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Hematopoietic Stem Cell Mobilization Is Necessary but Not Sufficient for Tolerance in Islet Transplantation.
Stocks BT, Thomas AB, Elizer SK, Zhu Y, Marshall AF, Wilson CS, Moore DJ
(2017) Diabetes 66: 127-133
MeSH Terms: Allografts, Animals, Female, Flow Cytometry, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cell Transplantation, Islets of Langerhans Transplantation, Leukocyte Common Antigens, Mice, Mice, Inbred NOD, Osteoblasts
Show Abstract · Added November 1, 2016
Overcoming the immune response to establish durable immune tolerance in type 1 diabetes remains a substantial challenge. The ongoing effector immune response involves numerous immune cell types but is ultimately orchestrated and sustained by the hematopoietic stem cell (HSC) niche. We therefore hypothesized that tolerance induction also requires these pluripotent precursors. In this study, we determined that the tolerance-inducing agent anti-CD45RB induces HSC mobilization in nonautoimmune B6 mice but not in diabetes-prone NOD mice. Ablation of HSCs impaired tolerance to allogeneic islet transplants in B6 recipients. Mobilization of HSCs resulted in part from decreasing osteoblast expression of HSC retention factors. Furthermore, HSC mobilization required a functioning sympathetic nervous system; sympathectomy prevented HSC mobilization and completely abrogated tolerance induction. NOD HSCs were held in their niche by excess expression of CXCR4, which, when blocked, led to HSC mobilization and prolonged islet allograft survival. Overall, these findings indicate that the HSC compartment plays an underrecognized role in the establishment and maintenance of immune tolerance, and this role is disrupted in diabetes-prone NOD mice. Understanding the stem cell response to immune therapies in ongoing human clinical studies may help identify and maximize the effect of immune interventions for type 1 diabetes.
© 2017 by the American Diabetes Association.
0 Communities
1 Members
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11 MeSH Terms
Single cell analysis of human tissues and solid tumors with mass cytometry.
Leelatian N, Doxie DB, Greenplate AR, Mobley BC, Lehman JM, Sinnaeve J, Kauffmann RM, Werkhaven JA, Mistry AM, Weaver KD, Thompson RC, Massion PP, Hooks MA, Kelley MC, Chambless LB, Ihrie RA, Irish JM
(2017) Cytometry B Clin Cytom 92: 68-78
MeSH Terms: Antigens, CD, Flow Cytometry, HLA-DR Antigens, Humans, Jurkat Cells, Leukocyte Common Antigens, Neoplasms, Single-Cell Analysis
Show Abstract · Added September 7, 2016
BACKGROUND - Mass cytometry measures 36 or more markers per cell and is an appealing platform for comprehensive phenotyping of cells in human tissue and tumor biopsies. While tissue disaggregation and fluorescence cytometry protocols were pioneered decades ago, it is not known whether established protocols will be effective for mass cytometry and maintain cancer and stromal cell diversity.
METHODS - Tissue preparation techniques were systematically compared for gliomas and melanomas, patient derived xenografts of small cell lung cancer, and tonsil tissue as a control. Enzymes assessed included DNase, HyQTase, TrypLE, collagenase (Col) II, Col IV, Col V, and Col XI. Fluorescence and mass cytometry were used to track cell subset abundance following different enzyme combinations and treatment times.
RESULTS - Mechanical disaggregation paired with enzymatic dissociation by Col II, Col IV, Col V, or Col XI plus DNase for 1 h produced the highest yield of viable cells per gram of tissue. Longer dissociation times led to increasing cell death and disproportionate loss of cell subsets. Key markers for establishing cell identity included CD45, CD3, CD4, CD8, CD19, CD64, HLA-DR, CD11c, CD56, CD44, GFAP, S100B, SOX2, nestin, vimentin, cytokeratin, and CD31. Mass and fluorescence cytometry identified comparable frequencies of cancer cell subsets, leukocytes, and endothelial cells in glioma (R = 0.97), and tonsil (R = 0.98).
CONCLUSIONS - This investigation establishes standard procedures for preparing viable single cell suspensions that preserve the cellular diversity of human tissue microenvironments. © 2016 International Clinical Cytometry Society.
© 2016 International Clinical Cytometry Society.
3 Communities
4 Members
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8 MeSH Terms
Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment.
Kordasti S, Costantini B, Seidl T, Perez Abellan P, Martinez Llordella M, McLornan D, Diggins KE, Kulasekararaj A, Benfatto C, Feng X, Smith A, Mian SA, Melchiotti R, de Rinaldis E, Ellis R, Petrov N, Povoleri GA, Chung SS, Thomas NS, Farzaneh F, Irish JM, Heck S, Young NS, Marsh JC, Mufti GJ
(2016) Blood 128: 1193-205
MeSH Terms: Adult, Aged, Anemia, Aplastic, Female, Forkhead Transcription Factors, Humans, Immunologic Memory, Immunosuppression, Interleukin-2, Interleukin-7 Receptor alpha Subunit, Leukocyte Common Antigens, Male, Middle Aged, Receptors, CCR4, STAT5 Transcription Factor, T-Lymphocytes, Regulatory, fas Receptor
Show Abstract · Added June 10, 2016
Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in vitro expandability for potential clinical use. Using mass cytometry and an unbiased multidimensional analytical approach, we identified 2 specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene expression, expandability, and function. Treg B predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4, and CD45RO within FOXP3(hi), CD127(lo) Tregs), expresses the interleukin-2 (IL-2)/STAT5 pathway and cell-cycle commitment genes. Furthermore, in vitro-expanded Tregs become functional and take on the characteristics of Treg B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2-sensitive and expandable in vitro, suggesting novel therapeutic approaches such as low-dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration.
2 Communities
1 Members
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17 MeSH Terms
Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes β cell regeneration.
Brissova M, Aamodt K, Brahmachary P, Prasad N, Hong JY, Dai C, Mellati M, Shostak A, Poffenberger G, Aramandla R, Levy SE, Powers AC
(2014) Cell Metab 19: 498-511
MeSH Terms: Animals, Antibiotics, Antineoplastic, Cell Differentiation, Cell Proliferation, Doxorubicin, Endothelial Cells, Gene Expression Profiling, Humans, Insulin-Secreting Cells, Islets of Langerhans, Islets of Langerhans Transplantation, Leukocyte Common Antigens, Macrophages, Mice, Mice, Inbred C57BL, Mice, Transgenic, Regeneration, Signal Transduction, Vascular Endothelial Growth Factor A
Show Abstract · Added June 1, 2014
Pancreatic islet endocrine cell and endothelial cell (EC) interactions mediated by vascular endothelial growth factor-A (VEGF-A) signaling are important for islet differentiation and the formation of highly vascularized islets. To dissect how VEGF-A signaling modulates intra-islet vasculature, islet microenvironment, and β cell mass, we transiently increased VEGF-A production by β cells. VEGF-A induction dramatically increased the number of intra-islet ECs but led to β cell loss. After withdrawal of the VEGF-A stimulus, β cell mass, function, and islet structure normalized as a result of a robust, but transient, burst in proliferation of pre-existing β cells. Bone marrow-derived macrophages (MΦs) recruited to the site of β cell injury were crucial for the β cell proliferation, which was independent of pancreatic location and circulating factors such as glucose. Identification of the signals responsible for the proliferation of adult, terminally differentiated β cells will improve strategies aimed at β cell regeneration and expansion.
Copyright © 2014 Elsevier Inc. All rights reserved.
2 Communities
2 Members
0 Resources
19 MeSH Terms
The diagnosis of insulitis in human type 1 diabetes.
Campbell-Thompson ML, Atkinson MA, Butler AE, Chapman NM, Frisk G, Gianani R, Giepmans BN, von Herrath MG, Hyöty H, Kay TW, Korsgren O, Morgan NG, Powers AC, Pugliese A, Richardson SJ, Rowe PA, Tracy S, In't Veld PA
(2013) Diabetologia 56: 2541-3
MeSH Terms: Diabetes Mellitus, Type 1, Humans, Immunohistochemistry, Islets of Langerhans, Leukocyte Common Antigens
Added July 16, 2016
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1 Members
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5 MeSH Terms
High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells.
Myklebust JH, Irish JM, Brody J, Czerwinski DK, Houot R, Kohrt HE, Timmerman J, Said J, Green MR, Delabie J, Kolstad A, Alizadeh AA, Levy R
(2013) Blood 121: 1367-76
MeSH Terms: CD4-Positive T-Lymphocytes, Cell Separation, Cells, Cultured, Child, Cytokines, E-Selectin, Flow Cytometry, Histiocytes, Humans, Interleukin-10, Interleukin-4, Interleukins, Leukocyte Common Antigens, Lymphoma, Follicular, Palatine Tonsil, Programmed Cell Death 1 Receptor, Signal Transduction, Tumor Microenvironment
Show Abstract · Added February 15, 2013
Defects in T-cell function in patients with cancer might influence their capacity to mount efficient antitumor immune responses. Here, we identified highly reduced IL-4-, IL-10-, and IL-21-induced phosphorylation of STAT6 and STAT3 in tumor-infiltrating T cells (TILs) in follicular lymphoma (FL) tumors, contrasting other non-Hodgkin lymphoma TILs. By combining phospho-protein-specific flow cytometry with several T-cell markers, we identified that CD4(+)CD45RO(+)CD62L(-) FL TILs were largely nonresponsive to cytokines, in contrast to the corresponding autologous peripheral blood subset. We observed differential expression of the inhibitory receptor PD-1 in FL TILs and peripheral blood T cells. Furthermore, CD4(+)PD-1(hi) FL TILs, containing T(FH) and non-T(FH) cells, had lost their cytokine responsiveness, whereas PD-1 TILs had normal cytokine signaling. However, this phenomenon was not tumor specific, because tonsil T cells were similar to FL TILs. FL tumor cells were negative for PD-1 ligands, but PD-L1(+) histiocytes were found within the T cell-rich zone of the neoplastic follicles. Disruption of the microenvironment and in vitro culture of FL TILs could restore cytokine signaling in the PD-1(hi) subset. Because FL TILs in vivo probably receive suppressive signals through PD-1, this provides a rationale for testing PD-1 Ab in combination with immunotherapy in patients with FL.
1 Communities
1 Members
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18 MeSH Terms
Feasibility and acute healing of vocal fold microflap incisions in a rabbit model.
Suehiro A, Bock JM, Hall JE, Garrett CG, Rousseau B
(2012) Laryngoscope 122: 600-5
MeSH Terms: Animals, Disease Models, Animal, Feasibility Studies, Follow-Up Studies, Immunohistochemistry, Leukocyte Common Antigens, Prospective Studies, Rabbits, Surgical Flaps, Treatment Outcome, Vocal Cords, Voice Disorders, Wound Healing
Show Abstract · Added February 12, 2015
OBJECTIVES/HYPOTHESIS - The purpose of this study was to investigate the feasibility of performing mucosal elevation of a vocal fold microflap in a rabbit model and to measure the acute healing of rabbit microflap incisions compared to control vocal folds.
STUDY DESIGN - Prospective animal study.
METHODS - Ten New Zealand white rabbits were used in this study. All rabbits received a 3-mm incision through the epithelium of one vocal fold using a sickle knife and mucosal elevation through this incision using a microlaryngeal fine-angled spatula. The contralateral vocal fold was left intact to serve as an internal control. Student t tests were used to investigate differences in epithelial thickness, immunohistochemical staining of CD45, and inflammatory and profibrotic gene expression between vocal folds undergoing microflap and control.
RESULTS - Exposure of the rabbit larynx was achieved, allowing for the identification of a surgical plane and the creation of a microflap and elevation of the vocal fold mucosa. Hematoxylin-and-eosin staining revealed no significant differences in epithelial thickness, immunohistochemistry for CD45 showed no significant differences in CD45-positive cells, and quantitative polymerase chain reaction revealed no significant differences in interleukin-1β, transforming growth factor β-1, or cyclooxygenase-2 gene expression between vocal folds undergoing microflap and control.
CONCLUSIONS - We demonstrate the feasibility of vocal fold microflap surgery in a rabbit model. With the advantage of greater access to primers and antibodies for molecular biologic studies, the application of the microflap technique in a small-animal model such as rabbit has broad implications for future experimental investigations in laryngology.
Copyright © 2011 The American Laryngological, Rhinological, and Otological Society, Inc.
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13 MeSH Terms
Isolation & characterization of Hoechst(low) CD45(negative) mouse lung mesenchymal stem cells.
Chow KS, Jun D, Helm KM, Wagner DH, Majka SM
(2011) J Vis Exp : e3159
MeSH Terms: Animals, Benzimidazoles, Cell Separation, Cytological Techniques, Flow Cytometry, Leukocyte Common Antigens, Lung, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL
Show Abstract · Added August 4, 2015
Tissue resident mesenchymal stem cells (MSC) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Taken together these studies suggest that resident lung MSC play a role during pulmonary tissue homeostasis, injury and repair during diseases such as pulmonary fibrosis (PF) and arterial hypertension (PAH). Here we describe a technology to define a population of resident lung MSC. The definition of this population in vivo pulmonary tissue using a define set of markers facilitates the repeated isolation of a well-characterized stem cell population by flow cytometry and the study of a specific cell type and function.
1 Communities
1 Members
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10 MeSH Terms
Inhibition of transplantation tolerance by immune senescence is reversed by endocrine modulation.
Zhao G, Moore DJ, Kim JI, Lee KM, O'Connor MR, Duff PE, Yang M, Lei J, Markmann JF, Deng S
(2011) Sci Transl Med 3: 87ra52
MeSH Terms: Aging, Animals, Antineoplastic Agents, Hormonal, Castration, Endocrine System, Gonads, Heart Transplantation, Humans, Immune System, Leukocyte Common Antigens, Leuprolide, Male, Mice, Mice, Inbred C3H, Mice, Inbred C57BL, Thymectomy, Thymus Gland, Transplantation Tolerance, Transplantation, Homologous
Show Abstract · Added October 24, 2013
The senescent immune system responds poorly to new stimuli; thymic involution, accumulation of memory cells against other specificities, and general refractoriness to antigen signaling all may contribute to poor resistance to infection. These same changes may pose a significant clinical barrier to organ transplantation, as transplantation tolerance requires thymic participation and integrated, tolerance-promoting responses to novel antigens. We found that after the age of 12 months, mice became resistant to the tolerance-inducing capacity of the monoclonal antibody therapy anti-CD45RB. This resistance to tolerance to cardiac allografts could be overcome by surgical castration of male mice, a procedure that led to thymic regeneration and long-term graft acceptance. The potential for clinical translation of this endocrine-immune interplay was confirmed by the ability of Lupron Depot injections, which temporarily disrupt gonadal function, to restore tolerance in aged mice. Furthermore, we demonstrated that the restoration of tolerance after surgical or chemical castration depended on thymic production of regulatory T cells (T(regs)); thymectomy or T(reg) depletion abrogated tolerance restoration. The aging of the immune system ("immune senescence") is a significant barrier to immune tolerance, but this barrier can be overcome by targeting sex steroid production with commonly used clinical therapeutics.
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19 MeSH Terms
The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR.
Liu G, Burns S, Huang G, Boyd K, Proia RL, Flavell RA, Chi H
(2009) Nat Immunol 10: 769-77
MeSH Terms: Adoptive Transfer, Animals, Animals, Newborn, CD4-Positive T-Lymphocytes, Carrier Proteins, Cell Differentiation, Colon, Female, Flow Cytometry, Forkhead Transcription Factors, Homeostasis, Immune Tolerance, Interleukin-2 Receptor alpha Subunit, Leukocyte Common Antigens, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Phosphotransferases (Alcohol Group Acceptor), Proto-Oncogene Proteins c-akt, Receptors, Lysosphingolipid, Signal Transduction, T-Lymphocytes, Regulatory, TOR Serine-Threonine Kinases, Thymus Gland
Show Abstract · Added March 5, 2014
Regulatory T cells (T(reg) cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P1) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of T(reg) cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic T(reg) precursors and function of mature T(reg) cells and affected T(reg) cell-mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of T(reg) cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing T(reg) cell-mediated immune suppression, the lipid-activated S1P1-Akt-mTOR pathway orchestrates adaptive immune responses.
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26 MeSH Terms