023
- Full Text
- View/download PDF
43. DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis
- Author
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Guirgis, Faheem W., primary, Jacob, Vinitha, additional, Wu, Dongyuan, additional, Henson, Morgan, additional, Daly-Crews, Kimberly, additional, Hopson, Charlotte, additional, Black, Lauren Page, additional, DeVos, Elizabeth L., additional, Sulaiman, Dawoud, additional, Labilloy, Guillaume, additional, Brusko, Todd M., additional, Shavit, Jordan A., additional, Bertrand, Andrew, additional, Feldhammer, Matthew, additional, Baskovich, Brett, additional, Graim, Kiley, additional, Datta, Susmita, additional, and Reddy, Srinivasa T., additional
- Published
- 2023
- Full Text
- View/download PDF
44. Pleiotropic roles of the insulin-like growth factor axis in type 1 diabetes
- Author
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Shapiro, Melanie R., Atkinson, Mark A., and Brusko, Todd M.
- Published
- 2019
- Full Text
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45. Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells
- Author
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Choi, Seung-Chul, Titov, Anton A., Abboud, Georges, Seay, Howard R., Brusko, Todd M., Roopenian, Derry C., Salek-Ardakani, Shahram, and Morel, Laurence
- Published
- 2018
- Full Text
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46. Immune engineered extracellular vesicles to modulate T cell activation in the context of type 1 diabetes
- Author
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Becker, Matthew W., primary, Peters, Leeana D., additional, Myint, Thinzar, additional, Brusko, Todd M., additional, and Phelps, Edward A., additional
- Published
- 2022
- Full Text
- View/download PDF
47. Biomaterials‐based nanoparticles conjugated to regulatory T cells provide a modular system for localized delivery of pharmacotherapeutic agents
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Marshall, Gregory P., primary, Cserny, Judit, additional, Wang, Chun‐Wei, additional, Looney, Benjamin, additional, Posgai, Amanda L., additional, Bacher, Rhonda, additional, Keselowsky, Benjamin, additional, and Brusko, Todd M., additional
- Published
- 2022
- Full Text
- View/download PDF
48. Modeling cell-mediated immunity in human type 1 diabetes by engineering autoreactive CD8+ T cells.
- Author
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Peters, Leeana D., Wen-I Yeh, Arnoletti, Juan M., Brown, Matthew E., Posgai, Amanda L., Mathews, Clayton E., and Brusko, Todd M.
- Subjects
TYPE 1 diabetes ,T cells ,CD25 antigen ,CELLULAR immunity ,GENETIC transformation ,REGULATORY T cells ,T cell receptors ,GRANZYMES ,CHIMERIC antigen receptors - Abstract
The autoimmune pathogenesis of type 1 diabetes (T1D) involves cellular infiltration from innate and adaptive immune subsets into the islets of Langerhans within the pancreas; however, the direct cytotoxic killing of insulin-producing b-cells is thought to be mediated primarily by antigenspecific CD8+ T cells. Despite this direct pathogenic role, key aspects of their receptor specificity and function remain uncharacterized, in part, due to their low precursor frequency in peripheral blood. The concept of engineering human T cell specificity, using T cell receptor (TCR) and chimeric antigen receptor (CAR)- based approaches, has been demonstrated to improve adoptive cell therapies for cancer, but has yet to be extensively employed for modeling and treating autoimmunity. To address this limitation, we sought to combine targeted genome editing of the endogenous TCRa chain gene (TRAC) via CRISPR/Cas9 in combination with lentiviral vector (LV)-mediated TCR gene transfer into primary human CD8+ T cells. We observed that knockout (KO) of endogenous TRAC enhanced de novo TCR pairing, which permitted increased peptide:MHCdextramer staining. Moreover, TRAC KO and TCR gene transfer increased markers of activation and effector function following activation, including granzyme B and interferon-g production. Importantly, we observed increased cytotoxicity toward an HLA-A*0201+ human b-cell line by HLA-A*02:01 restricted CD8+ T cells engineered to recognize islet-specific glucose-6-phosphatase catalytic subunit (IGRP). These data support the notion of altering the specificity of primary human T cells for mechanistic analyses of autoreactive antigen-specific CD8+ T cells and are expected to facilitate downstream cellular therapeutics to achieve tolerance induction through the generation of antigenspecific regulatory T cells. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
49. Immune Mechanisms and Pathways Targeted in Type 1 Diabetes
- Author
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Jacobsen, Laura M., Newby, Brittney N., Perry, Daniel J., Posgai, Amanda L., Haller, Michael J., and Brusko, Todd M.
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- 2018
- Full Text
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50. Deletion of CD226 in Foxp3+ T cells Reduces Diabetes Incidence in Non-Obese Diabetic Mice by Improving Regulatory T Cell Stability and Function
- Author
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Thirawatananond, Puchong, primary, Brown, Matthew E., additional, Sachs, Lindsey K., additional, Arnoletti, Juan M., additional, Yeh, Wen-I, additional, Posgai, Amanda L., additional, Shapiro, Melanie R., additional, Chen, Yi-Guang, additional, and Brusko, Todd M., additional
- Published
- 2022
- Full Text
- View/download PDF
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