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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
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17 MeSH Terms
Postoperative burden of hospital-acquired Clostridium difficile infection.
Abdelsattar ZM, Krapohl G, Alrahmani L, Banerjee M, Krell RW, Wong SL, Campbell DA, Aronoff DM, Hendren S
(2015) Infect Control Hosp Epidemiol 36: 40-6
MeSH Terms: Academic Medical Centers, Adult, Age Factors, Aged, Amputation, Clostridioides difficile, Digestive System Surgical Procedures, Emergency Service, Hospital, Endocrine Surgical Procedures, Enterocolitis, Pseudomembranous, Female, Gynecologic Surgical Procedures, Hospitals, Community, Humans, Hypoalbuminemia, Immunosuppression, Incidence, Length of Stay, Lower Extremity, Male, Middle Aged, Patient Readmission, Postoperative Complications, Preoperative Period, Prospective Studies, Risk Factors, Sepsis
Show Abstract · Added June 2, 2017
OBJECTIVE Clostridium difficile infection (CDI) is a common hospital-acquired infection. Previous reports on the incidence, risk factors, and impact of CDI on resources in the surgical population are limited. In this context, we study CDI across diverse surgical settings. METHODS We prospectively identified patients with laboratory-confirmed postoperative CDI after 40 different general, vascular, or gynecologic surgeries at 52 academic and community hospitals between July 2012 and September 2013. We used multivariable regression models to identify CDI risk factors and to determine the impact of CDI on resource utilization. RESULTS Of 35,363 patients, 179 (0.51%) developed postoperative CDI. The highest rates of CDI occurred after lower-extremity amputation (2.6%), followed by bowel resection or repair (0.9%) and gastric or esophageal operations (0.7%). Gynecologic and endocrine operations had the lowest rates (0.1% and 0%, respectively). By multivariable analyses, older age, chronic immunosuppression, hypoalbuminemia (≤3.5 g/dL), and preoperative sepsis were associated with CDI. Use of prophylactic antibiotics was not independently associated with CDI, neither was sex, body mass index (BMI), surgical priority, weight loss, or comorbid conditions. Three procedure groups had higher odds of postoperative CDI: lower-extremity amputations (adjusted odds ratio [aOR], 3.5; P=.03), gastric or esophageal operations (aOR, 2.1; P=.04), and bowel resection or repair (aOR, 2; P=.04). Postoperative CDI was independently associated with increased length of stay (mean, 13.7 d vs 4.5 d), emergency department presentations (18.9 vs 9.1%) and readmissions (38.9% vs 7.2%, all P<.001). CONCLUSIONS Incidence of postoperative CDI varies by surgical procedure. Postoperative CDI is also associated with higher rates of extended length of stay, emergency room presentations, and readmissions, which places a potentially preventable burden on hospital resources.
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27 MeSH Terms
Isoniazid induces apoptosis of activated CD4+ T cells: implications for post-therapy tuberculosis reactivation and reinfection.
Tousif S, Singh DK, Ahmad S, Moodley P, Bhattacharyya M, Van Kaer L, Das G
(2014) J Biol Chem 289: 30190-30195
MeSH Terms: Animals, Antitubercular Agents, Apoptosis, CD4-Positive T-Lymphocytes, Cell Proliferation, Cytokines, Humans, Immunosuppression, Isoniazid, Latent Tuberculosis, Lymphocyte Activation, Mice, Inbred BALB C, Mycobacterium tuberculosis, Spleen
Show Abstract · Added January 20, 2015
Tuberculosis (TB) remains the second highest killer from a single infectious disease worldwide. Current therapy of TB is lengthy and consists of multiple expensive antibiotics, in a strategy referred to as Directly Observed Treatment, Short Course (DOTS). Although this therapy is effective, it has serious disadvantages. These therapeutic agents are toxic and are associated with the development of a variety of drug-resistant TB strains. Furthermore, patients treated with DOTS exhibit enhanced post-treatment susceptibility to TB reactivation and reinfection, suggesting therapy-related immune impairment. Here we show that Isoniazid (INH) treatment dramatically reduces Mycobacterium tuberculosis antigen-specific immune responses, induces apoptosis in activated CD4(+) T cells, and renders treated animals vulnerable to TB reactivation and reinfection. Consequently, our findings suggest that TB treatment is associated with immune impairment.
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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14 MeSH Terms
Renal transplantation in the setting of early steroid withdrawal: a comparison of rabbit antithymocyte globulin induction dosing in two eras.
Rogers CC, Asipenko N, Horwedel T, Gautam S, Goldfarb-Rumyantzev AS, Pavlakis M, Johnson SR, Karp SJ, Evenson A, Khwaja K, Hanto DW, Mandelbrot DA
(2013) Am J Nephrol 38: 397-404
MeSH Terms: Aged, Animals, Antilymphocyte Serum, Drug Administration Schedule, Female, Graft Rejection, Graft Survival, Humans, Immunosuppression, Immunosuppressive Agents, Kidney Transplantation, Male, Middle Aged, Multivariate Analysis, Rabbits, Renal Insufficiency, Retrospective Studies, Steroids, Time Factors
Show Abstract · Added May 22, 2014
BACKGROUND - Modern immunosuppression and rabbit antithymocyte globulin (rATG) have facilitated the success of early steroid withdrawal (ESW) protocols. Little data exist on optimal rATG dosing in ESW protocols.
METHODS - Rejection at 12 months in era 1 (four doses of rATG, 1.25 mg/kg) vs. era 2 (three doses of rATG, 1.25 mg/kg) was the primary endpoint. Secondary endpoints included patient and graft survival, renal function and infectious complications. Factors associated with rejection at 1 year were identified.
RESULTS - 199 patients received rATG induction and ESW: 102 in era 1 and 97 in era 2. Compared to era 1, era 2 was not associated with worse outcomes, including rejection, renal function, infection or graft survival. Rejection at 1 year and uncensored graft survival differed between the dosing groups. Rejection rates were significantly higher in the <4 mg/kg group compared to the 4-5.9-mg/kg and the ≥6-mg/kg groups, whereas uncensored graft survival was the lowest in the ≥6-mg/kg group. Factors associated with rejection at 12 months included: rATG dose received of 4-5.9 versus <4 mg/kg (OR 0.20, 95% CI 0.036-0.85, p = 0.026); recipient age (per year, OR 0.94, 95% CI 0.89-1.0, p = 0.038); panel reactive antibody 10-79.9 versus <10% (OR 5.4, 95% CI 1.2-25, p = 0.030) and rATG dose held (OR 4.0, 95% CI 1.0-15, p = 0.049).
CONCLUSIONS - A comparison of rATG dosing based on era did not result in a significant difference in rejection, renal function, infection or graft survival. However, when evaluating the study population based on actual dose received there were notable differences in both rejection rates and uncensored graft survival.
© 2013 S. Karger AG, Basel.
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19 MeSH Terms
Glucocorticoid effects on skeletal muscle: benefit and risk in patients with autoimmune inflammatory rheumatoid diseases.
Hanaoka BY, Peterson CA, Crofford LJ
(2012) Expert Rev Clin Immunol 8: 695-7
MeSH Terms: Anti-Inflammatory Agents, Arthritis, Rheumatoid, Autoimmunity, Genetic Predisposition to Disease, Glucocorticoids, Homeostasis, Humans, Immunosuppression, Muscle, Skeletal, Polymorphism, Genetic, Precision Medicine, Receptors, Glucocorticoid, Risk, Treatment Outcome, Wound Healing
Added September 18, 2013
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15 MeSH Terms
What's New, What's Hot in Solid Organ Transplantation? Summary of the American Transplant Congress 2011.
Karp SJ, Mannon RB
(2011) Am J Transplant 11: 2308-16
MeSH Terms: Graft Rejection, Humans, Immune Tolerance, Immunosuppression, Immunosuppressive Agents, Organ Preservation, Organ Transplantation, Tissue Donors, Transplantation Immunology, Transplantation, Homologous, Treatment Failure
Show Abstract · Added May 22, 2014
Breakthroughs in basic and clinical science in solid organ transplantation were presented at the American Transplant Congress 2011. Key areas of presentation included the pathogenesis of late allograft failure, immune regulation and tolerance, pathways in allograft injury, electing appropriate patients for transplantation, determining the best allocation schemes to maximize effective utilization, organ preservation, monitoring the alloimmune response and immunosuppressive management. In this review, we present highlights of the meeting. These presentations demonstrate the exciting promise in translating from the bench to affect patient care.
©Copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.
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11 MeSH Terms
Human leukocyte antigen I knockdown human embryonic stem cells induce host ignorance and achieve prolonged xenogeneic survival.
Deuse T, Seifert M, Phillips N, Fire A, Tyan D, Kay M, Tsao PS, Hua X, Velden J, Eiermann T, Volk HD, Reichenspurner H, Robbins RC, Schrepfer S
(2011) Circulation 124: S3-9
MeSH Terms: Animals, Cell Survival, Cells, Cultured, Embryonic Stem Cells, Gene Knockdown Techniques, Graft Survival, HLA Antigens, Humans, Immune Tolerance, Immunosuppression, Male, Mice, Mice, Inbred BALB C, Mice, Knockout, Mice, Nude, Mice, SCID, Models, Animal, Stem Cell Transplantation, T-Lymphocytes, Time Factors, Transplantation, Heterologous
Show Abstract · Added October 19, 2016
BACKGROUND - Although human embryonic stem cells (hESC) have enormous potential for cell replacement therapy of heart failure, immune rejection of hESC derivatives inevitably would occur after transplantation. We therefore aimed to generate a hypoantigeneic hESC line with improved survival characteristics.
METHODS AND RESULTS - Using various in vivo, nonischemic, hindlimb xenotransplant models (immunocompetent and defined immunodefective mouse strains) as well as human in vitro T-cell and natural killer (NK)-cell assays, we revealed a central role for T cells in mediating hESC rejection. The NK-cell susceptibility of hESC in vivo was found to be low, and the NK response to hESC challenge in vitro was negligible. To reduce the antigenicity of hESC, we successfully generated human leukocyte antigen (HLA) I knockdown cells (hESC(siRNA+IB)) using both HLA I RNA interference (siRNA) and intrabody (IB) technology. HLA I expression was ≈99% reduced after 7 days and remained low for weeks. Cellular immune recognition of these hESC(siRNA+IB) was strongly reduced in both xenogeneic and allogeneic settings. Immune rejection was profoundly mitigated after hESC(siRNA+IB) transplantation into immunocompetent mice, and even long-term graft survival was achieved in one third of the animals without any immunosuppression. The survival benefit of hESC(siRNA+IB) was further confirmed under ischemic conditions in a left anterior descending coronary artery ligation model.
CONCLUSIONS - HLA I knockdown hESC(siRNA+IB) provoke T-cell ignorance and experience largely mitigated xenogeneic rejection. By generating hypoantigeneic hESC lines, the generation of acceptable hESC derivatives may become a practical concept and push cell replacement strategies forward.
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21 MeSH Terms
Mycobacterium tuberculosis evades host immunity by recruiting mesenchymal stem cells.
Raghuvanshi S, Sharma P, Singh S, Van Kaer L, Das G
(2010) Proc Natl Acad Sci U S A 107: 21653-8
MeSH Terms: Adult, Animals, Cytokines, Female, Granuloma, Humans, Immune System, Immunosuppression, Mesenchymal Stem Cells, Mice, Mice, Inbred C57BL, Middle Aged, Mycobacterium tuberculosis, Nitric Oxide, T-Lymphocytes
Show Abstract · Added March 20, 2014
Tuberculosis (TB) is the cause of 2 million deaths each year, which is the second highest cause of mortality from a single infectious disease worldwide. Resistance of these organisms to drugs has emerged as an important health concern. Alternative approaches to the prevention and treatment of tuberculosis are therefore urgently needed. Despite the generation of robust host immune responses, Mycobacterium tuberculosis (M. tb) successfully evades host immunity and establishes a persistent infection. The mechanism(s) by which M. tuberculosis manages to persist in the face of potent host immune responses remain(s) incompletely understood. Here, we demonstrate that M. tb suppresses T-lymphocyte responses by recruiting mesenchymal stem cells (MSCs) to the site of infection. We found that MSCs infiltrated tissues in mice containing M. tb organisms and T lymphocytes. We further demonstrate that MSCs suppressed T-cell responses by producing nitric oxide. Our findings reveal a key role of MSCs in the capacity of M. tb to evade host immune responses and identify these cells as unique targets for therapeutic intervention in tuberculosis.
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15 MeSH Terms
A case of pediatric PTLD following autologous stem cell transplantation and review of the literature.
Eckrich MJ, Frangoul H, Knight J, Mosse C, Domm J
(2012) Pediatr Transplant 16: E15-8
MeSH Terms: Antibodies, Monoclonal, Murine-Derived, Child, Child, Preschool, Female, Humans, Immune System, Immunosuppression, Lymphoma, Large B-Cell, Diffuse, Lymphoproliferative Disorders, Male, Postoperative Complications, Remission Induction, Rituximab, Stem Cell Transplantation, Treatment Outcome
Show Abstract · Added March 7, 2014
The development of PTLD is a rare severe adverse event following ASCT. We report on a child with DS who developed PTLD following autologous transplant for relapsed Hodgkin's disease. He was successfully treated with cyclophosphamide, prednisone and rituximab. We also present a comprehensive review of the literature of PTLD in pediatric patients following ASCT.
© 2010 John Wiley & Sons A/S.
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15 MeSH Terms
Minor histocompatibility antigens: presentation principles, recognition logic and the potential for a healing hand.
Spencer CT, Gilchuk P, Dragovic SM, Joyce S
(2010) Curr Opin Organ Transplant 15: 512-25
MeSH Terms: Animals, Graft Rejection, Graft Survival, Graft vs Host Disease, Humans, Immunosuppression, Inflammation, Isoantigens, Ligands, Minor Histocompatibility Antigens, Models, Molecular, Protein Conformation, Receptors, Antigen, T-Cell, Structure-Activity Relationship, T-Lymphocytes, Transplantation Tolerance, Transplantation, Homologous
Show Abstract · Added May 19, 2014
PURPOSE OF REVIEW - There is ample evidence indicating a pathologic role for minor histocompatibility antigens in inciting graft-versus-host disease in major histocompatibility complex (MHC)-matched bone marrow transplantation and rejection of solid organ allografts. Here we review the current knowledge of the genetic and biochemical bases for the cause of minor histoincompatibility and the structural basis for the recognition of the resulting alloantigens by the T-cell receptor.
RECENT FINDINGS - Recent evidence indicates that we as independently conceived individuals are genetically unique, thus, offering a mechanism for minor histoincompatibility between MHC-identical donor-recipient pairs. Furthermore, advances in delineating the mechanisms underlying antigen cross-presentation by MHC class I molecules and a critical role for autophagy in presenting cytoplasmic antigens by MHC class II molecules have been made. These new insights coupled with the X-ray crystallographic solution of several peptide/MHC-T-cell receptor structures have revealed mechanisms of histoincompatibility.
SUMMARY - On the basis of these new insights, ways to test for allograft compatibility and concoction of immunotherapies are discussed.
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17 MeSH Terms