Modeling human neurological disorders with induced pluripotent stem cells.

PubMed

Imaizumi, Yoichi; Okano, Hideyuki

2014-05-01

Human induced pluripotent stem (iPS) cells obtained by reprogramming technology are a source of great hope, not only in terms of applications in regenerative medicine, such as cell transplantation therapy, but also for modeling human diseases and new drug development. In particular, the production of iPS cells from the somatic cells of patients with intractable diseases and their subsequent differentiation into cells at affected sites (e.g., neurons, cardiomyocytes, hepatocytes, and myocytes) has permitted the in vitro construction of disease models that contain patient-specific genetic information. For example, disease-specific iPS cells have been established from patients with neuropsychiatric disorders, including schizophrenia and autism, as well as from those with neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. A multi-omics analysis of neural cells originating from patient-derived iPS cells may thus enable investigators to elucidate the pathogenic mechanisms of neurological diseases that have heretofore been unknown. In addition, large-scale screening of chemical libraries with disease-specific iPS cells is currently underway and is expected to lead to new drug discovery. Accordingly, this review outlines the progress made via the use of patient-derived iPS cells toward the modeling of neurological disorders, the testing of existing drugs, and the discovery of new drugs. The production of human induced pluripotent stem (iPS) cells from the patients' somatic cells and their subsequent differentiation into specific cells have permitted the in vitro construction of disease models that contain patient-specific genetic information. Furthermore, innovations of gene-editing technologies on iPS cells are enabling new approaches for illuminating the pathogenic mechanisms of human diseases. In this review article, we outlined the current status of neurological diseases-specific iPS cell research and described recently obtained knowledge in the form of actual examples. © 2013 International Society for Neurochemistry.

Neural stem cell-based treatment for neurodegenerative diseases.

PubMed

Kim, Seung U; Lee, Hong J; Kim, Yun B

2013-10-01

Human neurodegenerative diseases such as Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) are caused by a loss of neurons and glia in the brain or spinal cord. Neurons and glial cells have successfully been generated from stem cells such as embryonic stem cells (ESCs), mesenchymal stem cells (MSCs) and neural stem cells (NSCs), and stem cell-based cell therapies for neurodegenerative diseases have been developed. A recent advance in generation of a new class of pluripotent stem cells, induced pluripotent stem cells (iPSCs), derived from patients' own skin fibroblasts, opens doors for a totally new field of personalized medicine. Transplantation of NSCs, neurons or glia generated from stem cells in animal models of neurodegenerative diseases, including PD, HD, ALS and AD, demonstrates clinical improvement and also life extension of these animals. Additional therapeutic benefits in these animals can be provided by stem cell-mediated gene transfer of therapeutic genes such as neurotrophic factors and enzymes. Although further research is still needed, cell and gene therapy based on stem cells, particularly using neurons and glia derived from iPSCs, ESCs or NSCs, will become a routine treatment for patients suffering from neurodegenerative diseases and also stroke and spinal cord injury. © 2013 Japanese Society of Neuropathology.

Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease.

PubMed

Smith, R E; Reyes, N J; Khandelwal, P; Schlereth, S L; Lee, H S; Masli, S; Saban, D R

2016-08-01

Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity. © Society for Leukocyte Biology.

Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease

PubMed Central

Smith, R. E.; Reyes, N. J.; Khandelwal, P.; Schlereth, S. L.; Lee, H. S.; Masli, S.; Saban, D. R.

2016-01-01

Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re-exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin-1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin-1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin-1-deficient dendritic cells augmented activity of allergen-primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell-derived thrombospondin-1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin-1-sufficient dendritic cells to the ocular mucosa of thrombospondin-1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin-1-derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell-derived thrombospondin-1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell-derived thrombospondin-1 expression as a factor in allergic eye disease severity. PMID:26856994

The Players: Cells Involved in Glomerular Disease.

PubMed

Kitching, A Richard; Hutton, Holly L

2016-09-07

Glomerular diseases are common and important. They can arise from systemic inflammatory or metabolic diseases that affect the kidney. Alternately, they are caused primarily by local glomerular abnormalities, including genetic diseases. Both intrinsic glomerular cells and leukocytes are critical to the healthy glomerulus and to glomerular dysregulation in disease. Mesangial cells, endothelial cells, podocytes, and parietal epithelial cells within the glomerulus all play unique and specialized roles. Although a specific disease often primarily affects a particular cell type, the close proximity, and interdependent functions and interactions between cells mean that even diseases affecting one cell type usually indirectly influence others. In addition to those cells intrinsic to the glomerulus, leukocytes patrol the glomerulus in health and mediate injury in disease. Distinct leukocyte types and subsets are present, with some being involved in different ways in an individual glomerular disease. Cells of the innate and adaptive immune systems are important, directing systemic immune and inflammatory responses, locally mediating injury, and potentially dampening inflammation and facilitating repair. The advent of new genetic and molecular techniques, and new disease models means that we better understand both the basic biology of the glomerulus and the pathogenesis of glomerular disease. This understanding should lead to better diagnostic techniques, biomarkers, and predictors of prognosis, disease severity, and relapse. With this knowledge comes the promise of better therapies in the future, directed toward halting pathways of injury and fibrosis, or interrupting the underlying pathophysiology of the individual diseases that lead to significant and progressive glomerular disease. Copyright © 2016 by the American Society of Nephrology.

Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells

ClinicalTrials.gov

2016-06-21

Sickle Cell Disease; Thalassemia; Anemia; Granuloma; Wiskott-Aldrich Syndrome; Chediak Higashi Syndrome; Osteopetrosis; Neutropenia; Thrombocytopenia; Hurler Disease; Niemann-Pick Disease; Fucosidosis

The basics of cell therapy to treat cardiovascular disease: one cell does not fit all.

PubMed

Taylor, Doris A; Robertson, Matthew J

2009-09-01

Cardiovascular disease represents a continuum of disease entities whose medical treatments differ. Cell therapy is a 21st century approach to treating cardiovascular disease and is being applied worldwide. However, no concerted approach exists for defining the best cell population(s) to use, or the best treatment conditions. It is naïve to believe that a single treatment -even a stem cell- can be found to treat the entire spectrum of cardiovascular disease. We describe the continuum of ischemic heart disease, the potential uses of cells for treating this continuum, and the basic issues that must be considered when contemplating cardiovascular cell therapy. The clinical goal is cardiac and vascular regeneration. Whether cells can deliver this remains to be determined. The correct cell, the ideal therapeutic window, and the patient likewise are open to debate. This article is designed to provide insights into the early, middle, and later stages of cardiovascular disease and how cells might be used differently for treatment at each stage.

Human genome project and sickle cell disease.

PubMed

Norman, Brenda J; Miller, Sheila D

2011-01-01

Sickle cell disease is one of the most common genetic blood disorders in the United States that affects 1 in every 375 African Americans. Sickle cell disease is an inherited condition caused by abnormal hemoglobin in the red blood cells. The Human Genome Project has provided valuable insight and extensive research advances in the understanding of the human genome and sickle cell disease. Significant progress in genetic knowledge has led to an increase in the ability for researchers to map and sequence genes for diagnosis, treatment, and prevention of sickle cell disease and other chronic illnesses. This article explores some of the recent knowledge and advances about sickle cell disease and the Human Genome Project.

Gene therapy for sickle cell disease.

PubMed

Olowoyeye, Abiola; Okwundu, Charles I

2016-11-14

Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal hemoglobin polymerisation leading to a symptomatic disorder.Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. This is an update of a previously published Cochrane Review. The objectives of this review are:to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease;to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 15 August 2016. All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting. No trials of gene therapy for sickle cell disease were found. No trials of gene therapy for sickle cell disease were reported. No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.

Gene therapy for sickle cell disease.

PubMed

Olowoyeye, Abiola; Okwundu, Charles I

2014-10-10

Sickle cell disease encompasses a group of genetic disorders characterized by the presence of at least one hemoglobin S (Hb S) allele, and a second abnormal allele that could allow abnormal hemoglobin polymerisation leading to a symptomatic disorder.Autosomal recessive disorders (such as sickle cell disease) are good candidates for gene therapy because a normal phenotype can be restored in diseased cells with only a single normal copy of the mutant gene. The objectives of this review are:- to determine whether gene therapy can improve survival and prevent symptoms and complications associated with sickle cell disease;- to examine the risks of gene therapy against the potential long-term gain for people with sickle cell disease. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and searching relevant journals and abstract books of conference proceedings.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 21 July 2014. All randomised or quasi-randomised clinical trials (including any relevant phase 1, 2 or 3 trials) of gene therapy for all individuals with sickle cell disease, regardless of age or setting. No trials of gene therapy for sickle cell disease were found. No trials of gene therapy for sickle cell disease were reported. No randomised or quasi-randomised clinical trials of gene therapy for sickle cell disease were reported. Thus, no objective conclusions or recommendations in practice can be made on gene therapy for sickle cell disease. This systematic review has identified the need for well-designed, randomised controlled trials to assess the benefits and risks of gene therapy for sickle cell disease.

Microparticles in sickle cell anaemia: promise and pitfalls.

PubMed

Hebbel, Robert P; Key, Nigel S

2016-07-01

Blood from patients with sickle cell disease contains microparticles (MP) derived from multiple cell sources, including red cells, platelets, monocytes and endothelial cells. MPs are of great interest because of their disease associations, their status as promising biomarkers, and the intercellular communications they mediate. To illustrate the likelihood of their relevance in sickle cell disease, we discuss the nature of MP, their profiling in sickle disease, some caveats relevant to their detection, their roles in supporting coagulation and the disparate influences they may exert upon the pathobiology of sickle cell disease. © 2016 John Wiley & Sons Ltd.

Renal Failure in Sickle Cell Disease: Prevalence, Predictors of Disease, Mortality and Effect on Length of Hospital Stay.

PubMed

Yeruva, Sri L H; Paul, Yonette; Oneal, Patricia; Nouraie, Mehdi

2016-09-01

Renal dysfunction in sickle cell disease is not only a chronic comorbidity but also a mortality risk factor. Though renal dysfunction starts early in life in sickle cell patients, the predictors that can identify sickle cell disease patients at risk of developing renal dysfunction is not known. We used the Truven Health MarketScan ® Medicaid Databases from 2007 to 2012. Incidence of new acute renal failure (ARF) and chronic kidney disease (CKD) was calculated in this cohort. There were 9481 patients with a diagnosis of sickle cell disease accounting for 64,201 hospital admissions, during the study period. Both ARF and CKD were associated with higher risk of inpatient mortality, longer duration of the hospital stay and expensive hospitalizations. The yearly incidence of new ARF in sickle cell disease patients was 1.4% and annual CKD incidence was 1.3%. The annual rate of new ARF and CKD in the control group was 0.4 and 0.6%, respectively. The most important predictors of new CKD were proteinuria, ARF and hypertension. Chronic kidney disease, hypertension and sickle cell crisis were the most important predictors of new ARF. The annual rate of incidences of ARF and CKD were 2- to 3-fold higher in sickle cell disease compared to the non sickle cell disease group. Besides the common risk factors for renal disease in the general population, it is imperative to monitor the sickle cell disease patients with more severe disease to prevent them from developing renal dysfunction.

Stem cell transplantation for treating Parkinson's disease: Literature analysis based on the Web of Science.

PubMed

Li, Runhui

2012-06-05

To identify global research trends of stem cell transplantation for treating Parkinson's disease using a bibliometric analysis of the Web of Science. We performed a bibliometric analysis of data retrievals for stem cell transplantation for treating Parkinson's disease from 2002 to 2011 using the Web of Science. (a) peer-reviewed articles on stem cell transplantation for treating Parkinson's disease which were published and indexed in the Web of Science; (b) type of articles: original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material and news items; (c) year of publication: 2002-2011. (a) articles that required manual searching or telephone access; (b) we excluded documents that were not published in the public domain; (c) we excluded a number of corrected papers from the total number of articles. (1) Type of literature; (2) annual publication output; (3) distribution according to journals; (4) distribution according to subject areas; (5) distribution according to country; (6) distribution according to institution; (7) comparison of countries that published the most papers on stem cell transplantation from different cell sources for treating Parkinson's disease; (8) comparison of institutions that published the most papers on stem cell transplantation from different cell sources for treating Parkinson's disease in the Web of Science from 2002 to 2011; (9) comparison of studies on stem cell transplantation from different cell sources for treating Parkinson's disease. In total, 1 062 studies on stem cell transplantation for treating Parkinson's disease appeared in the Web of Science from 2002 to 2011, almost one third of which were from American authors and institutes. The number of studies on stem cell transplantation for treating Parkinson's disease had gradually increased over the past 10 years. Papers on stem cell transplantation for treating Parkinson's disease appeared in journals such as Stem Cells and Experimental Neurology. Although the United States published more articles addressing neural stem cell and embryonic stem cell transplantation for treating Parkinson's disease, China ranked first for articles published on bone marrow mesenchymal stem cell transplantation for treating Parkinson's disease. From our analysis of the literature and research trends, we found that stem cell transplantation for treating Parkinson's disease may offer further benefits in regenerative medicine.

Toward understanding family-related characteristics of young adults with sickle-cell disease or sickle-cell trait in the USA.

PubMed

Hershberger, Patricia E; Gallo, Agatha M; Molokie, Robert; Thompson, Alexis A; Suarez, Marie L; Yao, Yingwei; Dallas, Constance M; Wilkie, Diana J

2016-06-01

To describe the family-related characteristics of young adults with sickle-cell disease or sickle-cell trait prior to taking part in a randomised controlled trial on sickle-cell reproductive health education. There is a critical need for educational programmes that target the reproductive needs of young adults with sickle-cell disease or trait. However, little is known about the family-related characteristics (i.e., demographic attributes and reproductive health behaviours) in which these young adults live. A descriptive cross-sectional analysis. At study enrolment, 234 young adults (mean age = 25·9 years, 65% female) completed the SCKnowIQ questionnaire. Descriptive statistics depict the demographic attributes and reproductive health behaviours of young adults with sickle-cell disease (n = 138) or trait (n = 96). For group comparisons, independent t tests or Fisher's tests were used, as appropriate. Young adults with sickle-cell trait had significantly higher education, income and health insurance than those with sickle-cell disease. Both groups believed that sickle-cell disease was a severe condition. A majority of young adults with sickle-cell disease (65%) had no children compared to 42% of those with sickle-cell trait. Most young adults (85% sickle-cell disease, 82% sickle-cell trait) were not planning a pregnancy in the next six months, and many used condoms, withdrawal or oral contraceptives. Socioeconomic disparities exist between young adults with sickle-cell disease and sickle-cell trait. Future research that advances education about how and when to communicate appropriate genetic risk information to partners and children especially for young adults with sickle-cell trait would be beneficial. Awareness of the similarities and differences in the family-related characteristics among young adults with sickle-cell disease or trait can allow for more tailored reproductive education. © 2016 John Wiley & Sons Ltd.

Toward Understanding Family-Related Characteristics of Young Adults with Sickle Cell Disease or Sickle Cell Trait in the USA

PubMed Central

Hershberger, Patricia E.; Gallo, Agatha M.; Molokie, Robert; Thompson, Alexis A.; Suarez, Marie L.; Yao, Yingwei; Dallas, Constance M.; Wilkie, Diana J.

2016-01-01

Aims and objectives To describe the family-related characteristics of young adults with sickle cell disease or sickle cell trait prior to taking part in a randomized controlled trial on sickle cell reproductive health education. Background There is a critical need for educational programs that target the reproductive needs of young adults with sickle cell disease or trait. However, little is known about the family-related characteristics (i.e., demographic attributes and reproductive health behaviors) in which these young adults live. Design A descriptive cross-sectional analysis. Method At study enrollment, 234 young adults (mean age = 25.9 years, 65% female) completed the SCKnowIQ questionnaire. Descriptive statistics depict the demographic attributes and reproductive health behaviors of young adults with sickle cell disease (n = 138) or trait (n = 96). For group comparisons, independent t tests or Fisher’s tests were used, as appropriate. Results Young adults with sickle cell trait had significantly higher education, income, and health insurance than those with sickle cell disease. Both groups believed that sickle cell disease was a severe condition. A majority of young adults with sickle cell disease (65%) had no children compared to 42% of those with sickle cell trait. Most young adults (85% sickle cell disease, 82% sickle cell trait) were not planning a pregnancy in the next six months and many used condoms, withdrawal, or oral contraceptives. Conclusions Socioeconomic disparities exist between young adults with sickle cell disease and sickle cell trait. Future research that advances education about how and when to communicate appropriate genetic risk information to partners and children especially for young adults with sickle cell trait would be beneficial. Relevance to clinical practice Awareness of the similarities and differences in the family-related characteristics among young adults with sickle cell disease or trait can allow for more tailored reproductive education. PMID:26970444

Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells.

PubMed

Xu, Xiao-hong; Zhong, Zhong

2013-06-01

With the general decline of pharmaceutical research productivity, there are concerns that many components of the drug discovery process need to be redesigned and optimized. For example, the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases, leading to biases in assays, targets, or compounds that do not effectively address disease mechanisms. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells. In this article, we will review the progress made to date on cellular disease models using human stem cells, with a focus on patient-specific iPSCs for neurological diseases. We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases, diseases with various known genetic components, and complex diseases caused by a combination of genetic, environmental and other factors.

Stem cell transplantation as rescue therapy for refractory Crohn's disease: a sytematic review.

PubMed

Labidi, Asma; Serghini, Meriem; Ben Mustapha, Nadia; Fekih, Monia; Boubaker, Jalel; Filali, Azza

2014-11-01

Crohn's disease is a chronic relapsing- remitting affection. It has a strong immunologic component which represent the target of standard therapies including immunosppressants and biological therapies. However, many patients remain refracory or intolerant to these therapies. The aim of this review is to determine the effects of stem cell transplantation in patients with refractory Crohn's disease. Systematic review of observational studies, clinical trials and case reports that focused on the effectiveness and safety of stem cell transplantation in patients with refractory Crohn's disease. Hematopoietic stem cell transplantation seems to be efficient in maintaining clinical and endoscopic remission in patients with Crohn's disease refractory or intolerant to current therapies. However, it has been associated to high morbidity and mortality due to chemotherapy. Mesenchymal stem cell transplantation could induce remission in patients with fistulising refractory Crohns disease with no severe side effects. Its impact on luminal Crohns disease is still controversial. Stem cell transplantation seems to hold promising in patients with refractory Crohn's disease. However, because of the high morbidity and mortality related to chemotherapy, hematopoietic stem cell transplantation should be used as last resort to control this disease. Effectiveness of mesenchymal stem cell transplantation in luminal Crohn's disease has yet to be proven.

75 FR 54496 - Diseases Associated With Exposure to Certain Herbicide Agents (Hairy Cell Leukemia and Other...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-08

... Certain Herbicide Agents (Hairy Cell Leukemia and Other Chronic B-Cell Leukemias, Parkinson's Disease and..., VA published in the Federal Register (75 FR 53202), an amendment to 38 CFR 3.309 to add hairy cell leukemia and other chronic B-cell leukemias, Parkinson's disease and ischemic heart disease to the list of...

Immunotherapy with iTreg and nTreg Cells in a Murine Model of Inflammatory Bowel Disease.

PubMed

Haribhai, Dipica; Chatila, Talal A; Williams, Calvin B

2016-01-01

Regulatory T (Treg) cells that express the transcription factor Foxp3 are essential for maintaining tolerance at mucosal interfaces, where they act by controlling inflammation and promoting epithelial cell homeostasis. There are two major regulatory T-cell subsets, "natural" CD4(+) Treg (nTreg) cells that develop in the thymus and "induced" Treg (iTreg) cells that develop from conventional CD4(+) T (Tconv) cells in the periphery. Dysregulated Treg cell responses are associated with autoimmune diseases, including inflammatory bowel disease (IBD) and arthritis. Adoptive transfer of Treg cells can modulate innate and adaptive immune responses and cure disease in animal models, which has generated considerable interest in using Treg cells to treat human autoimmune disease, prevent rejection of transplanted organs, and to control graft-versus-host disease following hematopoietic stem cell transplantation. Herein, we describe our modifications of a treatment model of T-cell transfer colitis designed to allow mechanistic investigation of the two major Treg cell subsets and to compare their specific roles in mucosal tolerance.

Regulatory T cells in Allergic Diseases

PubMed Central

Rivas, Magali Noval; Chatila, Talal A.

2016-01-01

The pathogenesis of allergic diseases entails an ineffective tolerogenic immune response towards allergens. Regulatory T cells (TReg) cells play a key role in sustaining immune tolerance to allergens, yet mechanisms by which TReg cells fail to maintain tolerance in allergic diseases are not well understood. We review current concepts and established mechanisms regarding how TReg cells regulate different components of allergen-triggered immune responses to promote and maintain tolerance. We will also discuss more recent advances that emphasize the “dual” functionality of TReg cells in allergic diseases: how TReg cells are essential in promoting tolerance to allergens but also how a pro-allergic inflammatory environment can skew TReg cells towards a pathogenic phenotype that aggravates and perpetuates disease. These advances highlight opportunities for novel therapeutic strategies that aim to re-establish tolerance in chronic allergic diseases by promoting TReg cell and stability function. PMID:27596705

Pyrogen release in vitro by lymphoid tissues from patients with Hodgkin's disease.

PubMed

Bodel, P

1974-01-01

The mechanism of fever in patients with Hodgkin's disease was investigated by examining endogenous pyrogen production by blood, spleen, and lymph node cells incubated in vitro. Blood leucocytes from febrile or afebrile patients with Hodgkin's disease did not produce pyrogen spontaneously. Spleen cells, however, frequently released pyrogen during initial incubations, unlike spleen cells from patients with non-malignant diseases. Pyrogen production occurred from spleens without observed pathologic infiltrates of Hodgkin's disease. Lymph nodes involved with Hodgkin's disease produced pyrogen more frequently than did nodes involved with other diseases. Pyrogen production by tissue cells was prolonged, required protein synthesis, and in some cases was due to mononuclear cells; it did not correlate with fever in the patient. These studies demonstrate spontaneous production of endogenous pyrogen in vitro by lymphoid tissue cells from patients with Hodgkin's disease.

Sickle Cell Research: Yesterday, Today, and Tomorrow | NIH MedlinePlus the Magazine

MedlinePlus

... this page please turn Javascript on. Special Section: Sickle Cell Disease Sickle Cell Research: Yesterday, Today, and Tomorrow Past ... live productively. Sickle cell disease (also known as sickle cell anemia) is a serious disease in which the body ...

PT2385 for the Treatment of Von Hippel-Lindau Disease-Associated Clear Cell Renal Cell Carcinoma

ClinicalTrials.gov

2017-08-23

VHL Gene Mutation; VHL; VHL Syndrome; VHL Gene Inactivation; Von Hippel; Von Hippel-Lindau Disease; Von Hippel's Disease; Von Hippel-Lindau Syndrome, Modifiers of; Clear Cell Renal Cell Carcinoma; Clear Cell RCC; ccRCC

Stem Cell Transplant for Inborn Errors of Metabolism

ClinicalTrials.gov

2017-12-03

Adrenoleukodystrophy; Metachromatic Leukodystrophy; Globoid Cell Leukodystrophy; Gaucher's Disease; Fucosidosis; Wolman Disease; Niemann-Pick Disease; Batten Disease; GM1 Gangliosidosis; Tay Sachs Disease; Sandhoff Disease

Conjugates of Cell Adhesion Peptides for Therapeutics and Diagnostics Against Cancer and Autoimmune Diseases.

PubMed

Moral, Mario E G; Siahaan, Teruna J

2017-01-01

Overexpressed cell-surface receptors are hallmarks of many disease states and are often used as markers for targeting diseased cells over healthy counterparts. Cell adhesion peptides, which are often derived from interacting regions of these receptor-ligand proteins, mimic surfaces of intact proteins and, thus, have been studied as targeting agents for various payloads to certain cell targets for cancers and autoimmune diseases. Because many cytotoxic agents in the free form are often harmful to healthy cells, the use of cell adhesion peptides in targeting their delivery to diseased cells has been studied to potentially reduce required effective doses and associated harmful side-effects. In this review, multiple cell adhesion peptides from extracellular matrix and ICAM proteins were used to selectively direct drug payloads, signal-inhibitor peptides, and diagnostic molecules, to diseased cells over normal counterparts. RGD constructs have been used to improve the selectivity and efficacy of diagnostic and drug-peptide conjugates against cancer cells. From this precedent, novel conjugates of antigenic and cell adhesion peptides, called Bifunctional Peptide Inhibitors (BPIs), have been designed to selectively regulate immune cells and suppress harmful inflammatory responses in autoimmune diseases. Similar peptide conjugations with imaging agents have delivered promising diagnostic methods in animal models of rheumatoid arthritis. BPIs have also been shown to generate immune tolerance and suppress autoimmune diseases in animal models of type-1 diabetes, rheumatoid arthritis, and multiple sclerosis. Collectively, these studies show the potential of cell adhesion peptides in improving the delivery of drugs and diagnostic agents to diseased cells in clinical settings. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease.

PubMed

Takeuchi, Mai; Sato, Yasuharu; Ohno, Kyotaro; Tanaka, Satoshi; Takata, Katsuyoshi; Gion, Yuka; Orita, Yorihisa; Ito, Toshihiro; Tachibana, Tomoyasu; Yoshino, Tadashi

2014-08-01

IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffin-embedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGFβ1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease pathogenesis.

New lessons learned from disease modeling with induced Pluripotent Stem Cells

PubMed Central

Onder, Tamer T.; Daley, George Q.

2012-01-01

Cellular reprogramming and generation of induced pluripotent stem cells (iPSCs) from adult cell types has enabled the creation of patient-specific stem cells for use in disease modeling. To date, many iPSC lines have been generated from a variety of disorders, which have then been differentiated into disease-relevant cell types. When a disease-specific phenotype is detectable in such differentiated cells, the reprogramming technology provides a new opportunity to identify aberrant disease-associated pathways and drugs that can block them. Here, we highlight recent progress as well as limitations in the use of iPSCs to recapitulate disease phenotypes and to screen for therapeutics in vitro. PMID:22749051

The Epidemiology and Management of Lung Diseases in Sickle Cell Disease: Lessons Learned from Acute and Chronic Lung Disease in Cystic Fibrosis.

PubMed

Willen, Shaina M; DeBaun, Michael R

2018-06-01

Although sickle cell disease and cystic fibrosis are two of the most common monogenic diseases presenting in childhood worldwide, cystic fibrosis and sickle cell disease enjoy vastly different funding and collaborative research efforts. Pulmonary complications in cystic fibrosis have well established guidelines and multidisciplinary involvement focusing on comorbidities, routine monitoring, infectious complications, nutrition, and treatment recommendations. These guidelines can provide a framework on which to build knowledge of lung disease in sickle cell disease. Copyright © 2018 Elsevier Inc. All rights reserved.

78 FR 66747 - Sickle Cell Disease Public Meeting on Patient-Focused Drug Development

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-06

...] Sickle Cell Disease Public Meeting on Patient-Focused Drug Development AGENCY: Food and Drug... Development for sickle cell disease. Patient-Focused Drug Development is part of FDA's performance commitments... intended to allow FDA to obtain patients' perspectives on the impact of sickle cell disease on daily life...

The Epimmunity Theory: The Single Cell Defenses against Infectious and Genetic Diseases.

PubMed

Barghouthi, Sameer A

2017-01-01

Single cell defense against diseases defines "epimmunity." Epimmunity is complementary to the immune system and can neither be substituted by innate nor by acquired immunity. Epimmunity, the proposed new branch of immunity, is further explored and analyzed for enucleated mature mammalian erythrocytes and nucleated erythrocytes of non-mammalian vertebrates leading to the development of "The Epimmunity Theory." Enucleation of mammalian erythroblast and inactivation of nuclei in erythrocytes of non-mammalian vertebrates are major contributors to the collective immunity: epimmunity, innate, and acquired. The fact that diseases of mature erythrocytes (MEs) are rare supports the notion that a single cell can resist microbial and genetic diseases; MEs are refractory to malaria and cancer. Nucleated cells, such as B-cells, T-cells, hepatocytes, and cell developmental stages are susceptible to genetic and specific microbial diseases depending on their nuclear activities and the receptors they express; such cells show lower epimmunity relative to MEs. Epimmunity is important as a disease insulator that prevents the spread of diseases from an infected tissue to the majority of other tissues. Breakdown of epimmunity may lead to disease development.

Perceptions of young adults with sickle cell disease concerning their disease experience.

PubMed

Matthie, Nadine; Hamilton, Jill; Wells, Diana; Jenerette, Coretta

2016-06-01

To describe the perceptions of young adults with sickle cell disease concerning their disease experience. Sickle cell disease is a lifelong, genetic condition with both acute and chronic painful exacerbations. Little is known of the experiences of young adults with sickle cell disease. This study used a qualitative, descriptive design with semi-structured, life review interviews. Between August 2010-September 2012, purposive sampling was used to recruit participants with a known sickle cell disease diagnosis who were ages 18-35 years, were being seen in an outpatient sickle cell clinic and were English speaking. Participants provided demographic information and responded to two interviews. A content analysis was then used to interpret participants' narratives of their experiences of living with sickle cell disease. A sample of 29 young adults with sickle cell disease consisted of 79·3% females, 35·6% employed full-time or part-time, 71·6% single/never married and 57·8% with sickle cell anaemia. Their mean age was 25·8 with 13·2 years of education. Four major interview themes were identified: (1) struggles to maintain or achieve good quality of life or life satisfactions; (2) strategies to maintain self-care; (3) interruptions to family, work and social roles; and (4) difficulties accessing needed health care. Young adults face many challenges while living with sickle cell disease. With a better understanding of their disease experience and how it influences their quality of life, researchers can begin tailoring appropriate interventions to improve health outcomes in this vulnerable, minority population. © 2015 John Wiley & Sons Ltd.

Key endothelial cell angiogenic mechanisms are stimulated by the circulating milieu in sickle cell disease and attenuated by hydroxyurea

PubMed Central

Lopes, Flavia C. M.; Traina, Fabiola; Almeida, Camila B.; Leonardo, Flavia C.; Franco-Penteado, Carla F.; Garrido, Vanessa T.; Colella, Marina P.; Soares, Raquel; Olalla-Saad, Sara T.; Costa, Fernando F.; Conran, Nicola

2015-01-01

As hypoxia-induced inflammatory angiogenesis may contribute to the manifestations of sickle cell disease, we compared the angiogenic molecular profiles of plasma from sickle cell disease individuals and correlated these with in vitro endothelial cell-mediated angiogenesis-stimulating activity and in vivo neovascularization. Bioplex demonstrated that plasma from patients with steady-state sickle cell anemia contained elevated concentrations of pro-angiogenic factors (angiopoietin-1, basic fibroblast growth factor, vascular endothelial growth factor, vascular endothelial growth factor-D and placental growth factor) and displayed potent pro-angiogenic activity, significantly increasing endothelial cell proliferation, migration and capillary-like structure formation. In vivo neovascularization of Matrigel plugs was significantly greater in sickle cell disease mice than in non-sickle cell disease mice, consistent with an up-regulation of angiogenesis in the disease. In plasma from patients with hemoglobin SC disease without proliferative retinopathy, anti-angiogenic endostatin and thrombospondin-2 were significantly elevated. In contrast, plasma from hemoglobin SC individuals with proliferative retinopathy had a pro-angiogenic profile and more significant effects on endothelial cell proliferation and capillary formation than plasma from patients without retinopathy. Hydroxyurea therapy was associated with significant reductions in plasma angiogenic factors and inhibition of endothelial cell-mediated angiogenic mechanisms and neovascularization. Thus, individuals with sickle cell anemia or hemoglobin SC disease with retinopathy present a highly angiogenic circulating milieu, capable of stimulating key endothelial cell-mediated angiogenic mechanisms. Combination anti-angiogenic therapy to prevent the progression of unregulated neovascularization and associated manifestations in sickle cell disease, such as pulmonary hypertension, may be indicated; furthermore, the benefits and drawbacks of the potent anti-angiogenic effects of hydroxyurea should be clarified. PMID:25769545

ARQ 092, an orally-available, selective AKT inhibitor, attenuates neutrophil-platelet interactions in sickle cell disease

PubMed Central

Kim, Kyungho; Li, Jing; Barazia, Andrew; Tseng, Alan; Youn, Seock-Won; Abbadessa, Giovanni; Yu, Yi; Schwartz, Brian; Andrews, Robert K.; Gordeuk, Victor R.; Cho, Jaehyung

2017-01-01

Previous studies identified the Ser/Thr protein kinase, AKT, as a therapeutic target in thrombo-inflammatory diseases. Here we report that specific inhibition of AKT with ARQ 092, an orally-available AKT inhibitor currently in phase Ib clinical trials as an anti-cancer drug, attenuates the adhesive function of neutrophils and platelets from sickle cell disease patients in vitro and cell-cell interactions in a mouse model of sickle cell disease. Studies using neutrophils and platelets isolated from sickle cell disease patients revealed that treatment with 50–500 nM ARQ 092 significantly blocks αMβ2 integrin function in neutrophils and reduces P-selectin exposure and glycoprotein Ib/IX/V-mediated agglutination in platelets. Treatment of isolated platelets and neutrophils with ARQ 092 inhibited heterotypic cell-cell aggregation under shear conditions. Intravital microscopic studies demonstrated that short-term oral administration of ARQ 092 or hydroxyurea, a major therapy for sickle cell disease, diminishes heterotypic cell-cell interactions in venules of sickle cell disease mice challenged with tumor necrosis factor-α. Co-administration of hydroxyurea and ARQ 092 further reduced the adhesive function of neutrophils in venules and neutrophil transmigration into alveoli, inhibited expression of E-selectin and intercellular adhesion molecule-1 in cremaster vessels, and improved survival in these mice. Ex vivo studies in sickle cell disease mice suggested that co-administration of hydroxyurea and ARQ 092 efficiently blocks neutrophil and platelet activation and that the beneficial effect of hydroxyurea results from nitric oxide production. Our results provide important evidence that ARQ 092 could be a novel drug for the prevention and treatment of acute vaso-occlusive complications in patients with sickle cell disease. PMID:27758820

Stem cells for the treatment of neurodegenerative diseases

PubMed Central

2010-01-01

Stem cells offer an enormous pool of resources for the understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and although great care will need to be taken when moving forward with prospective treatments, the application of stem cells is highly promising. PMID:21144012

Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease.

PubMed

Lafaille, J J; Keere, F V; Hsu, A L; Baron, J L; Haas, W; Raine, C S; Tonegawa, S

1997-07-21

Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4(+) Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in alphabeta T cell-deficient mice, albeit after a longer preclinical phase. Normal or gammadelta T cell-deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.

Stem Cell Therapy for the Central Nervous System in Lysosomal Storage Diseases.

PubMed

Siddiqi, Faez; Wolfe, John H

2016-10-01

Neurological diseases with genetic etiologies result in the loss or dysfunction of neural cells throughout the CNS. At present, few treatment options exist for the majority of neurogenetic diseases. Stem cell transplantation (SCT) into the CNS has the potential to be an effective treatment modality because progenitor cells may replace lost cells in the diseased brain, provide multiple trophic factors, or deliver missing proteins. This review focuses on the use of SCT in lysosomal storage diseases (LSDs), a large group of monogenic disorders with prominent CNS disease. In most patients the CNS disease results in intellectual disability that is refractory to current standard-of-care treatment. A large amount of preclinical work on brain-directed SCT has been performed in rodent LSD models. Cell types that have been used for direct delivery into the CNS include neural stem cells, embryonic and induced pluripotent stem cells, and mesenchymal stem cells. Hematopoietic stem cells have been an effective therapy for the CNS in a few LSDs and may be augmented by overexpression of the missing gene. Current barriers and potential strategies to improve SCT for translation into effective patient therapies are discussed.

Hematopoietic and mesenchymal stem cells for the treatment of chronic respiratory diseases: role of plasticity and heterogeneity.

PubMed

Conese, Massimo; Piro, Donatella; Carbone, Annalucia; Castellani, Stefano; Di Gioia, Sante

2014-01-01

Chronic lung diseases, such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD) are incurable and represent a very high social burden. Stem cell-based treatment may represent a hope for the cure of these diseases. In this paper, we revise the overall knowledge about the plasticity and engraftment of exogenous marrow-derived stem cells into the lung, as well as their usefulness in lung repair and therapy of chronic lung diseases. The lung is easily accessible and the pathophysiology of these diseases is characterized by injury, inflammation, and eventually by remodeling of the airways. Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal (stem) cells (MSCs), encompass a wide array of cell subsets with different capacities of engraftment and injured tissue regenerating potential. Proof-of-principle that marrow cells administered locally may engraft and give rise to specialized epithelial cells has been given, but the efficiency of this conversion is too limited to give a therapeutic effect. Besides the identification of plasticity mechanisms, the characterization/isolation of the stem cell subpopulations represents a major challenge to improving the efficacy of transplantation protocols used in regenerative medicine for lung diseases.

Membrane microparticles and diseases.

PubMed

Wu, Z-H; Ji, C-L; Li, H; Qiu, G-X; Gao, C-J; Weng, X-S

2013-09-01

Membrane microparticles (MPs) are plasma membrane-derived vesicles shed by various types of activated or apoptotic cells including platelets, monocytes, endothelial cells, red blood cells, and granulocytes. MPs are being increasingly recognized as important regulators of cell-to-cell interactions. Recent evidences suggest they may play important functions not only in homeostasis but also in the pathogenesis of a number of diseases such as vascular diseases, cancer, infectious diseases and diabetes mellitus. Accordingly, inhibiting the production of MPs may serve as a novel therapeutic strategy for these diseases. Here we review recent advances on the mechanism underlying the generation of MPs and the role of MPs in vascular diseases, cancer, diabetes, inflammation, and pathogen infection.

Circulating Follicular Helper-Like T Cells in Systemic Lupus Erythematosus: Association with Disease Activity

PubMed Central

Choi, Jin-Young; Ho, John Hsi-en; Pasoto, Sandra G; Bunin, Viviane; Kim, Sangtaek; Carrasco, Solange; Borba, Eduardo F; Gonçalves, Celio R; Costa, Priscila R; Kallas, Esper G; Bonfa, Eloisa; Craft, Joe

2015-01-01

Objective To assess circulating follicular helper-like CD4+ T (cTfh-like) cells in systemic lupus erythematosus (SLE) and determine their relationship to disease activity. Methods We analyzed blood samples from SLE patients, and as controls, Behçet’s disease (BD) patients and healthy individuals. We used flow cytometry to enumerate cTfh-like cells using as markers the C-X-C chemokine receptor type 5 (CXCR5), inducible T-cell costimulator (ICOS), programmed cell death protein-1 (PCDC1, PD-1), and secretion of interleukin-21 (IL-21). We compared the frequency of cTfh-like cells with that of circulating plasmablasts (CD19+IgD−CD38+) and evaluated their possible association with disease activity. Results cTfh-like T cells, identified as CXCR5hiICOShiPD-1hi, were expanded in the blood of SLE patients compared to BD and healthy controls. Such cells produced IL-21 with lower expression of CCR7, compared to circulating CXCR5hi central memory (Tcm) cells, enabling their distinction. PD-1, not ICOS or CXCR5, expression was significantly elevated in cTfh-like cells from SLE patients compared to controls. PD-1 expression among CXCR5hi cTfh-like cells correlated with disease activity, circulating plasmablasts, and anti-dsDNA antibody positivity, but not disease duration nor past organ injury; rather, it reflected current active disease. Conclusion We found that cTfh-like cells are associated with disease activity in SLE, suggesting that their presence indicates abnormal homeostasis of T-B cell collaboration with a causal relationship central to disease pathogenesis. These findings also suggest that cTfh-like cells provide a surrogate for aberrant GC activity in SLE, and that their PD-1 expression offers a tool for following disease activity and response to therapies. PMID:25581113

[Cell therapy for Parkinson's disease: III. Neonatal, fetal and embryonic stem cell-based applications].

PubMed

Anisimov, S V

2009-01-01

Motor dysfunctions in Parkinson's disease are believed to be primarily due to the degeneration of dopaminergic neurons located in the substantia nigra pars compacta. Numerous cell replacement therapy approaches have been developed and tested, including these based on donor cell transplantation (embryonic and adult tissue-derived), adult mesenchymal stem cells (hMSCs)-, neural stem cells (hNSCs)- and finally human embryonic stem cells (hESCs)-based. Despite the progress achieved, numerous difficulties prevent wider practical application of stem cell-based therapy approaches for the treatment of Parkinson's disease. Among the latter, ethical, safety and technical issues stand out. Current series of reviews (Cell therapy for Parkinson's disease: I. Embryonic and adult donor tissue-based applications; II. Adult stem cell-based applications; III. Neonatal, fetal and embryonic stem cell-based applications; IV. Risks and future trends) aims providing a balanced and updated view on various issues associated with cell types (including stem cells) in regards to their potential in the treatment of Parkinson's disease. Essential features of the individual cell subtypes, principles of available cell handling protocols, transplantation, and safety issues are discussed extensively.

CD4+ Foxp3+ T cells promote aberrant immunoglobulin G production and maintain CD8+ T-cell suppression during chronic liver disease.

PubMed

Tedesco, Dana; Thapa, Manoj; Gumber, Sanjeev; Elrod, Elizabeth J; Rahman, Khalidur; Ibegbu, Chris C; Magliocca, Joseph F; Adams, Andrew B; Anania, Frank; Grakoui, Arash

2017-02-01

Persistent hepatotropic viral infections are a common etiologic agent of chronic liver disease. Unresolved infection can be attributed to nonfunctional intrahepatic CD8+ T-cell responses. In light of dampened CD8 + T-cell responses, liver disease often manifests systemically as immunoglobulin (Ig)-related syndromes due to aberrant B-cell functions. These two opposing yet coexisting phenomena implicate the potential of altered CD4 + T-cell help. Elevated CD4 + forkhead box P3-positive (Foxp3+) T cells were evident in both human liver disease and a mouse model of chemically induced liver injury despite marked activation and spontaneous IgG production by intrahepatic B cells. While this population suppressed CD8 + T-cell responses, aberrant B-cell activities were maintained due to expression of CD40 ligand on a subset of CD4 + Foxp3+ T cells. In vivo blockade of CD40 ligand attenuated B-cell abnormalities in a mouse model of liver injury. A phenotypically similar population of CD4 + Foxp3+, CD40 ligand-positive T cells was found in diseased livers explanted from patients with chronic hepatitis C infection. This population was absent in nondiseased liver tissues and peripheral blood. Liver disease elicits alterations in the intrahepatic CD4 + T-cell compartment that suppress T-cell immunity while concomitantly promoting aberrant IgG mediated manifestations. (Hepatology 2017;65:661-677). © 2016 by the American Association for the Study of Liver Diseases.

Natural killer cells: In health and disease.

PubMed

Mandal, Arundhati; Viswanathan, Chandra

2015-06-01

Natural killer (NK) cells constitute our bodies' frontline defense system, guarding against tumors and launching attacks against infections. The activities of NK cells are regulated by the interaction of various receptors expressed on their surfaces with cell surface ligands. While the role of NK cells in controlling tumor activity is relatively clear, the fact that they are also linked to various other disease conditions is now being highlighted. Here, we present an overview of the role of NK cells during normal body state as well as under diseased state. We discuss the possible utilization of these powerful cells as immunotherapeutic agents in combating diseases such as asthma, autoimmune diseases, and HIV-AIDS. This review also outlines current challenges in NK cell therapy. Copyright © 2015. Published by Elsevier B.V.

Favorable outcome of Epstein-Barr virus-associated B-cell lymphoproliferative disorder complicated by immunoglobulin G4-related disease treated with rituximab-based therapy: a case report.

PubMed

Ueda, Koki; Ikeda, Kazuhiko; Ogawa, Kazuei; Sukegawa, Masumi; Sano, Takahiro; Kimura, Satoshi; Suzuki, Osamu; Hashimoto, Yuko; Takeishi, Yasuchika

2016-08-24

After acute infection of Epstein-Barr virus, Epstein-Barr virus-infected B cells survive but usually do not show clonal proliferation. However, Epstein-Barr virus-infected B cells occasionally acquire a proliferative capacity that provokes clonal lymphoproliferative disorders. We herein present a case with Epstein-Barr virus-infected CD30+ B cell and immunoglobulin G4+ plasmacytoid cell proliferation in the lymph nodes, suggesting a pathological and clinical interaction between Epstein-Barr virus-associated B-cell lymphoproliferative disorders and immunoglobulin G4-related disease. Immunoglobulin G4-related disease has been recognized as a benign disease with proliferation of IgG4-related disease+ plasmacytoid cells. Several studies have recently reported the coexistence of immunoglobulin G4-related disease+ plasmacytoid cells with Epstein-Barr virus-infected B cells in lymph nodes in some immunoglobulin G4-related disease cases. However, the pathogenic role of the clonal proliferation of Epstein-Barr virus-infected B cells in immunoglobulin G4-related disease, as well as the treatments for patients with both Epstein-Barr virus-infected B cells and immunoglobulin G4-related disease, have never been discussed. A 50-year-old Japanese man was referred to us for persistent fatigue and lymphadenopathy. His blood examination showed elevated IgG4, and detected high levels of Epstein-Barr virus DNA. A lymph node biopsy revealed IgG4+ plasmacytoid cells and infiltration of large lymphoid cells, which were positive for CD20, CD30, Epstein-Barr virus-related late membrane protein 1, and Epstein-Barr virus-encoded RNA, and were negative for IgG4. Based on the diagnosis of both Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease, the patient received eight cycles of rituximab combined with cyclophosphamide and prednisolone, which resulted in the complete disappearance of lymphadenopathy. Moreover, his serum IgG4 level was significantly reduced, and plasma Epstein-Barr virus DNA became undetectable. Although prednisolone was transiently administered in each cycle of immunochemotherapy, the therapeutic effect has persisted for Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease as of 1 year after finishing treatment. In the present case, clinical presentation and pathological findings revealed that Epstein-Barr virus-associated B-cell lymphoproliferative disorder coexisted with IgG4-related disease. Although several studies have described the relationship between Epstein-Barr virus-infected B cells and IgG4-related disease, this is the first report of a patient whose plasma Epstein-Barr virus DNA level, which correlated with the disease statuses of both diseases, was monitored. Moreover, rituximab-based immunochemotherapy was highly effective for both diseases. Our findings are suggestive for establishing a novel treatment strategy for IgG4-related disorders associated with chronic Epstein-Barr virus infection.

UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells

ClinicalTrials.gov

2018-03-15

Adrenoleukodystrophy; Batten Disease; Mucopolysaccharidosis II; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Neimann Pick Disease; Pelizaeus-Merzbacher Disease; Sandhoff Disease; Tay-Sachs Disease; Brain Diseases, Metabolic, Inborn; Alpha-Mannosidosis; Sanfilippo Mucopolysaccharidoses

Update: new guidelines for the treatment of infants with sickle cell disease. Agency for Health Care Policy and Research.

PubMed

Selekman, J

1993-01-01

These clinical practice guidelines set forth a comprehensive program for identifying, diagnosing, and treating newborns and infants with sickle cell disease and recommend education and counseling strategies for their parents. Sickle cell disease comprises a group of genetic disorders characterized by the production of hemoglobin S, anemia, and acute and chronic tissue damage secondary to the blockage of blood flow by abnormally shaped red cells. Sickle cell anemia is the most common form of the disease, and it affects approximately 1 in 375 African-American infants. Although in the United States sickle cell disease is most commonly found in persons of African ancestry, it also affects other populations. The panel recommends screening of all newborns for sickle cell disease, since targeting specific groups will miss some infected infants. Samples of dried blood on filter paper or liquid blood samples should be used for hemoglobinopathy screening. Hemoglobin electrophoresis, isoelectric focusing, and high performance liquid chromatography are acceptable, reliable, and accurate testing methods. Infants identified on initial screening must be retested to establish a definitive diagnosis. Affected infants must be given twice-daily oral penicillin beginning at 2 months of age to reduce pneumococcal, conjugated Haemophilus influenzae, and hepatitis B vaccines. Infants with sickle cell disease require the same well-child care as infants without the disease. Education and nondirective genetic counseling should be offered to all parents of infants with sickle cell disease. The guidelines stress the need for a comprehensive and fully integrated approach to reduce morbidity and mortality from sickle cell disease.(ABSTRACT TRUNCATED AT 250 WORDS)

N-acetylcysteine normalizes the urea cycle and DNA repair in cells from patients with Batten disease.

PubMed

Kim, June-Bum; Lim, Nary; Kim, Sung-Jo; Heo, Tae-Hwe

2012-12-01

Batten disease is an inherited disorder characterized by early onset neurodegeneration due to the mutation of the CLN3 gene. The function of the CLN3 protein is not clear, but an association with oxidative stress has been proposed. Oxidative stress and DNA damage play critical roles in the pathogenesis of neurodegenerative diseases. Antioxidants are of interest because of their therapeutic potential for treating neurodegenerative diseases. We tested whether N-acetylcysteine (NAC), a well-known antioxidant, improves the pathology of cells from patients with Batten disease. At first, the expression levels of urea cycle components and DNA repair enzymes were compared between Batten disease cells and normal cells. We used both mRNA expression levels and Western blot analysis. We found that carbamoyl phosphate synthetase 1, an enzyme involved in the urea cycle, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta, enzymes involved in DNA repair, were expressed at higher levels in Batten disease cells than in normal cells. The treatment of Batten disease cells with NAC for 48 h attenuated activities of the urea cycle and of DNA repair, as indicated by the substantially decreased expression levels of carbamoyl phosphate synthetase 1, 8-oxoguanine DNA glycosylase 1 and DNA polymerase beta proteins compared with untreated Batten cells. NAC may serve in alleviating the burden of urea cycle and DNA repair processes in Batten disease cells. We propose that NAC may have beneficial effects in patients with Batten disease. Copyright © 2012 John Wiley & Sons, Ltd.

Evaluation of a neonatal screening program for sickle-cell disease.

PubMed

Eller, Rodrigo; da Silva, Denise Bousfield

2016-01-01

Evaluate the Neonatal Screening Program of the Health Secretariat of the State of Santa Catarina for sickle-cell disease, from January 2003 to December 2012, regarding program coverage and disease frequency. Descriptive, observational, cross-sectional study with retrospective data collection. The variables analyzed were: number of live births in the State of Santa Catarina; number of screened children; number of children diagnosed with sickle-cell trait and sickle-cell disease; type of sickle-cell disease diagnosed; age at the time of sample collection, ethnicity/skin color, gender, and origin of children with sickle-cell disease. Descriptive measures and frequency tables were used for data analysis. During the study period, there were 848,833 live births and 730,412 samples were screened by the program, resulting in a coverage of 86.0%. There were 6173 samples positive for sickle-cell trait and 39 for sickle-cell disease. Among children with sickle-cell disease, the median age at the time of sample collection was 6 days. Regarding the ethnicity/skin color, 25 (64.1%) children were white, seven were black, and seven others were not specified. The Midwest and the Highland (Planalto Serrano) of Santa Catarina were the regions with the highest incidence of sickle-cell disease. Coverage by the Neonatal Screening Program of Santa Catarina is good, but did not demonstrate an improvement trend over the years. The frequency of sickle-cell disease is low and lower than in the North, Northeast, and Midwest regions. The median age in days at the time of collection is older than the age recommended by the Ministry of Health. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Hearing Loss and Auditory Function in Sickle Cell Disease

ERIC Educational Resources Information Center

Burch-Sims, G.P.; Matlock, V.R.

2005-01-01

Sickle cell disease was first reported in 1910 by J. Herrick, and since then, various associated conditions and complications have been described. Sickle cell disease is a hereditary disorder characterized by abnormality of the hemoglobin in the red blood cell. During periods of decreased oxygen tension in the red blood cell's environment, the…

[Cell therapy for Parkinson's disease: IV. Risks and future trends].

PubMed

Anisimov, S V

2009-01-01

Motor dysfunctions in Parkinson's disease are believed to be primarily due to the degeneration of dopaminergic neurons located in the substantia nigra pars compacta. Numerous cell replacement therapy approaches have been developed and tested, including these based on donor cell transplantation (embryonic and adult tissue-derived), adult mesenchymal stem cells (hMSCs)-, neural stem cells (hNSCs)- and finally human embryonic stem cells (hESCs)-based. Despite the progress achieved, numerous difficulties prevent wider practical application of stem cell-based therapy approaches for the treatment of Parkinson's disease. Among the latter, ethical, safety and technical issues stand out. Current series of reviews (Cell therapy for Parkinson's disease: I. Embryonic and adult donor tissue-based applications; II. Adult stem cell-based applications; III. Neonatal, fetal and embryonic stem cell-based applications; IV. Risks and future trends) aims providing a balanced and updated view on various issues associated with cell types (including stem cells) in regards to their potential in the treatment of Parkinson's disease. Essential features of the individual cell subtypes, principles of available cell handling protocols, transplantation, and safety issues are discussed extensively.

A unified pathogenesis for kidney diseases, including genetic diseases and cancers, by the protein-homeostasis-system hypothesis.

PubMed

Lee, Kyung-Yil

2017-06-01

Every cell of an organism is separated and protected by a cell membrane. It is proposed that harmony between intercellular communication and the health of an organism is controlled by a system, designated the protein-homeostasis-system (PHS). Kidneys consist of a variety of types of renal cells, each with its own characteristic cell-receptor interactions and producing characteristic proteins. A functional union of these renal cells can be determined by various renal function tests, and harmonious intercellular communication is essential for the healthy state of the host. Injury to a kind of renal cells can impair renal function and induce an imbalance in total body health. Every acute or chronic renal disease has unknown etiologic substances that are responsible for renal cell injury at the molecular level. The immune/repair system of the host should control the etiologic substances acting against renal cells; if this system fails, the disease progresses to end stage renal disease. Each renal disease has its characteristic pathologic lesions where immune cells and immune proteins, such as immunoglobulins and complements, are infiltrated. These immune cells and immune proteins may control the etiologic substances involved in renal pathologic lesions. Also, genetic renal diseases and cancers may originate from a protein deficiency or malfunctioning protein under the PHS. A unified pathogenesis for renal diseases, including acute glomerulonephritis, idiopathic nephrotic syndrome, immunoglobulin A nephropathy, genetic renal diseases such as Alport syndrome, and malignancies such as Wilms tumor and renal cell carcinoma, is proposed using the PHS hypothesis.

Evaluation of IgG4+ Plasma Cell Infiltration in Patients with Systemic Plasmacytosis and Other Plasma Cell-infiltrating Skin Diseases.

PubMed

Takeoka, Shintaro; Kamata, Masahiro; Hau, Carren Sy; Tateishi, Mihoko; Fukaya, Saki; Hayashi, Kotaro; Fukuyasu, Atsuko; Tanaka, Takamitsu; Ishikawa, Takeko; Ohnishi, Takamitsu; Sasajima, Yuko; Watanabe, Shinichi; Tada, Yayoi

2018-04-27

Systemic plasmacytosis is a rare skin disorder characterized by marked infiltration of plasma cells in the dermis. IgG4-related disease is pathologically characterized by lymphoplasmacytic infiltration rich in IgG4+ plasma cells, storiform fibrosis, and obliterative phlebitis, accompanied by elevated levels of serum IgG4. Reports of cases of systemic plasmacytosis with abundant infiltration of IgG4+ plasma cells has led to discussion about the relationship between systemic plasmacytosis and IgG4-related disease. This study examined IgG4+/IgG+ plasma cell ratios in 4 patients with systemic plasmacytosis and 12 patients with other skin diseases that show marked infiltration of plasma cells. Furthermore, we examined whether these cases met one of the pathological diagnostic criteria for IgG4-related disease (i.e. IgG4+/IgG plasma cells ratio of over 40%). Only one out of 4 patients with systemic plasmacytosis met the criterion. These results suggest that systemic plasmacytosis and IgG4-related disease are distinct diseases.

Acute pancreatitis during sickle cell vaso-occlusive painful crisis.

PubMed

Ahmed, Shahid; Siddiqui, Anita K; Siddiqui, Rina K; Kimpo, Miriam; Russo, Linda; Mattana, Joseph

2003-07-01

Sickle cell disease is characterized by chronic hemolytic anemia and vaso-occlusive painful crisis. The vascular occlusion in sickle cell disease is a complex process and accounts for the majority of the clinical manifestations of the disease. Abdominal pain is an important component of vaso-occlusive painful crisis and may mimic diseases such as acute appendicitis and cholecystitis. Acute pancreatitis is rarely included as a cause of abdominal pain in patients with sickle cell disease. When it occurs it may result form biliary obstruction, but in other instances it might be a consequence of microvessel occlusion causing ischemia. In this series we describe four cases of acute pancreatitis in patients with sickle cell disease apparently due to microvascular occlusion and ischemic injury to the pancreas. All patients responded to conservative management. Acute pancreatitis should be considered in the differential diagnosis of abdominal pain in patients with sickle cell disease. Copyright 2003 Wiley-Liss, Inc.

The Role of Biologically Active Ingredients from Chinese Herbal Medicines in the Regulation of Autophagy in Treating Cardiovascular Diseases and Other Chronic Diseases.

PubMed

Li, Jie; Gao, Yonghong; Ren, Xiaomeng; Li, Yanda; Wu, Lijun; Yang, Xinyu; Wang, Jie; Shang, Hongcai; Xiong, Xingjiang; Xing, Yanwei

2017-01-01

Autophagy, a highly conserved starvation response mechanism with both defensive and protective effects in eukaryotic cells, is a lysosome-mediated degradation process for non-essential or damaged cellular constituents. It plays an important role in the cell survival, differentiation and development to maintain homeostasis. Autophagy is involved in cardiovascular diseases, cerebrovascular diseases, and neurodegenerative diseases, as well as tumours. Thus, modulating autophagy may provide potential therapeutic strategies. Recently, many active components of Chinese herbal medicines (CHM) have been found to modulate autophagy in myocardial cells, cerebral vascular cells, endothelial cells and tumour cells. This paper reviews the advances in studies on the active components of CHM that modulating autophagy in treating cardiovascular diseases and other chronic diseases over the past five years. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Interplay between coagulation and vascular inflammation in sickle cell disease

PubMed Central

Sparkenbaugh, Erica; Pawlinski, Rafal

2013-01-01

Sickle cell disease is the most common inherited hematologic disorder that leads to the irreversible damage of multiple organs. Although sickling of red blood cells and vaso-occlusion are central to the pathophysiology of sickle cell disease the importance of hemolytic anemia and vasculopathy has been recently recognized. Hypercoagulation state is another prominent feature of sickle cell disease and is mediated by activation of both intrinsic and extrinsic coagulation pathways. Growing evidence demonstrates that coagulation may not only contribute to the thrombotic complications, but also to vascular inflammation associated with this disease. This article summarizes the role of vascular inflammation and coagulation activation, discusses potential mechanisms responsible for activation of coagulation and reviews recent data demonstrating the crosstalk between coagulation and vascular inflammation in sickle cell disease. PMID:23593937

Malignant histiocytic lymphoma with large lacunar cells.

PubMed

Leahu, S; Dobrea, M

1997-01-01

A case of lymph node biopsy with a peculiar histological aspect is described. The clinical data suggest a malignant lymphoid disease. The histological picture is that of a malignant histiocytosis but, among the majority of small histiocytes, there are some large cells like the large lacunar cells from Hodgkin's disease. These large cells (and some small cells) contain the CD 30 antigen of Reed-Sternberg cells. It is discussed whether the appropriate diagnosis is Hodgkin's disease, malignant histiocytosis, or non-Hodgkin's malignant lymphoma. Our diagnosis is Hodgkin's disease, the nodular sclerosing form.

Similar Responses of Intestinal T Cells From Untreated Children and Adults With Celiac Disease to Deamidated Gluten Epitopes.

PubMed

Ráki, Melinda; Dahal-Koirala, Shiva; Yu, Hao; Korponay-Szabó, Ilma R; Gyimesi, Judit; Castillejo, Gemma; Jahnsen, Jørgen; Qiao, Shuo-Wang; Sollid, Ludvig M

2017-09-01

Celiac disease is a chronic small intestinal inflammatory disorder mediated by an immune response to gluten peptides in genetically susceptible individuals. Celiac disease is often diagnosed in early childhood, but some patients receive a diagnosis late in life. It is uncertain whether pediatric celiac disease is distinct from adult celiac disease. It has been proposed that gluten-reactive T cells in children recognize deamidated and native gluten epitopes, whereas T cells from adults only recognize deamidated gluten peptides. We studied the repertoire of gluten epitopes recognized by T cells from children and adults. We examined T-cell responses against gluten by generating T-cell lines and T-cell clones from intestinal biopsies of adults and children and tested proliferative response to various gluten peptides. We analyzed T cells from 14 children (2-5 years old) at high risk for celiac disease who were followed for celiac disease development. We also analyzed T cells from 6 adults (26-55 years old) with untreated celiac disease. All children and adults were positive for HLA-DQ2.5. Biopsies were incubated with gluten digested with chymotrypsin (modified or unmodified by the enzyme transglutaminase 2) or the peptic-tryptic digest of gliadin (in native and deamidated forms) before T-cell collection. Levels of T-cell responses were higher to deamidated gluten than to native gluten in children and adults. T cells from children and adults each reacted to multiple gluten epitopes. Several T-cell clones were cross-reactive, especially clones that recognized epitopes from γ-and ω-gliadin. About half of the generated T-cell clones from children and adults reacted to unknown epitopes. T-cell responses to different gluten peptides appear to be similar between adults and children at the time of diagnosis of celiac disease. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Isolation and evaluation of dental pulp stem cells from teeth with advanced periodontal disease.

PubMed

Derakhshani, Ali; Raoof, Maryam; Dabiri, Shahriar; Farsinejad, Ali Reza; Gorjestani, Hedayat; Yaghoobi, Mohammad Mehdi; Shokouhinejad, Noushin; Ehsani, Maryam

2015-04-01

Successful isolation of mesenchymal stem cells from waste tissues might be extremely promising for developing stem cell-based therapies. This study aimed to explore whether cells retrieved from teeth extracted due to advanced periodontal disease present mesenchymal stem cell-like properties. Pulp cells were isolated from 15 intact molars and 15 teeth with advanced periodontal disease. Cell proliferation and markers of mesenchymal stem cells were evaluated. Based on the RT-PCR and agarose gel electrophoresis, nucleostemin, Oct-4 and jmj2c, but not Nanog, were expressed in undifferentiated mesenchymal stem cells of both groups. Interestingly, diseased pulp exhibited higher gene expressions although it was not statistically significant. The average percentage of BrdU positive cells in the diseased group (84.4%, n = 5) was significantly higher than that of the control group (65.4%, n = 5) (t-test, P = 0.001). Our results indicate the successful isolation of mesenchymal stem cells from the pulp tissue of hopeless periodontally involved teeth.

Prospects of Pluripotent and Adult Stem Cells for Rare Diseases.

PubMed

García-Castro, Javier; Singeç, Ilyas

2017-01-01

Rare diseases are highly diverse and complex regarding molecular underpinning and clinical manifestation and afflict millions of patients worldwide. The lack of appropriate model systems with face and construct validity and the limited availability of live tissues and cells from patients has largely hampered the understanding of underlying disease mechanisms. As a consequence, there are no adequate treatment options available for the vast majority of rare diseases. Over the last decade, remarkable progress in pluripotent and adult stem cell biology and the advent of powerful genomic technologies opened up exciting new avenues for the investigation, diagnosis, and personalized therapy of intractable human diseases. Utilizing the entire range of available stem cell types will continue to cross-fertilize different research areas and leverage the investigation of rare diseases based on evidence-based medicine. Standardized cell engineering and manufacturing from inexhaustible stem cell sources should lay the foundation for next-generation drug discovery and cell therapies that are broadly applicable in regenerative medicine. In this chapter we discuss how patient- and disease-specific iPS cells as well as adult stem cells are changing the pace of biomedical research and the translational landscape.

Chemokine receptors CCR6 and CXCR3 are necessary for CD4(+) T cell mediated ocular surface disease in experimental dry eye disease.

PubMed

Coursey, Terry G; Gandhi, Niral B; Volpe, Eugene A; Pflugfelder, Stephen C; de Paiva, Cintia S

2013-01-01

CD4(+) T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4(+) T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4(+) T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4(+) T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease.

Chemokine Receptors CCR6 and CXCR3 Are Necessary for CD4+ T Cell Mediated Ocular Surface Disease in Experimental Dry Eye Disease

PubMed Central

Coursey, Terry G.; Gandhi, Niral B.; Volpe, Eugene A.; Pflugfelder, Stephen C.; de Paiva, Cintia S.

2013-01-01

CD4+ T cells are essential to pathogenesis of ocular surface disease in dry eye. Two subtypes of CD4+ T cells, Th1 and Th17 cells, function concurrently in dry eye to mediate disease. This occurs in spite of the cross-regulation of IFN-γ and IL-17A, the prototypical cytokines Th1 and Th17 cells, respectively. Essential to an effective immune response are chemokines that direct and summon lymphocytes to specific tissues. T cell trafficking has been extensively studied in other models, but this is the first study to examine the role of chemokine receptors in ocular immune responses. Here, we demonstrate that the chemokine receptors, CCR6 and CXCR3, which are expressed on Th17 and Th1 cells, respectively, are required for the pathogenesis of dry eye disease, as CCR6KO and CXCR3KO mice do not develop disease under desiccating stress. CD4+ T cells from CCR6KO and CXCR3KO mice exposed to desiccating stress (DS) do not migrate to the ocular surface, but remain in the superficial cervical lymph nodes. In agreement with this, CD4+ T cells from CCR6 and CXCR3 deficient donors exposed to DS, when adoptively transferred to T cell deficient recipients manifest minimal signs of dry eye disease, including significantly less T cell infiltration, goblet cell loss, and expression of inflammatory cytokine and matrix metalloproteinase expression compared to wild-type donors. These findings highlight the important interaction of chemokine receptors on T cells and chemokine ligand expression on epithelial cells of the cornea and conjunctiva in dry eye pathogenesis and reveal potential new therapeutic targets for dry eye disease. PMID:24223818

Versican and the regulation of cell phenotype in disease.

PubMed

Wight, Thomas N; Kinsella, Michael G; Evanko, Stephen P; Potter-Perigo, Susan; Merrilees, Mervyn J

2014-08-01

Versican is an extracellular matrix (ECM) proteoglycan that is present in the pericellular environment of most tissues and increases in many different diseases. Versican interacts with cells to influence the ability of cells to proliferate, migrate, adhere and assemble an ECM. The structure of the versican molecule is briefly reviewed and studies highlighting those factors that promote versican synthesis and degradation and their impact on cell phenotype in disease are discussed. Particular attention is given to vascular disease, but other diseases where versican is important are covered as well, most notably different forms of cancers. Attention is given to mechanisms(s) by which versican influences cell behaviors through either direct or indirect processes. Versican produced by either stromal cells or myeloid cells can have a major impact influencing immunity and inflammation. Finally, studies controlling versican accumulation that either delay or inhibit the progression of disease will be highlighted. Versican is one component of the ECM that can influence the ability of cells to proliferate, migrate, adhere, and remodel the ECM. Targeting versican as a way to control cell phenotype offers a novel approach in the treatment of disease. ECM molecules such as versican contribute to the structural integrity of tissues and interact with cells through direct and indirect means to regulate, in part, cellular events that form the basis of disease. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. Copyright © 2014 Elsevier B.V. All rights reserved.

Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

PubMed

Wu, Meiqing; Huang, Fen; Jiang, Xinmiao; Fan, Zhiping; Zhou, Hongsheng; Liu, Can; Jiang, Qianli; Zhang, Yu; Zhao, Ke; Xuan, Li; Zhai, Xiao; Zhang, Fuhua; Yin, Changxin; Sun, Jing; Feng, Ru; Liu, Qifa

2013-01-01

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ± 1.9% and 4.1% ± 1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19(+)CD20(+) B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.

Human embryonic stem cell therapies for neurodegenerative diseases.

PubMed

Tomaskovic-Crook, Eva; Crook, Jeremy M

2011-06-01

There is a renewed enthusiasm for the clinical translation of human embryonic stem (hES) cells. This is abetted by putative clinically-compliant strategies for hES cell maintenance and directed differentiation, greater understanding of and accessibility to cells through formal cell registries and centralized cell banking for distribution, the revised US government policy on funding hES cell research, and paradoxically the discovery of induced pluripotent stem (iPS) cells. Additionally, as we consider the constraints (practical and fiscal) of delivering cell therapies for global healthcare, the more efficient and economical application of allogeneic vs autologous treatments will bolster the clinical entry of hES cell derivatives. Neurodegenerative disorders such as Parkinson's disease are primary candidates for hES cell therapy, although there are significant hurdles to be overcome. The present review considers key advances and challenges to translating hES cells into novel therapies for neurodegenerative diseases, with special consideration given to Parkinson's disease and Alzheimer's disease. Importantly, despite the focus on degenerative brain disorders and hES cells, many of the issues canvassed by this review are relevant to systemic application of hES cells and other pluripotent stem cells such as iPS cells.

78 FR 44575 - Sickle Cell Disease Treatment Demonstration Program

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-24

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Health Resources and Services Administration Sickle Cell... Extension: Sickle Cell Disease Treatment Demonstration Program (U1E) Awards to Three Currently Funded... the Sickle Cell Disease Treatment Demonstration Program. Three of these awards will end on August 31...

Quantification of mast cells in different stages of periodontal disease.

PubMed

Marjanović, Dragan; Andjelković, Zlatibor; Brkić, Zlata; Videnović, Goran; Šehalić, Meliha; Matvjenko, Vladimir; Leštarević, Snežana; Djordjević, Nadica

2016-05-01

Mast cells are mononuclear cells originating from bone marrow. They produce various biologically active substances, which allow them to actively participate in immune and inflammatory processes associated with periodontal disease. The study focused on distribution and density of mast cells in healthy gingiva as well as in different stages of periodontal disease. The material used for this purpose was gingival biopsies taken from 96 patients classified into 4 groups: healthy gingiva, gingivitis, initial and severe periodontal disease. Toluidine blue staining according to Spicer was utilized for identifying mast cells. Basing on our study, the density of mast cells in the gingival tissue increases with the progression of the infection, which means they are more numerous in gingivitis compared to healthy gingiva, as well as in periodontal disease compared to gingivitis. Increase in the number of mast cells in the infected gingiva can be correlated with an increased influx of inflammatory cells from blood circulation into the gingival stroma, as well as with the collagen lysis, since these cells produce substances with collagenolytic potential. Based on the distribution of mast cells, it could be concluded that in the evolution of periodontal disease there are significant dynamic alterations in migration and localization of these cells.

Regulatory B cells in human inflammatory and autoimmune diseases: from mouse models to clinical research.

PubMed

Miyagaki, Tomomitsu; Fujimoto, Manabu; Sato, Shinichi

2015-10-01

B cells have been generally considered to be positive regulators of immune responses because of their ability to produce antigen-specific antibodies and to activate T cells through antigen presentation. Impairment of B cell development and function may cause inflammatory and autoimmune diseases. Recently, specific B cell subsets that can negatively regulate immune responses have been described in mouse models of a wide variety of inflammatory and autoimmune diseases. The concept of those B cells, termed regulatory B cells, is now recognized as important in the murine immune system. Among several regulatory B cell subsets, IL-10-producing regulatory B cells are the most widely investigated. On the basis of discoveries from studies of such mice, human regulatory B cells that produce IL-10 in most cases are becoming an active area of research. There have been emerging data suggesting the importance of human regulatory B cells in various diseases. Revealing the immune regulation mechanisms of human regulatory B cells in human inflammatory and autoimmune diseases could lead to the development of novel B cell targeted therapies. This review highlights the current knowledge on regulatory B cells, mainly IL-10-producing regulatory B cells, in animal models of inflammatory and autoimmune diseases and in clinical research using human samples. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The role of natural killer cells in autoimmune blistering diseases.

PubMed

Zakka, L R; Fradkov, E; Keskin, D B; Tabansky, I; Stern, J N H; Ahmed, A R

2012-02-01

The major focus of this paper is to describe and evaluate current information on the role of natural killer cells (NK cells) in the pathogenesis of blistering diseases. Until now, only pemphigus vulgaris (PV) has been studied. One co-culture study demonstrated that CD4+ T cells from the peripheral blood or perilesional skin of patients with active disease proliferate and secrete cytokines in the presence of major histocompatibility class II-expressing NK cells loaded with antigenic desmoglein self-peptides. Another study showed that NK cells can contribute to a T helper type 2-biased immune response through impaired interleukins (IL)-12 signaling and upregulation of IL, IL-10 and IL-5. Although significant data on other blistering diseases are unavailable at present, some studies implicate NK cells in disease progression. For instance, information on the role of NK cells in psoriasis and their production of tumor necrosis factor-α (TNF-α) will be provided since several TNF-α-inhibitors are used in its treatment. Studies on alopecia areata are also included in this paper because NK cells seem to play a key role in its pathogenesis. This review highlights the potential importance of NK cells and NKT cells as members of the large repertoire of cells and soluble mediators that play a critical role in pathogenesis of blistering diseases and other autoimmune diseases involving the skin. Therefore, the authors advocate a greater focus and interest on the study of the interaction of NK cells and the skin.

Targeting B Cells and Plasma Cells in Autoimmune Diseases

PubMed Central

Hofmann, Katharina; Clauder, Ann-Katrin; Manz, Rudolf Armin

2018-01-01

Success with B cell depletion using rituximab has proven the concept that B lineage cells represent a valid target for the treatment of autoimmune diseases, and has promoted the development of other B cell targeting agents. Present data confirm that B cell depletion is beneficial in various autoimmune disorders and also show that it can worsen the disease course in some patients. These findings suggest that B lineage cells not only produce pathogenic autoantibodies, but also significantly contribute to the regulation of inflammation. In this review, we will discuss the multiple pro- and anti-inflammatory roles of B lineage cells play in autoimmune diseases, in the context of recent findings using B lineage targeting therapies. PMID:29740441

Sickle cell disease incidence among newborns in New York State by maternal race/ethnicity and nativity.

PubMed

Wang, Ying; Kennedy, Joseph; Caggana, Michele; Zimmerman, Regina; Thomas, Sanil; Berninger, John; Harris, Katharine; Green, Nancy S; Oyeku, Suzette; Hulihan, Mary; Grant, Althea M; Grosse, Scott D

2013-03-01

Sickle cell disease is estimated to occur in 1:300-400 African-American births, with higher rates among immigrants from Africa and the Caribbean, and is less common among Hispanic births. This study determined sickle cell disease incidence among New York State newborns stratified by maternal race/ethnicity and nativity. Newborns with confirmed sickle cell disease born to New York State residents were identified by the New York State newborn screening program for the years 2000-2008 and matched to birth records to obtain birth and maternal information. Annual incidence rates were computed and bivariate analyses were conducted to examine associations with maternal race/ethnicity and nativity. From 2000 to 2008, 1,911 New York State newborns were diagnosed with sickle cell disease and matched to the birth certificate files. One in every 1,146 live births was diagnosed with sickle cell disease. Newborns of non-Hispanic black mothers accounted for 86% of sickle cell disease cases whereas newborns of Hispanic mothers accounted for 12% of cases. The estimated incidence was 1:230 live births for non-Hispanic black mothers, 1:2,320 births for Hispanic mothers, and 1:41,647 births for non-Hispanic white mothers. Newborns of foreign-born non-Hispanic black mothers had a twofold higher incidence of sickle cell disease than those born to US-born non-Hispanic black mothers (P < 0.001). This study provides the first US estimates of sickle cell disease incidence by maternal nativity. Women born outside the United States account for the majority of children with sickle cell disease born in New York State. Such findings identify at-risk populations and inform outreach activities that promote ongoing, high-quality medical management to affected children.

Disease modeling using human induced pluripotent stem cells: lessons from the liver.

PubMed

Gieseck, Richard L; Colquhoun, Jennifer; Hannan, Nicholas R F

2015-01-01

Human pluripotent stem cells (hPSCs) have the capacity to differentiate into any of the hundreds of distinct cell types that comprise the human body. This unique characteristic has resulted in considerable interest in the field of regenerative medicine, given the potential for these cells to be used to protect, repair, or replace diseased, injured, and aged cells within the human body. In addition to their potential in therapeutics, hPSCs can be used to study the earliest stages of human development and to provide a platform for both drug screening and disease modeling using human cells. Recently, the description of human induced pluripotent stem cells (hIPSCs) has allowed the field of disease modeling to become far more accessible and physiologically relevant, as pluripotent cells can be generated from patients of any genetic background. Disease models derived from hIPSCs that manifest cellular disease phenotypes have been established to study several monogenic diseases; furthermore, hIPSCs can be used for phenotype-based drug screens to investigate complex diseases for which the underlying genetic mechanism is unknown. As a result, the use of stem cells as research tools has seen an unprecedented growth within the last decade as researchers look for in vitro disease models which closely mimic in vivo responses in humans. Here, we discuss the beginnings of hPSCs, starting with isolation of human embryonic stem cells, moving into the development and optimization of hIPSC technology, and ending with the application of hIPSCs towards disease modeling and drug screening applications, with specific examples highlighting the modeling of inherited metabolic disorders of the liver. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Mortality of New York children with sickle cell disease identified through newborn screening.

PubMed

Wang, Ying; Liu, Gang; Caggana, Michele; Kennedy, Joseph; Zimmerman, Regina; Oyeku, Suzette O; Werner, Ellen M; Grant, Althea M; Green, Nancy S; Grosse, Scott D

2015-06-01

Long-term follow-up of newborn screening for conditions such as sickle cell disease can be conducted using linkages to population-based data. We sought to estimate childhood sickle cell disease mortality and risk factors among a statewide birth cohort with sickle cell disease identified through newborn screening. Children with sickle cell disease identified by newborn screening and born to New York residents in 2000-2008 were matched to birth and death certificates. Mortality rates were calculated (using numbers of deaths and observed person-years at risk) and compared with mortality rates for all New York children by maternal race/ethnicity. Stratified analyses were conducted to examine associations between selected factors and mortality. Among 1,911 infants with sickle cell disease matched to birth certificates, 21 deaths were identified. All-cause mortality following diagnosis was 3.8 per 1,000 person-years in the first 2 years of life and 1.0 per 1,000 person-years at ages 2-9 years. The mortality rate was significantly lower among children of foreign-born mothers and was significantly higher among preterm infants with low birth weight. The mortality rates were not significantly higher for infants after 28 days with sickle cell disease than for all New York births, but they were 2.7-8.4 times higher for children 1 through 9 years old with homozygous sickle cell disease than for those of all non-Hispanic black or Hispanic children born to New York residents. Estimated mortality risk in children with homozygous sickle cell disease remains elevated even after adjustment for maternal race/ethnicity. These results provide evidence regarding the current burden of child mortality among children with sickle cell disease despite newborn screening.Genet Med 17 6, 452-459.

Materials for Neural Differentiation, Trans-Differentiation, and Modeling of Neurological Disease.

PubMed

Gong, Lulu; Cao, Lining; Shen, Zhenmin; Shao, Li; Gao, Shaorong; Zhang, Chao; Lu, Jianfeng; Li, Weida

2018-04-01

Neuron regeneration from pluripotent stem cells (PSCs) differentiation or somatic cells trans-differentiation is a promising approach for cell replacement in neurodegenerative diseases and provides a powerful tool for investigating neural development, modeling neurological diseases, and uncovering the mechanisms that underlie diseases. Advancing the materials that are applied in neural differentiation and trans-differentiation promotes the safety, efficiency, and efficacy of neuron regeneration. In the neural differentiation process, matrix materials, either natural or synthetic, not only provide a structural and biochemical support for the monolayer or three-dimensional (3D) cultured cells but also assist in cell adhesion and cell-to-cell communication. They play important roles in directing the differentiation of PSCs into neural cells and modeling neurological diseases. For the trans-differentiation of neural cells, several materials have been used to make the conversion feasible for future therapy. Here, the most current applications of materials for neural differentiation for PSCs, neuronal trans-differentiation, and neurological disease modeling is summarized and discussed. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Sickle cell anemia

MedlinePlus

Anemia - sickle cell; Hemoglobin SS disease (Hb SS); Sickle cell disease ... Sickle cell anemia is caused by an abnormal type of hemoglobin called hemoglobin S. Hemoglobin is a protein inside red blood cells ...

Induced Pluripotent Stem Cell Therapies for Degenerative Disease of the Outer Retina: Disease Modeling and Cell Replacement.

PubMed

Di Foggia, Valentina; Makwana, Priyanka; Ali, Robin R; Sowden, Jane C

2016-06-01

Stem cell therapies are being explored as potential treatments for retinal disease. How to replace neurons in a degenerated retina presents a continued challenge for the regenerative medicine field that, if achieved, could restore sight. The major issues are: (i) the source and availability of donor cells for transplantation; (ii) the differentiation of stem cells into the required retinal cells; and (iii) the delivery, integration, functionality, and survival of new cells in the host neural network. This review considers the use of induced pluripotent stem cells (iPSC), currently under intense investigation, as a platform for cell transplantation therapy. Moreover, patient-specific iPSC are being developed for autologous cell transplantation and as a tool for modeling specific retinal diseases, testing gene therapies, and drug screening.

The Application of Nanomaterials in Stem Cell Therapy for Some Neurological Diseases.

PubMed

Zhang, Guilong; Khan, Ahsan Ali; Wu, Hao; Chen, Lukui; Gu, Yuchun; Gu, Ning

2018-02-08

Stem cell therapy provides great promising therapeutic benefits for various neurological disorders. Cell transplantation has emerged as cell replacement application for nerve damage. Recently, nanomaterials obtain wide development in various industrial and medical fields, and nanoparticles have been applied in the neurological field for tracking and treating nervous system diseases. Combining stem cells with nanotechnology has raised more and more attentions; and it has demonstrated that the combination has huge effects on clinical diagnosis and therapeutics in multiple central nervous system diseases, meanwhile, improves prognosis. The aim of this review was to give a brief overview of the application of nanomaterials in stem cell therapy for neurological diseases. Nanoparticles not only promote stem cell proliferation and differentiation in vitro or in vivo, but also play dominant roles on stem cell imaging and tracking. Furthermore, via delivering genes or drugs, nanoparticles can participate in stem cell therapeutic applications for various neurological diseases, such as ischemic stroke, spinal cord injury (SCI), multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and gliomas. However, nanoparticles have potential cytotoxic effects on nerve cells, which are related to their physicochemical properties. Nano-stem cell-based therapy as a promising strategy has the ability to affect neuronal repair and regeneration in the central nervous system. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Indoleamine 2,3-dioxygenase and regulatory t cells in intestinal mucosa in children with inflammatory bowel disease.

PubMed

Sznurkowska, K; Żawrocki, A; Sznurkowski, J; Iżycka-Świeszewska, E; Landowski, P; Szlagatys-Sidorkiewicz, A; Plata-Nazar, K; Kamińska, B

2017-01-01

Impaired immune regulation has been suggested as an underlying mechanism of inflammatory bowel disease. Indoleamine 2,3-dioxygenase (IDO) and regulatory T cells expressing FOXP3 are crucial elements of immune regulation. Conversion of FOXP3- lymphocytes to Tregs is one of the functions of IDO. The aim of this study was to evaluate the number of cells expressing FOXP3 and IDO in the lamina propria of intestinal mucosa and to evaluate correlations between these parameters and disease activity. Sixty-six children newly diagnosed with inflammatory bowel disease (41 patients with ulcerative colitis and 25 patients with Crohn’s disease) were included in the study. Clinical activity of the disease was assessed by the Pediatric Ulcerative Colitis Activity Index and the Pediatric Crohn’s Disease Activity Index. Histopathological activity was scored according to the system described by Geboes. The infiltration of FOXP3+ and IDO+ cells was evaluated by immunohistochemistry. Sixteen patients with a diagnosis of irritable bowel syndrome (IBS) served as a control group. Lamina propria demonstrated a significantly higher infiltration of FOXP3+ and IDO+ cells in inflammatory bowel disease compared to the control group (p=0.001, p=0.004, respectively). The number of IDO+ and FOXP3+ cells correlated with clinical and histopathologic activity of Crohn’s disease. A positive correlation between the number of IDO+ and FOXP3+ cells was found in both types of inflammatory disease but not in patients with IBS. We conclude that indoleamine dioxygenase and FOXP3+ cells are upregulated in the intestinal mucosa of children with inflammatory bowel disease. IDO mediated conversion of FOXP3 -T cells to Tregs predominantly occurs in inflammation.

The ubiquitin proteasome system in glia and its role in neurodegenerative diseases

PubMed Central

Jansen, Anne H. P.; Reits, Eric A. J.; Hol, Elly M.

2014-01-01

The ubiquitin proteasome system (UPS) is crucial for intracellular protein homeostasis and for degradation of aberrant and damaged proteins. The accumulation of ubiquitinated proteins is a hallmark of many neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s disease, leading to the hypothesis that proteasomal impairment is contributing to these diseases. So far, most research related to the UPS in neurodegenerative diseases has been focused on neurons, while glial cells have been largely disregarded in this respect. However, glial cells are essential for proper neuronal function and adopt a reactive phenotype in neurodegenerative diseases, thereby contributing to an inflammatory response. This process is called reactive gliosis, which in turn affects UPS function in glial cells. In many neurodegenerative diseases, mostly neurons show accumulation and aggregation of ubiquitinated proteins, suggesting that glial cells may be better equipped to maintain proper protein homeostasis. During an inflammatory reaction, the immunoproteasome is induced in glia, which may contribute to a more efficient degradation of disease-related proteins. Here we review the role of the UPS in glial cells in various neurodegenerative diseases, and we discuss how studying glial cell function might provide essential information in unraveling mechanisms of neurodegenerative diseases. PMID:25152710

Therapeutic effect of the natural compounds baicalein and baicalin on autoimmune diseases.

PubMed

Xu, Jian; Liu, Jinlong; Yue, Guolin; Sun, Mingqiang; Li, Jinliang; Xiu, Xia; Gao, Zhenzhong

2018-05-23

A series of natural compounds have been implicated to be useful in regulating the pathogenesis of various autoimmune diseases. The present study demonstrated that the Scutellariae radix compounds baicalein and baicalin may serve as drugs for the treatment of autoimmune diseases, including rheumatoid arthritis and inflammatory bowel disease. Following the administration of baicalein and baicalin in vivo, T cell‑mediated autoimmune diseases in the mouse model were profoundly ameliorated: In the collagen‑induced arthritis model (CIA), the severity of the disease was reduced by baicalein and, consistently, baicalein was demonstrated to suppress T cell proliferation in CIA mice. In the dextran sodium sulfate (DSS)‑induced colitis model, the disease was attenuated by baicalin, and baicalin promoted colon epithelial cell (CEC) proliferation in vitro. The present study further revealed that the mRNA expression of signal transducer and activator of transcription (STAT)3 and STAT4 in the tyrosine‑protein kinase JAK‑STAT signaling pathway in T cells was downregulated by baicalein, contributing to its regulation of T cell proliferation. However, in the DSS model, the STAT4 transcription in CECs, which are the target cells of activated T cells in the gut, was downregulated by baicalin, suggesting that baicalein and baicalin mediated similar STAT expression in different cell types in autoimmune diseases. In conclusion, the similarly structured compounds baicalein and baicalin selectively exhibited therapeutic effects on autoimmune diseases by regulating cell proliferation and STAT gene expression, albeit in different cell types.

Modeling Human Neurological and Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Neuronal Differentiation and Its Applications in Neurotrauma.

PubMed

Bahmad, Hisham; Hadadeh, Ola; Chamaa, Farah; Cheaito, Katia; Darwish, Batoul; Makkawi, Ahmad-Kareem; Abou-Kheir, Wassim

2017-01-01

With the help of several inducing factors, somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) lines. The success is in obtaining iPSCs almost identical to embryonic stem cells (ESCs), therefore various approaches have been tested and ultimately several ones have succeeded. The importance of these cells is in how they serve as models to unveil the molecular pathways and mechanisms underlying several human diseases, and also in its potential roles in the development of regenerative medicine. They further aid in the development of regenerative medicine, autologous cell therapy and drug or toxicity screening. Here, we provide a comprehensive overview of the recent development in the field of iPSCs research, specifically for modeling human neurological and neurodegenerative diseases, and its applications in neurotrauma. These are mainly characterized by progressive functional or structural neuronal loss rendering them extremely challenging to manage. Many of these diseases, including Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) have been explored in vitro . The main purpose is to generate patient-specific iPS cell lines from the somatic cells that carry mutations or genetic instabilities for the aim of studying their differentiation potential and behavior. This new technology will pave the way for future development in the field of stem cell research anticipating its use in clinical settings and in regenerative medicine in order to treat various human diseases, including neurological and neurodegenerative diseases.

Transplantation of cerebellar neural stem cells improves motor coordination and neuropathology in Machado-Joseph disease mice.

PubMed

Mendonça, Liliana S; Nóbrega, Clévio; Hirai, Hirokazu; Kaspar, Brian K; Pereira de Almeida, Luís

2015-02-01

Machado-Joseph disease is a neurodegenerative disease without effective treatment. Patients with Machado-Joseph disease exhibit significant motor impairments such as gait ataxia, associated with multiple neuropathological changes including mutant ATXN3 inclusions, marked neuronal loss and atrophy of the cerebellum. Thus, an effective treatment of symptomatic patients with Machado-Joseph disease may require cell replacement, which we investigated in this study. For this purpose, we injected cerebellar neural stem cells into the cerebellum of adult Machado-Joseph disease transgenic mice and assessed the effect on the neuropathology, neuroinflammation mediators and neurotrophic factor levels and motor coordination. We found that upon transplantation into the cerebellum of adult Machado-Joseph disease mice, cerebellar neural stem cells differentiate into neurons, astrocytes and oligodendrocytes. Importantly, cerebellar neural stem cell transplantation mediated a significant and robust alleviation of the motor behaviour impairments, which correlated with preservation from Machado-Joseph disease-associated neuropathology, namely reduction of Purkinje cell loss, reduction of cellular layer shrinkage and mutant ATXN3 aggregates. Additionally, a significant reduction of neuroinflammation and an increase of neurotrophic factors levels was observed, indicating that transplantation of cerebellar neural stem cells also triggers important neuroprotective effects. Thus, cerebellar neural stem cells have the potential to be used as a cell replacement and neuroprotective approach for Machado-Joseph disease therapy. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Using induced pluripotent stem cells derived neurons to model brain diseases.

PubMed

McKinney, Cindy E

2017-07-01

The ability to use induced pluripotent stem cells (iPSC) to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders. Rodent models of brain diseases have spurred understanding of pathology but the concern arises that they may not recapitulate the full spectrum of neuron disruptions associated with human neuropathology. iPSC derived neurons, or other neural cell types, provide the ability to access pathology in cells derived directly from a patient's blood sample or skin biopsy where availability of brain tissue is limiting. Thus, utilization of iPSC to study brain diseases provides an unlimited resource for disease modelling but may also be used for drug screening for effective therapies and may potentially be used to regenerate aged or damaged cells in the future. Many brain diseases across the spectrum of neurodevelopment, neurodegenerative and neuropsychiatric are being approached by iPSC models. The goal of an iPSC based disease model is to identify a cellular phenotype that discriminates the disease-bearing cells from the control cells. In this mini-review, the importance of iPSC cell models validated for pluripotency, germline competency and function assessments is discussed. Selected examples for the variety of brain diseases that are being approached by iPSC technology to discover or establish the molecular basis of the neuropathology are discussed.

Looking into the future: Using induced pluripotent stem cells to build two and three dimensional ocular tissue for cell therapy and disease modeling.

PubMed

Song, Min Jae; Bharti, Kapil

2016-05-01

Retinal degenerative diseases are the leading cause of irreversible vision loss in developed countries. In many cases the diseases originate in the homeostatic unit in the back of the eye that contains the retina, retinal pigment epithelium (RPE) and the choriocapillaris. RPE is a central and a critical component of this homeostatic unit, maintaining photoreceptor function and survival on the apical side and choriocapillaris health on the basal side. In diseases like age-related macular degeneration (AMD), it is thought that RPE dysfunctions cause disease-initiating events and as the RPE degenerates photoreceptors begin to die and patients start loosing vision. Patient-specific induced pluripotent stem (iPS) cell-derived RPE provides direct access to a patient's genetics and allow the possibility of identifying the initiating events of RPE-associated degenerative diseases. Furthermore, iPS cell-derived RPE cells are being tested as a potential cell replacement in disease stages with RPE atrophy. In this article we summarize the recent progress in the field of iPS cell-derived RPE "disease modeling" and cell therapies and also discuss the possibilities of developing a model of the entire homeostatic unit to aid in studying disease processes in the future. This article is part of a Special Issue entitled SI: PSC and the brain. Published by Elsevier B.V.

Transmission of hemic neoplasia in the bay mussel, Mytilus edulis, using whole cells and cell homogenate.

PubMed

Elston, R A; Kent, M L; Drum, A S

1988-01-01

Experimental studies with hemic neoplasia in the bay mussel indicated that the condition can be transmitted allogeneically with intact whole cells and cell-free homogenate. A differential pathogenesis of the disease in mussels receiving the two different inocula supports the argument that actual cell transplantation occurred. In addition to the first demonstration of the infectious nature of the disease with cell-free homogenates, it was also shown that the disease is transmitted by cohabitation. Remission of the disease occurred in some mussels indicating individual variation in recognition mechanisms.

Mast Cells in Gastrointestinal Disease

PubMed Central

Ramsay, David B.; Stephen, Sindu; Borum, Marie; Voltaggio, Lysandra

2010-01-01

The function of mast cells in allergic inflammatory reactions is well documented in the literature. Mast cells also play an important role in the regulation of gastrointestinal visceral sensitivity and vascular permeability. Several studies have noted an increased number of mast cells in the mucosa of patients with gastrointestinal diseases such as irritable bowel syndrome, mastocytic enterocolitis, and systemic mastocytosis. The role of mast cells in the symptomatology of these and other diseases has only recently been fully appreciated and could provide avenues for new therapeutic opportunities. This paper examines studies that have evaluated the role of mast cells in various gastrointestinal diseases. PMID:21301631

A Comprehensive Fluid Dynamic-Diffusion Model of Blood Microcirculation with Focus on Sickle Cell Disease

NASA Astrophysics Data System (ADS)

Le Floch, Francois; Harris, Wesley L.

2009-11-01

A novel methodology has been developed to address sickle cell disease, based on highly descriptive mathematical models for blood flow in the capillaries. Our investigations focus on the coupling between oxygen delivery and red blood cell dynamics, which is crucial to understanding sickle cell crises and is unique to this blood disease. The main part of our work is an extensive study of blood dynamics through simulations of red cells deforming within the capillary vessels, and relies on the use of a large mathematical system of equations describing oxygen transfer, blood plasma dynamics and red cell membrane mechanics. This model is expected to lead to the development of new research strategies for sickle cell disease. Our simulation model could be used not only to assess current researched remedies, but also to spur innovative research initiatives, based on our study of the physical properties coupled in sickle cell disease.

The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders

PubMed Central

Smith, Derek K.; He, Miao; Zhang, Chun-Li; Zheng, Jialin C.

2018-01-01

Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies. PMID:26844759

[Acute painful crisis in a female Nigerian patient with sickle cell disease].

PubMed

Nin, Sayaka; Seki, Masanori; Maie, Koichiro; Kuroda, Akihiro; Miyamoto, Kana; Ogawa, Shinichi; Ito, Yufu; Kurita, Naoki; Yokoyama, Yasuhisa; Sakata Yanagimoto, Mamiko; Obara, Naoshi; Hasegawa, Yuichi; Ogino, Yasuko; Ito, Takayoshi; Chiba, Shigeru

2015-01-01

We report a 38-year-old Nigerian woman with sickle cell disease. Sickle cell disease had been diagnosed when she experienced her first sickle cell crisis episode at age 8 years. Thereafter, she had infrequent minor episodes. She visited a hospital presenting with fever, anemia, jaundice, and systemic pain, and was then transferred to our hospital. Together with rehydration and red blood cell transfusion, analgesics and antibiotics were prescribed, and produced gradual improvement of all symptoms and signs. The patient was discharged on day 9 of hospitalization. Sickle cell crisis is an acute painful episode caused by occlusion of arterioles. The degree of pain and accompanying symptoms, as well as the frequencies of crises, are variable. Moreover, one third of individuals with sickle cell disease never experience a crisis. As our society becomes increasingly globalized, the probabilities of encountering sickle cell disease patients will be higher.

Functional relevance of intestinal epithelial cells in inflammatory bowel disease.

PubMed

Okamoto, Ryuichi; Watanabe, Mamoru

2016-01-01

The intestinal epithelium constitutes a physical barrier between inner and outer side of our body. It also functions as a "hub" which connects factors that determine the development of inflammatory bowel disease, such as microbiota, susceptibility genes, and host immune response. Accordingly, recent studies have implicated and further featured the role of intestinal epithelial cell dysfunction in the pathophysiology of inflammatory bowel disease. For example, mucin producing goblet cells are usually "depleted" in ulcerative colitis patients. Studies have shown that those goblet cells exhibit various immune-regulatory functions in addition to mucin production, such as antigen presentation or cytokine production. Paneth cells are another key cell lineage that has been deeply implicated in the pathophysiology of Crohn's disease. Several susceptibility genes for Crohn's disease may lead to impairment of anti-bacterial peptide production and secretion by Paneth cells. Also, other susceptibility genes may determine the survival of Paneth cells, which leads to reduced Paneth cell function in the patient small intestinal mucosa. Further studies may reveal other unexpected roles of the intestinal epithelium in the pathophysiology of inflammatory bowel disease, and may help to develop alternative therapies targeted to intestinal epithelial cell functions.

The role of colonic mast cells and myenteric plexitis in patients with diverticular disease.

PubMed

Bassotti, Gabrio; Villanacci, Vincenzo; Nascimbeni, Riccardo; Antonelli, Elisabetta; Cadei, Moris; Manenti, Stefania; Lorenzi, Luisa; Titi, Amin; Salerni, Bruno

2013-02-01

Gut mast cells represent an important cell population involved in intestinal homeostasis and inflammatory processes. However, their possible role has not to date been investigated in colonic diverticular disease. This study aims to evaluate colonic mast cells in patients undergoing surgery for diverticular disease. Surgical resection samples from 27 patients undergoing surgery for diverticular disease (12 emergency procedures for severe disease and 15 elective procedures) were evaluated. The number of mast cells was assessed in the various layers by means of a specific antibody (tryptase) and compared with those evaluated in ten controls. In patients with mast cells degranulation, double immunohistochemistry, also assessing nerve fibres, was carried out. In addition, the presence of myenteric plexitis was sought. Compared with controls, the number of mast cells in diverticular patients was significantly increased, both as an overall figure and in the various layers of the large bowel. In patients in whom mast cells degranulation was present, these were always closed to nerve fibres. No differences were found between the two subgroups of patients with respect to the number and distribution of mast cells; however, all patients undergoing emergency surgery (but none of those undergoing elective procedures) had myenteric plexitis, represented by lymphocytic infiltration in 67 % and eosinophilic infiltration in 33 % of cases. Patients with diverticular disease display an increase of mast cells in the large bowel. The presence of myenteric plexitis in those with complicated, severe disease, suggest that this could represent a histopathologic marker of more aggressive disease.

Circulating gluten-specific FOXP3+CD39+ regulatory T cells have impaired suppressive function in patients with celiac disease.

PubMed

Cook, Laura; Munier, C Mee Ling; Seddiki, Nabila; van Bockel, David; Ontiveros, Noé; Hardy, Melinda Y; Gillies, Jana K; Levings, Megan K; Reid, Hugh H; Petersen, Jan; Rossjohn, Jamie; Anderson, Robert P; Zaunders, John J; Tye-Din, Jason A; Kelleher, Anthony D

2017-12-01

Celiac disease is a chronic immune-mediated inflammatory disorder of the gut triggered by dietary gluten. Although the effector T-cell response in patients with celiac disease has been well characterized, the role of regulatory T (Treg) cells in the loss of tolerance to gluten remains poorly understood. We sought to define whether patients with celiac disease have a dysfunction or lack of gluten-specific forkhead box protein 3 (FOXP3) + Treg cells. Treated patients with celiac disease underwent oral wheat challenge to stimulate recirculation of gluten-specific T cells. Peripheral blood was collected before and after challenge. To comprehensively measure the gluten-specific CD4 + T-cell response, we paired traditional IFN-γ ELISpot with an assay to detect antigen-specific CD4 + T cells that does not rely on tetramers, antigen-stimulated cytokine production, or proliferation but rather on antigen-induced coexpression of CD25 and OX40 (CD134). Numbers of circulating gluten-specific Treg cells and effector T cells both increased significantly after oral wheat challenge, peaking at day 6. Surprisingly, we found that approximately 80% of the ex vivo circulating gluten-specific CD4 + T cells were FOXP3 + CD39 + Treg cells, which reside within the pool of memory CD4 + CD25 + CD127 low CD45RO + Treg cells. Although we observed normal suppressive function in peripheral polyclonal Treg cells from patients with celiac disease, after a short in vitro expansion, the gluten-specific FOXP3 + CD39 + Treg cells exhibited significantly reduced suppressive function compared with polyclonal Treg cells. This study provides the first estimation of FOXP3 + CD39 + Treg cell frequency within circulating gluten-specific CD4 + T cells after oral gluten challenge of patients with celiac disease. FOXP3 + CD39 + Treg cells comprised a major proportion of all circulating gluten-specific CD4 + T cells but had impaired suppressive function, indicating that Treg cell dysfunction might be a key contributor to disease pathogenesis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

T cells promote the regeneration of neural precursor cells in the hippocampus of Alzheimer's disease mice.

PubMed

Liu, Jing; Ma, Yuxin; Tian, Sumin; Zhang, Li; Zhao, Mengmeng; Zhang, Yaqiong; Xu, Dachuan

2014-08-15

Alzheimer's disease is closely associated with disorders of neurogenesis in the brain, and growing evidence supports the involvement of immunological mechanisms in the development of the disease. However, at present, the role of T cells in neuronal regeneration in the brain is unknown. We injected amyloid-beta 1-42 peptide into the hippocampus of six BALB/c wild-type mice and six BALB/c-nude mice with T-cell immunodeficiency to establish an animal model of Alzheimer's disease. A further six mice of each genotype were injected with same volume of normal saline. Immunohistochemistry revealed that the number of regenerated neural progenitor cells in the hippocampus of BALB/c wild-type mice was significantly higher than that in BALB/c-nude mice. Quantitative fluorescence PCR assay showed that the expression levels of peripheral T cell-associated cytokines (interleukin-2, interferon-γ) and hippocampal microglia-related cytokines (interleukin-1β, tumor necrosis factor-α) correlated with the number of regenerated neural progenitor cells in the hippocampus. These results indicate that T cells promote hippocampal neurogenesis in Alzheimer's disease and T-cell immunodeficiency restricts neuronal regeneration in the hippocampus. The mechanism underlying the promotion of neuronal regeneration by T cells is mediated by an increased expression of peripheral T cells and central microglial cytokines in Alzheimer's disease mice. Our findings provide an experimental basis for understanding the role of T cells in Alzheimer's disease.

Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease.

PubMed

Fox, Ira J; Daley, George Q; Goldman, Steven A; Huard, Johnny; Kamp, Timothy J; Trucco, Massimo

2014-08-22

Pluripotent stem cells (PSCs) directed to various cell fates holds promise as source material for treating numerous disorders. The availability of precisely differentiated PSC-derived cells will dramatically affect blood component and hematopoietic stem cell therapies and should facilitate treatment of diabetes, some forms of liver disease and neurologic disorders, retinal diseases, and possibly heart disease. Although an unlimited supply of specific cell types is needed, other barriers must be overcome. This review of the state of cell therapies highlights important challenges. Successful cell transplantation will require optimizing the best cell type and site for engraftment, overcoming limitations to cell migration and tissue integration, and occasionally needing to control immunologic reactivity, as well as a number of other challenges. Collaboration among scientists, clinicians, and industry is critical for generating new stem cell-based therapies. Copyright © 2014, American Association for the Advancement of Science.

Desmosomes in acquired disease

PubMed Central

Stahley, Sara N.; Kowalczyk, Andrew P.

2015-01-01

Desmosomes are cell-cell junctions that mediate adhesion and couple the intermediate filament cytoskeleton to sites of cell-cell contact. This architectural arrangement functions to integrate adhesion and cytoskeletal elements of adjacent cells. The importance of this robust adhesion system is evident in numerous human diseases, both inherited and acquired, that occur when desmosome function is compromised. This review focuses on autoimmune and infectious diseases that impair desmosome function. In addition, we discuss emerging evidence that desmosomal genes are often misregulated in cancer. The emphasis of our discussion is placed on how human diseases inform our understanding of basic desmosome biology, and in turn, how fundamental advances in the cell biology of desmosomes may lead to new treatments for acquired diseases of the desmosome. PMID:25795143

Potential importance of B cells in aging and aging-associated neurodegenerative diseases.

PubMed

Biragyn, Arya; Aliseychik, Maria; Rogaev, Evgeny

2017-04-01

Our understanding of B cells as merely antibody producers is slowly changing. Alone or in concert with antibody, they control outcomes of seemingly different diseases such as cancer, rheumatoid arthritis, diabetes, and multiple sclerosis. While their role in activation of effector immune cells is beneficial in cancer but bad in autoimmune diseases, their immunosuppressive and regulatory subsets (Bregs) inhibit autoimmune and anticancer responses. These pathogenic and suppressive functions are not static and appear to be regulated by the nature and strength of inflammation. Although aging increases inflammation and changes the composition and function of B cells, surprisingly, little is known whether the change affects aging-associated neurodegenerative disease, such as Alzheimer's disease (AD). Here, by analyzing B cells in cancer and autoimmune and neuroinflammatory diseases, we elucidate their potential importance in AD and other aging-associated neuroinflammatory diseases.

Gastroesophageal reflux disease and its association with bronchiolitis obliterans syndrome in allogeneic hematopoietic stem cell transplant recipients.

PubMed

Khalid, Mohammed; Aljurf, Mahmoud; Saleemi, Sarfraz; Khan, Mohammed Qaseem; Khan, Basha; Ahmed, Shad; Ibrahim, Khalid El Tayeb; Mobeireek, Abdullah; Al Mohareb, Fahad; Chaudhri, Naeem

2013-06-01

Bronchiolitis obliterans syndrome is a significant postallogeneic hematopoietic stem cell transplant problem. Recent data in lung transplant patients suggest an association with gastroesophageal reflux disease and bronchiolitis obliterans syndrome. We studied posthematopoietic stem cell transplant patients with bronchiolitis obliterans syndrome for gastroesophageal reflux disease and its response to a proton pump inhibitor. Seven postallogeneic hematopoietic stem cell transplant patients with bronchiolitis obliterans syndrome were studied. Gastroesophageal reflux disease was assessed by 24-hour pH monitoring with a Bravo catheter-free radio pH capsule. Patients with positive gastroesophageal reflux disease were started on omeprazole. Pretreatment and posttreatment pulmonary function tests were done at 3-month intervals. Of 7 patients, 5 had positive results for gastroesophageal reflux disease (71%). Omeprazole had a disease-stabilizing effect on the patients' pulmonary function tests. Our study shows a significant association between bronchiolitis obliterans syndrome and gastroesophageal reflux disease in postallogeneic hematopoietic stem cell transplant patients. Use of omeprazole may have a disease-stabilizing effect in short-term follow-up.

Control of Cross Talk between Angiogenesis and Inflammation by Mesenchymal Stem Cells for the Treatment of Ocular Surface Diseases.

PubMed

Li, Fei; Zhao, Shao-Zhen

2016-01-01

Angiogenesis is beneficial in the treatment of ischemic heart disease and peripheral artery disease. However, it facilitates inflammatory cell filtration and inflammation cascade that disrupt the immune and angiogenesis privilege of the avascular cornea, resulting in ocular surface diseases and even vision loss. Although great progress has been achieved, healing of severe ocular surface injury and immunosuppression of corneal transplantation are the most difficult and challenging step in the treatment of ocular surface disorders. Mesenchymal stem cells (MSCs), derived from various adult tissues, are able to differentiate into different cell types such as endothelial cells and fat cells. Although it is still under debate whether MSCs could give rise to functional corneal cells, recent results from different study groups showed that MSCs could improve corneal disease recovery through suppression of inflammation and modulation of immune cells. Thus, MSCs could become a promising tool for ocular surface disorders. In this review, we discussed how angiogenesis and inflammation are orchestrated in the pathogenesis of ocular surface disease. We overviewed and updated the knowledge of MSCs and then summarized the therapeutic potential of MSCs via control of angiogenesis, inflammation, and immune response in the treatment of ocular surface disease.

Numerical chromosomal aberrations in Hodgkin's disease detected by in situ hybridisation on routine paraffin sections.

PubMed Central

Pringle, J H; Shaw, J A; Gillies, A; Lauder, I

1997-01-01

AIMS: To visualise directly numerical chromosomal aberrations and polyploidy in both Hodgkin and Reed Sternberg (HRS) cells and background cells from cases of Hodgkin's disease using in situ hybridisation. METHODS: Non-isotopic DNA in situ hybridisation was applied to interphase cell nuclei of Hodgkin's disease within routine paraffin embedded tissue sections. Two a satellite DNA probes, specific for chromosomes 3 and 12, were used to evaluate the feasibility of this approach. Double labelling with immunocytochemical detection of the CD30 antigen was used to identify HRS cells. Cytogenetic normal diploid and triploid placental tissue served as controls. RESULTS: The eight cases of Hodgkin's disease investigated displayed frequent polysomy, while the majority of background cells showed disomy signals. CONCLUSIONS: Numerical chromosomal aberrations were detected in HRS cells from eight cases of Hodgkin's disease by in situ hybridisation. These data show that in Hodgkin's disease HRS cells frequently display polyploidy compared with background cells and are, therefore, probably the only neoplastic component in this disease. Correlations between polysomy and tumour type or grade could not be made from these data owing to the limited number of cases examined and to problems with interpreting data from truncated nuclei. Images PMID:9306933

Sickle cell dehydration: Pathophysiology and therapeutic applications.

PubMed

Brugnara, Carlo

2018-01-01

Cell dehydration is a distinguishing characteristic of sickle cell disease and an important contributor to disease pathophysiology. Due to the unique dependence of Hb S polymerization on cellular Hb S concentration, cell dehydration promotes polymerization and sickling. In double heterozygosis for Hb S and C (SC disease) dehydration is the determining factor in disease pathophysiology. Three major ion transport pathways are involved in sickle cell dehydration: the K-Cl cotransport (KCC), the Gardos channel (KCNN4) and Psickle, the polymerization induced membrane permeability, most likely mediated by the mechano-sensitive ion channel PIEZO1. Each of these pathways exhibit unique characteristics in regulation by oxygen tension, intracellular and extracellular environment, and functional expression in reticulocytes and mature red cells. The unique dependence of K-Cl cotransport on intracellular Mg and the abnormal reduction of erythrocyte Mg content in SS and SC cells had led to clinical studies assessing the effect of oral Mg supplementation. Inhibition of Gardos channel by clotrimazole and senicapoc has led to Phase 1,2,3 trials in patients with sickle cell disease. While none of these studies has resulted in the approval of a novel therapy for SS disease, they have highlighted the key role played by these pathways in disease pathophysiology.

Exploring parent-sibling communication in families of children with sickle cell disease.

PubMed

Graff, J Carolyn; Hankins, Jane S; Hardy, Belinda T; Hall, Heather R; Roberts, Ruth J; Neely-Barnes, Susan L

2010-01-01

Communication within families of children with sickle cell disease is important yet has not been adequately investigated. Focus group interviews were conducted with parents of children with sickle cell disease to explore parent-sibling communication about sickle cell disease. Communication was influenced by attributes and behaviors of the parent, the child with sickle cell disease, and the sibling; extended family, neighbors, friends, and church members or social networks; and available, accessible resources related to the child's health, child's school, and parent employment. Outcomes that influenced and were influenced by factors within and outside the parent-sibling dyad and nuclear family included parent satisfaction, parent roles, family intactness, and status attainment. These findings support previous research with African-American families and expand our views of the importance of educating parents, family members, and others about sickle cell disease. The findings suggest a need to explore sibling perception of this communication, parent and sibling perception of the impact of frequent hospitalizations and clinic visits on the sibling and family, and variations within families of children with sickle cell disease.

Tissue mechanics regulate brain development, homeostasis and disease

PubMed Central

Barnes, J. Matthew

2017-01-01

ABSTRACT All cells sense and integrate mechanical and biochemical cues from their environment to orchestrate organismal development and maintain tissue homeostasis. Mechanotransduction is the evolutionarily conserved process whereby mechanical force is translated into biochemical signals that can influence cell differentiation, survival, proliferation and migration to change tissue behavior. Not surprisingly, disease develops if these mechanical cues are abnormal or are misinterpreted by the cells – for example, when interstitial pressure or compression force aberrantly increases, or the extracellular matrix (ECM) abnormally stiffens. Disease might also develop if the ability of cells to regulate their contractility becomes corrupted. Consistently, disease states, such as cardiovascular disease, fibrosis and cancer, are characterized by dramatic changes in cell and tissue mechanics, and dysregulation of forces at the cell and tissue level can activate mechanosignaling to compromise tissue integrity and function, and promote disease progression. In this Commentary, we discuss the impact of cell and tissue mechanics on tissue homeostasis and disease, focusing on their role in brain development, homeostasis and neural degeneration, as well as in brain cancer. PMID:28043968

Bioengineering and Stem Cell Technology in the Treatment of Congenital Heart Disease

PubMed Central

Bosman, Alexis; Edel, Michael J.; Blue, Gillian; Dilley, Rodney J.; Harvey, Richard P.; Winlaw, David S.

2015-01-01

Congenital heart disease places a significant burden on the individual, family and community despite significant advances in our understanding of aetiology and treatment. Early research in ischaemic heart disease has paved the way for stem cell technology and bioengineering, which promises to improve both structural and functional aspects of disease. Stem cell therapy has demonstrated significant improvements in cardiac function in adults with ischaemic heart disease. This finding, together with promising case studies in the paediatric setting, demonstrates the potential for this treatment in congenital heart disease. Furthermore, induced pluripotent stems cell technology, provides a unique opportunity to address aetiological, as well as therapeutic, aspects of disease. PMID:26239354

Current Status of Stem Cells and Regenerative Medicine in Lung Biology and Diseases

PubMed Central

Weiss, Daniel J.

2014-01-01

Lung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPD), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the 3rd leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and chronic obstructive pulmonary disease (COPD) with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been utilized to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy based clinical trials in lung diseases. PMID:23959715

Insights from zebrafish on human pigment cell disease and treatment.

PubMed

Cooper, Cynthia D

2017-11-01

Black pigment cells, melanocytes, arise early during development from multipotent neural crest cells. Melanocytes protect human skin from DNA damaging sunrays and provide color for hair, eyes, and skin. Several disorders and diseases originate from these cells, including the deadliest skin cell cancer, melanoma. Thus, melanocytes are critical for a healthy life and for protecting humans from disease. Due to the ease of visualizing pigment cells through transparent larvae skin and conserved roles for zebrafish melanophore genes to mammalian melanocyte genes, zebrafish larvae offer a biologically relevant model for understanding pigment cell development and disease in humans. This review discusses our current knowledge of melanophore biology and how zebrafish are contributing to improving how diseases of melanocytes are understood and treated in humans. Developmental Dynamics 246:889-896, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Dietary gluten triggers concomitant activation of CD4+ and CD8+ αβ T cells and γδ T cells in celiac disease

PubMed Central

Han, Arnold; Newell, Evan W.; Glanville, Jacob; Fernandez-Becker, Nielsen; Khosla, Chaitan; Chien, Yueh-hsiu; Davis, Mark M.

2013-01-01

Celiac disease is an intestinal autoimmune disease driven by dietary gluten and gluten-specific CD4+ T-cell responses. In celiac patients on a gluten-free diet, exposure to gluten induces the appearance of gluten-specific CD4+ T cells with gut-homing potential in the peripheral blood. Here we show that gluten exposure also induces the appearance of activated, gut-homing CD8+ αβ and γδ T cells in the peripheral blood. Single-cell T-cell receptor sequence analysis indicates that both of these cell populations have highly focused T-cell receptor repertoires, indicating that their induction is antigen-driven. These results reveal a previously unappreciated role of antigen in the induction of CD8+ αβ and γδ T cells in celiac disease and demonstrate a coordinated response by all three of the major types of T cells. More broadly, these responses may parallel adaptive immune responses to viral pathogens and other systemic autoimmune diseases. PMID:23878218

The role of regulatory B cells in digestive system diseases.

PubMed

Zhou, Zhenyu; Gong, Lei; Wang, Xiaoyun; Hu, Zhen; Wu, Gaojue; Tang, Xuejun; Peng, Xiaobin; Tang, Shuan; Meng, Miao; Feng, Hui

2017-04-01

The past decade has provided striking insights into a newly identified subset of B cells known as regulatory B cells (Bregs). In addition to producing antibody, Bregs also regulate diseases via cytokine production and antigen presentation. This subset of B cells has protective and potentially therapeutic effects. However, the particularity of Bregs has caused some difficulties in conducting research on their roles. Notably, human B10 cells, which are Bregs that produce interleukin 10, share phenotypic characteristics with other previously defined B cell subsets, and currently, there is no known surface phenotype that is unique to B10 cells. An online search was performed in the PubMed and Web of Science databases for articles published providing evidences on the role of regulatory B cells in digestive system diseases. Abundant evidence has demonstrated that Bregs play a regulatory role in inflammatory, autoimmune, and tumor diseases, and regulatory B cells play different roles in different diseases, but future work needs to determine the mechanisms by which Bregs are activated and how these cells affect their target cells.

Comparative Studies of the Proteome, Glycoproteome, and N-Glycome of Clear Cell Renal Cell Carcinoma Plasma before and after Curative Nephrectomy

PubMed Central

2015-01-01

Clear cell renal cell carcinoma is the most prevalent of all reported kidney cancer cases, and currently there are no markers for early diagnosis. This has stimulated great research interest recently because early detection of the disease can significantly improve the low survival rate. Combining the proteome, glycoproteome, and N-glycome data from clear cell renal cell carcinoma plasma has the potential of identifying candidate markers for early diagnosis and prognosis and/or to monitor disease recurrence. Here, we report on the utilization of a multi-dimensional fractionation approach (12P-M-LAC) and LC–MS/MS to comprehensively investigate clear cell renal cell carcinoma plasma collected before (disease) and after (non-disease) curative nephrectomy (n = 40). Proteins detected in the subproteomes were investigated via label-free quantification. Protein abundance analysis revealed a number of low-level proteins with significant differential expression levels in disease samples, including HSPG2, CD146, ECM1, SELL, SYNE1, and VCAM1. Importantly, we observed a strong correlation between differentially expressed proteins and clinical status of the patient. Investigation of the glycoproteome returned 13 candidate glycoproteins with significant differential M-LAC column binding. Qualitative analysis indicated that 62% of selected candidate glycoproteins showed higher levels (upregulation) in M-LAC bound fraction of disease samples. This observation was further confirmed by released N-glycans data in which 53% of identified N-glycans were present at different levels in plasma in the disease vs non-disease samples. This striking result demonstrates the potential for significant protein glycosylation alterations in clear cell renal cell carcinoma cancer plasma. With future validation in a larger cohort, information derived from this study may lead to the development of clear cell renal cell carcinoma candidate biomarkers. PMID:25184692

Th40 cells (CD4+CD40+ Tcells) drive a more severe form of Experimental Autoimmune Encephalomyelitis than conventional CD4 T cells

PubMed Central

Vaitaitis, Gisela M.; Yussman, Martin G.; Waid, Dan M.; Wagner, David H.

2017-01-01

CD40-CD154 interaction is critically involved in autoimmune diseases, and CD4 T cells play a dominant role in the Experimental Autoimmune Encephalomyelitis (EAE) model of Multiple Sclerosis (MS). CD4 T cells expressing CD40 (Th40) are pathogenic in type I diabetes but have not been evaluated in EAE. We demonstrate here that Th40 cells drive a rapid, more severe EAE disease course than conventional CD4 T cells. Adoptively transferred Th40 cells are present in lesions in the CNS and are associated with wide spread demyelination. Primary Th40 cells from EAE-induced donors adoptively transfer EAE without further in-vitro expansion and without requiring the administration of the EAE induction regimen to the recipient animals. This has not been accomplished with primary, non-TCR-transgenic donor cells previously. If co-injection of Th40 donor cells with Freund’s adjuvant (CFA) in the recipient animals is done, the disease course is more severe. The CFA component of the EAE induction regimen causes generalized inflammation, promoting expansion of Th40 cells and infiltration of the CNS, while MOG-antigen shapes the antigen-specific TCR repertoire. Those events are both necessary to precipitate disease. In MS, viral infections or trauma may induce generalized inflammation in susceptible individuals with subsequent disease onset. It will be important to further understand the events leading up to disease onset and to elucidate the contributions of the Th40 T cell subset. Also, evaluating Th40 levels as predictors of disease onset would be highly useful because if either the generalized inflammation event or the TCR-honing can be interrupted, disease onset may be prevented. PMID:28192476

Ionizing radiation and autoimmunity: Induction of autoimmune disease in mice by high dose fractionated total lymphoid irradiation and its prevention by inoculating normal T cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sakaguchi, N.; Sakaguchi, S.; Miyai, K.

1992-11-01

Ionizing radiation can functionally alter the immune system and break self-tolerance. High dose (42.5 Gy), fractionated (2.5 Gy 17 times) total lymphoid irradiation (TLI) on mice caused various organ-specific autoimmune diseases, such as gastritis, thyroiditis, and orchitis, depending on the radiation dosages, the extent of lymphoid irradiation, and the genetic background of the mouse strains. Radiation-induced tissue damage is not the primary cause of the autoimmune disease because irradiation of the target organs alone failed to elicit the autoimmunity and shielding of the organs from irradiation was unable to prevent it. In contrast, irradiation of both the thymus and themore » peripheral lymphoid organs/tissues was required for efficient induction of autoimmune disease by TLI. TLI eliminated the majority of mature thymocytes and the peripheral T cells for 1 mo, and inoculation of spleen cell, thymocyte, or bone marrow cell suspensions (prepared from syngeneic nonirradiated mice) within 2 wk after TLI effectively prevented the autoimmune development. Depletion of T cells from the inocula abrogated the preventive activity. CD4[sup +] T cells mediated the autoimmune prevention but CD8[sup +] T cells did not. CD4[sup +] T cells also appeared to mediate the TLI-induced autoimmune disease because CD4[sup +] T cells from disease-bearing TLI mice adoptively transferred the autoimmune disease to syngeneic naive mice. Taken together, these results indicate that high dose, fractionated ionizing radiation on the lymphoid organs/tissues can cause autoimmune disease by affecting the T cell immune system, rather than the target self-Ags, presumably by altering T cell-dependent control of self-reactive T cells. 62 refs., 9 figs., 2 tabs.« less

Use of genome editing tools in human stem cell-based disease modeling and precision medicine.

PubMed

Wei, Yu-da; Li, Shuang; Liu, Gai-gai; Zhang, Yong-xian; Ding, Qiu-rong

2015-10-01

Precision medicine emerges as a new approach that takes into account individual variability. The successful conduct of precision medicine requires the use of precise disease models. Human pluripotent stem cells (hPSCs), as well as adult stem cells, can be differentiated into a variety of human somatic cell types that can be used for research and drug screening. The development of genome editing technology over the past few years, especially the CRISPR/Cas system, has made it feasible to precisely and efficiently edit the genetic background. Therefore, disease modeling by using a combination of human stem cells and genome editing technology has offered a new platform to generate " personalized " disease models, which allow the study of the contribution of individual genetic variabilities to disease progression and the development of precise treatments. In this review, recent advances in the use of genome editing in human stem cells and the generation of stem cell models for rare diseases and cancers are discussed.

Regulation of pulmonary inflammation by mesenchymal cells.

PubMed

Alkhouri, Hatem; Poppinga, Wilfred Jelco; Tania, Navessa Padma; Ammit, Alaina; Schuliga, Michael

2014-12-01

Pulmonary inflammation and tissue remodelling are common elements of chronic respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PH). In disease, pulmonary mesenchymal cells not only contribute to tissue remodelling, but also have an important role in pulmonary inflammation. This review will describe the immunomodulatory functions of pulmonary mesenchymal cells, such as airway smooth muscle (ASM) cells and lung fibroblasts, in chronic respiratory disease. An important theme of the review is that pulmonary mesenchymal cells not only respond to inflammatory mediators, but also produce their own mediators, whether pro-inflammatory or pro-resolving, which influence the quantity and quality of the lung immune response. The notion that defective pro-inflammatory or pro-resolving signalling in these cells potentially contributes to disease progression is also discussed. Finally, the concept of specifically targeting pulmonary mesenchymal cell immunomodulatory function to improve therapeutic control of chronic respiratory disease is considered. Copyright © 2014 Elsevier Ltd. All rights reserved.

Colon-targeted delivery of live bacterial cell biotherapeutics including microencapsulated live bacterial cells

PubMed Central

Prakash, Satya; Malgorzata Urbanska, Aleksandra

2008-01-01

There has been an ample interest in delivery of therapeutic molecules using live cells. Oral delivery has been stipulated as best way to deliver live cells to humans for therapy. Colon, in particular, is a part of gastrointestinal (GI) tract that has been proposed to be an oral targeted site. The main objective of these oral therapy procedures is to deliver live cells not only to treat diseases like colorectal cancer, inflammatory bowel disease, and other GI tract diseases like intestinal obstruction and gastritis, but also to deliver therapeutic molecules for overall therapy in various diseases such as renal failure, coronary heart disease, hypertension, and others. This review provides a comprehensive summary of recent advancement in colon targeted live bacterial cell biotherapeutics. Current status of bacterial cell therapy, principles of artificial cells and its potentials in oral delivery of live bacterial cell biotherapeutics for clinical applications as well as biotherapeutic future perspectives are also discussed in our review. PMID:19707368

Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases

PubMed Central

Naylor, RM; Baker, DJ; van Deursen, JM

2014-01-01

Aging is the main risk factor for most chronic diseases, disabilities, and declining health. It has been proposed that senescent cells—damaged cells that have lost the ability to divide—drive the deterioration that underlies aging and age-related diseases. However, definitive evidence for this relationship has been lacking. The use of a progeroid mouse model (which expresses low amounts of the mitotic checkpoint protein BubR1) has been instrumental in demonstrating that p16Ink4a-positive senescent cells drive age-related pathologies and that selective elimination of these cells can prevent or delay age-related deterioration. These studies identify senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. Here, we describe how senescent cells develop, the experimental evidence that causally implicates senescent cells in age-related dysfunction, the chronic diseases and disorders that are characterized by the accumulation of senescent cells at sites of pathology, and the therapeutic approaches that could specifically target senescent cells. PMID:23212104

Type two innate lymphoid cells; the Janus cells in health and disease

PubMed Central

Maazi, Hadi; Akbari, Omid

2017-01-01

Summary Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2 and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by costimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. PMID:28658553

T Cells and Pathogenesis of Hantavirus Cardiopulmonary Syndrome and Hemorrhagic Fever with Renal Syndrome

PubMed Central

Terajima, Masanori; Ennis, Francis A.

2011-01-01

We previously hypothesized that increased capillary permeability observed in both hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) may be caused by hantavirus-specific cytotoxic T cells attacking endothelial cells presenting viral antigens on their surface based on clinical observations and in vitro experiments. In HCPS, hantavirus-specific T cell responses positively correlated with disease severity. In HFRS, in one report, contrary to HCPS, T cell responses negatively correlated with disease severity, but in another report the number of regulatory T cells, which are thought to suppress T cell responses, negatively correlated with disease severity. In rat experiments, in which hantavirus causes persistent infection, depletion of regulatory T cells helped infected rats clear virus without inducing immunopathology. These seemingly contradictory findings may suggest delicate balance in T cell responses between protection and immunopathogenesis. Both too strong and too weak T cell responses may lead to severe disease. It is important to clarify the role of T cells in these diseases for better treatment (whether to suppress T cell functions) and protection (vaccine design) which may need to take into account viral factors and the influence of HLA on T cell responses. PMID:21994770

T cells and pathogenesis of hantavirus cardiopulmonary syndrome and hemorrhagic fever with renal syndrome.

PubMed

Terajima, Masanori; Ennis, Francis A

2011-07-01

We previously hypothesized that increased capillary permeability observed in both hantavirus cardiopulmonary syndrome (HCPS) and hemorrhagic fever with renal syndrome (HFRS) may be caused by hantavirus-specific cytotoxic T cells attacking endothelial cells presenting viral antigens on their surface based on clinical observations and in vitro experiments. In HCPS, hantavirus-specific T cell responses positively correlated with disease severity. In HFRS, in one report, contrary to HCPS, T cell responses negatively correlated with disease severity, but in another report the number of regulatory T cells, which are thought to suppress T cell responses, negatively correlated with disease severity. In rat experiments, in which hantavirus causes persistent infection, depletion of regulatory T cells helped infected rats clear virus without inducing immunopathology. These seemingly contradictory findings may suggest delicate balance in T cell responses between protection and immunopathogenesis. Both too strong and too weak T cell responses may lead to severe disease. It is important to clarify the role of T cells in these diseases for better treatment (whether to suppress T cell functions) and protection (vaccine design) which may need to take into account viral factors and the influence of HLA on T cell responses.

Ocular Stem Cell Research from Basic Science to Clinical Application: A Report from Zhongshan Ophthalmic Center Ocular Stem Cell Symposium

PubMed Central

Ouyang, Hong; Goldberg, Jeffrey L.; Chen, Shuyi; Li, Wei; Xu, Guo-Tong; Li, Wei; Zhang, Kang; Nussenblatt, Robert B.; Liu, Yizhi; Xie, Ting; Chan, Chi-Chao; Zack, Donald J.

2016-01-01

Stem cells hold promise for treating a wide variety of diseases, including degenerative disorders of the eye. The eye is an ideal organ for stem cell therapy because of its relative immunological privilege, surgical accessibility, and its being a self-contained system. The eye also has many potential target diseases amenable to stem cell-based treatment, such as corneal limbal stem cell deficiency, glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa (RP). Among them, AMD and glaucoma are the two most common diseases, affecting over 200 million people worldwide. Recent results on the clinical trial of retinal pigment epithelial (RPE) cells from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) in treating dry AMD and Stargardt’s disease in the US, Japan, England, and China have generated great excitement and hope. This marks the beginning of the ocular stem cell therapy era. The recent Zhongshan Ophthalmic Center Ocular Stem Cell Symposium discussed the potential applications of various stem cell types in stem cell-based therapies, drug discoveries and tissue engineering for treating ocular diseases. PMID:27102165

Dysregulated MicroRNA Involvement in Multiple Sclerosis by Induction of T Helper 17 Cell Differentiation

PubMed Central

Chen, Chen; Zhou, Yifan; Wang, Jingqi; Yan, Yaping; Peng, Lisheng; Qiu, Wei

2018-01-01

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system. Growing evidence has proven that T helper 17 (Th17) cells are one of the regulators of neuroinflammation mechanisms in MS disease. Researchers have demonstrated that some microRNAs (miRNAs) are associated with disease activity and duration, even with different MS patterns. miRNAs regulate CD4+ T cells to differentiate toward various T cell subtypes including Th17 cells. In this review, we discuss the possible mechanisms of miRNAs in MS pathophysiology by regulating CD4+ T cell differentiation into Th17 cells, and potential miRNA targets for current disease-modifying treatments.

RSV Vaccine-Enhanced Disease Is Orchestrated by the Combined Actions of Distinct CD4 T Cell Subsets

PubMed Central

Knudson, Cory J.; Hartwig, Stacey M.; Meyerholz, David K.; Varga, Steven M.

2015-01-01

There is no currently licensed vaccine for respiratory syncytial virus (RSV) despite being the leading cause of lower respiratory tract infections in children. Children previously immunized with a formalin-inactivated RSV (FI-RSV) vaccine exhibited enhanced respiratory disease following natural RSV infection. Subsequent studies in animal models have implicated roles for CD4 T cells, eosinophils and non-neutralizing antibodies in mediating enhanced respiratory disease. However, the underlying immunological mechanisms responsible for the enhanced respiratory disease and other disease manifestations associated with FI-RSV vaccine-enhanced disease remain unclear. We demonstrate for the first time that while CD4 T cells mediate all aspects of vaccine-enhanced disease, distinct CD4 T cell subsets orchestrate discrete and specific disease parameters. A Th2-biased immune response, but not eosinophils specifically, was required for airway hyperreactivity and mucus hypersecretion. In contrast, the Th1-associated cytokine TNF-α was necessary to mediate airway obstruction and weight loss. Our data demonstrate that individual disease manifestations associated with FI-RSV vaccine-enhanced disease are mediated by distinct subsets of CD4 T cells. PMID:25769044

Patient-Specific Pluripotent Stem Cells in Neurological Diseases

PubMed Central

Durnaoglu, Serpen; Genc, Sermin; Genc, Kursad

2011-01-01

Many human neurological diseases are not currently curable and result in devastating neurologic sequelae. The increasing availability of induced pluripotent stem cells (iPSCs) derived from adult human somatic cells provides new prospects for cellreplacement strategies and disease-related basic research in a broad spectrum of human neurologic diseases. Patient-specific iPSC-based modeling of neurogenetic and neurodegenerative diseases is an emerging efficient tool for in vitro modeling to understand disease and to screen for genes and drugs that modify the disease process. With the exponential increase in iPSC research in recent years, human iPSCs have been successfully derived with different technologies and from various cell types. Although there remain a great deal to learn about patient-specific iPSC safety, the reprogramming mechanisms, better ways to direct a specific reprogramming, ideal cell source for cellular grafts, and the mechanisms by which transplanted stem cells lead to an enhanced functional recovery and structural reorganization, the discovery of the therapeutic potential of iPSCs offers new opportunities for the treatment of incurable neurologic diseases. However, iPSC-based therapeutic strategies need to be thoroughly evaluated in preclinical animal models of neurological diseases before they can be applied in a clinical setting. PMID:21776279

Infectious Prion Protein Alters Manganese Transport and Neurotoxicity in a Cell Culture Model of Prion Disease

PubMed Central

Martin, Dustin P.; Anantharam, Vellareddy; Jin, Huajun; Witte, Travis; Houk, Robert; Kanthasamy, Arthi; Kanthasamy, Anumantha G.

2011-01-01

Protein misfolding and aggregation are considered key features of many neurodegenerative diseases, but biochemical mechanisms underlying protein misfolding and the propagation of protein aggregates are not well understood. Prion disease is a classical neurodegenerative disorder resulting from the misfolding of endogenously expressed normal cellular prion protein (PrPC). Although the exact function of PrPC has not been fully elucidated, studies have suggested that it can function as a metal binding protein. Interestingly, increased brain manganese (Mn) levels have been reported in various prion diseases indicating divalent metals also may play a role in the disease process. Recently, we reported that PrPC protects against Mn-induced cytotoxicity in a neural cell culture model. To further understand the role of Mn in prion diseases, we examined Mn neurotoxicity in an infectious cell culture model of prion disease. Our results show CAD5 scrapie-infected cells were more resistant to Mn neurotoxicity as compared to uninfected cells (EC50 = 428.8 μM for CAD5 infected cells vs. 211.6 μM for uninfected cells). Additionally, treatment with 300 μM Mn in persistently infected CAD5 cells showed a reduction in mitochondrial impairment, caspase-3 activation, and DNA fragmentation when compared to uninfected cells. Scrapie-infected cells also showed significantly reduced Mn uptake as measured by inductively coupled plasma-mass spectrometry (ICP-MS), and altered expression of metal transporting proteins DMT1 and transferrin. Together, our data indicate that conversion of PrP to the pathogenic isoform enhances its ability to regulate Mn homeostasis, and suggest that understanding the interaction of metals with disease-specific proteins may provide further insight to protein aggregation in neurodegenerative diseases. PMID:21871919

Blocking of CD1d Decreases Trypanosoma cruzi-Induced Activation of CD4-CD8- T Cells and Modulates the Inflammatory Response in Patients With Chagas Heart Disease.

PubMed

Passos, Lívia Silva Araújo; Villani, Fernanda Nobre Amaral; Magalhães, Luísa Mourão Dias; Gollob, Kenneth J; Antonelli, Lis Ribeiro do Vale; Nunes, Maria Carmo Pereira; Dutra, Walderez Ornelas

2016-09-15

The control of inflammatory responses to prevent the deadly cardiac pathology in human Chagas disease is a desirable and currently unattained goal. Double-negative (DN) T cells are important sources of inflammatory and antiinflammatory cytokines in patients with Chagas heart disease and those with the indeterminate clinical form of Chagas disease, respectively. Given the importance of DN T cells in immunoregulatory processes and their potential as targets for controlling inflammation-induced pathology, we studied the involvement of CD1 molecules in the activation and functional profile of Trypanosoma cruzi-specific DN T cells. We observed that parasite stimulation significantly increased the expression of CD1a, CD1b, CD1c, and CD1d by CD14(+) cells from patients with Chagas disease. Importantly, among the analyzed molecules, only CD1d expression showed an association with the activation of DN T cells, as well as with worse ventricular function in patients with Chagas disease. Blocking of CD1d-mediated antigen presentation led to a clear reduction of DN T-cell activation and a decrease in the expression of interferon γ (IFN-γ) by DN T cells. Thus, our results showed that antigen presentation via CD1d is associated with activation of DN T cells in Chagas disease and that CD1d blocking leads to downregulation of IFN-γ by DN T cells from patients with Chagas heart disease, which may be a potential target for preventing progression of inflammation-mediated dilated cardiomyopathy. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Ethical clinical translation of stem cell interventions for neurologic disease.

PubMed

Cote, David J; Bredenoord, Annelien L; Smith, Timothy R; Ammirati, Mario; Brennum, Jannick; Mendez, Ivar; Ammar, Ahmed S; Balak, Naci; Bolles, Gene; Esene, Ignatius Ngene; Mathiesen, Tiit; Broekman, Marike L

2017-01-17

The application of stem cell transplants in clinical practice has increased in frequency in recent years. Many of the stem cell transplants in neurologic diseases, including stroke, Parkinson disease, spinal cord injury, and demyelinating diseases, are unproven-they have not been tested in prospective, controlled clinical trials and have not become accepted therapies. Stem cell transplant procedures currently being carried out have therapeutic aims, but are frequently experimental and unregulated, and could potentially put patients at risk. In some cases, patients undergoing such operations are not included in a clinical trial, and do not provide genuinely informed consent. For these reasons and others, some current stem cell interventions for neurologic diseases are ethically dubious and could jeopardize progress in the field. We provide discussion points for the evaluation of new stem cell interventions for neurologic disease, based primarily on the new Guidelines for Stem Cell Research and Clinical Translation released by the International Society for Stem Cell Research in May 2016. Important considerations in the ethical translation of stem cells to clinical practice include regulatory oversight, conflicts of interest, data sharing, the nature of investigation (e.g., within vs outside of a clinical trial), informed consent, risk-benefit ratios, the therapeutic misconception, and patient vulnerability. To help guide the translation of stem cells from the laboratory into the neurosurgical clinic in an ethically sound manner, we present an ethical discussion of these major issues at stake in the field of stem cell clinical research for neurologic disease. © 2016 American Academy of Neurology.

A Study of Varlilumab (Anti-CD27) and Sunitinib in Patients With Metastatic Clear Cell Renal Cell Carcinoma

ClinicalTrials.gov

2017-11-10

Carcinoma, Renal Cell; Kidney Diseases; Kidney Neoplasms; Urogenital Neoplasms; Urologic Diseases; Urologic Neoplasms; Neoplasms; Neoplasms by Histologic Type; Clear-cell Metastatic Renal Cell Carcinoma

A massive intestinal vaso-occlusive crisis or "girdle syndrome" in a 6-year-old boy observed as a first manifestation of sickle cell disease.

PubMed

Knorr, M; Bienemann, K; Walde, G; Kaufhold, A; Schündeln, M M

2014-11-01

Sickle cell disease is a chronic hematologic disease with variable but often severe systemic symptoms. In this report, we describe a 6-year-old boy presenting with acute bowel pseudo-obstruction. During this episode, previously undiagnosed sickle cell disease was discovered upon peripheral blood smear analysis. The condition was therefore interpreted as a massive intestinal vaso-occlusive crisis or "girdle syndrome". Conservative treatment with hydration therapy, analgesia and a manual partial exchange transfusion was initiated. The patient fully recovered within 5 days. Girdle syndrome is a rare but severe adverse event associated with sickle cell disease that must be considered as differential diagnosis in patients with sickle cell disease. © Georg Thieme Verlag KG Stuttgart · New York.

Stem cell therapy for ischemic heart diseases.

PubMed

Yu, Hong; Lu, Kai; Zhu, Jinyun; Wang, Jian'an

2017-01-01

Ischemic heart diseases, especially the myocardial infarction, is a major hazard problem to human health. Despite substantial advances in control of risk factors and therapies with drugs and interventions including bypass surgery and stent placement, the ischemic heart diseases usually result in heart failure (HF), which could aggravate social burden and increase the mortality rate. The current therapeutic methods to treat HF stay at delaying the disease progression without repair and regeneration of the damaged myocardium. While heart transplantation is the only effective therapy for end-stage patients, limited supply of donor heart makes it impossible to meet the substantial demand from patients with HF. Stem cell-based transplantation is one of the most promising treatment for the damaged myocardial tissue. Key recent published literatures and ClinicalTrials.gov. Stem cell-based therapy is a promising strategy for the damaged myocardial tissue. Different kinds of stem cells have their advantages for treatment of Ischemic heart diseases. The efficacy and potency of cell therapies vary significantly from trial to trial; some clinical trials did not show benefit. Diverged effects of cell therapy could be affected by cell types, sources, delivery methods, dose and their mechanisms by which delivered cells exert their effects. Understanding the origin of the regenerated cardiomyocytes, exploring the therapeutic effects of stem cell-derived exosomes and using the cell reprogram technology to improve the efficacy of cell therapy for cardiovascular diseases. Recently, stem cell-derived exosomes emerge as a critical player in paracrine mechanism of stem cell-based therapy. It is promising to exploit exosomes-based cell-free therapy for ischemic heart diseases in the future. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Role of regulatory T cell in the pathogenesis of inflammatory bowel disease.

PubMed

Yamada, Akiko; Arakaki, Rieko; Saito, Masako; Tsunematsu, Takaaki; Kudo, Yasusei; Ishimaru, Naozumi

2016-02-21

Regulatory T (Treg) cells play key roles in various immune responses. For example, Treg cells contribute to the complex pathogenesis of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis during onset or development of that disease. Many animal models of IBD have been used to investigate factors such as pathogenic cytokines, pathogenic bacteria, and T-cell functions, including those of Treg cells. In addition, analyses of patients with IBD facilitate our understanding of the precise mechanism of IBD. This review article focuses on the role of Treg cells and outlines the pathogenesis and therapeutic strategies of IBD based on previous reports.

Understanding the application of stem cell therapy in cardiovascular diseases.

PubMed

Sharma, Rakesh K; Voelker, Donald J; Sharma, Roma; Reddy, Hanumanth K

2012-10-30

Throughout their lifetime, an individual may sustain many injuries and recover spontaneously over a period of time, without even realizing the injury in the first place. Wound healing occurs due to a proliferation of stem cells capable of restoring the injured tissue. The ability of adult stem cells to repair tissue is dependent upon the intrinsic ability of tissues to proliferate. The amazing capacity of embryonic stem cells to give rise to virtually any type of tissue has intensified the search for similar cell lineage in adults to treat various diseases including cardiovascular diseases. The ability to convert adult stem cells into pluripotent cells that resemble embryonic cells, and to transplant those in the desired organ for regenerative therapy is very attractive, and may offer the possibility of treating harmful disease-causing mutations. The race is on to find the best cells for treatment of cardiovascular disease. There is a need for the ideal stem cell, delivery strategies, myocardial retention, and time of administration in the ideal patient population. There are multiple modes of stem cell delivery to the heart with different cell retention rates that vary depending upon method and site of injection, such as intra coronary, intramyocardial or via coronary sinus. While there are crucial issues such as retention of stem cells, microvascular plugging, biodistribution, homing to myocardium, and various proapoptotic factors in the ischemic myocardium, the regenerative potential of stem cells offers an enormous impact on clinical applications in the management of cardiovascular diseases.

Disease and Stem Cell-Based Analysis of the 2014 ASNTR Meeting

PubMed Central

Eve, David J.

2015-01-01

A wide variety of subjects are presented at the annual American Society of Neural Therapy and Repair meeting every year, as typified by this summary of the 2014 meeting. Parkinson’s disease-related presentations were again the most popular topic, with traumatic brain injury, spinal cord injury, and stroke being close behind. Other disorders included Huntington’s disease, brain cancer, and bipolar disorders. Several studies were related to multiple diseases, and many studies attempted to reveal more about the disease process. The use of scaffolds, drugs, and gene therapy as disease models and/or potential therapies were also featured. An increasing proportion of presentations related to stem cells, with the study of multiple stem cell types being the most common. Induced pluripotent stem cells were increasingly popular, including two presentations each on a muscle-derived dedifferentiated cell type and cells derived from bipolar patients. Other stem cells, including neural stem cells, mesenchymal stem cells, umbilical cord blood cells, and embryonic stem cells, were featured. More than 55% of the stem cell studies involved transplantation, with human-derived cells being the most frequently transplanted, while rats were the most common recipient. Two human autologous studies for spinal cord injury and hypoxia-derived encephalopathy, while a further three allogenic studies for stroke and spinal cord injury, were also featured. This year’s meeting highlights the increasing promise of stem cells and other therapies for the treatment of neurodegenerative disorders. PMID:26858901

Mechanisms Linking Red Blood Cell Disorders and Cardiovascular Diseases

PubMed Central

2015-01-01

The present paper aims to review the main pathophysiological links between red blood cell disorders and cardiovascular diseases, provides a brief description of the latest studies in this area, and considers implications for clinical practice and therapy. Anemia is associated with a special risk in proatherosclerotic conditions and heart disease and became a new therapeutic target. Guidelines must be updated for the management of patients with red blood cell disorders and cardiovascular diseases, and targets for hemoglobin level should be established. Risk scores in several cardiovascular diseases should include red blood cell count and RDW. Complete blood count and hemorheological parameters represent useful, inexpensive, widely available tools for the management and prognosis of patients with coronary heart disease, heart failure, hypertension, arrhythmias, and stroke. Hypoxia and iron accumulation cause the most important cardiovascular effects of sickle cell disease and thalassemia. Patients with congenital chronic hemolytic anemia undergoing splenectomy should be monitored, considering thromboembolic and cardiovascular risk. PMID:25710019

Stem cell transplant in inflammatory bowel disease: a promising modality of treatment for a complicated disease course.

PubMed

Salem, George A; Selby, George B

2017-01-01

Inflammatory bowel disease (IBD) is a complex, relapsing and remitting, disease characterized by an exaggerated immune response in a susceptible host. The symptoms and complications of the disease can be debilitating. Advances in medical treatment in the last decade changed the course of the disease in many patients. Despite the use of novel agents for controlling disease, a proportion of patients' disease courses continue to be either refractory, or become resistant, to available therapeutic options. Stem-cell therapy, with hematopoietic stem cells (HSCs) or mesenchymal stem cells (MSCs), is a promising modality of treatment for severe refractory cases, mainly Crohn's disease (CD) patients. HSCs have the ability to migrate to damaged tissue, which provides them with further properties to differentiate to epithelial or immune-modulatory cells to restore normal mucosal tissue and integrity. MSCs therapy is a promising model for patients with perianal CD due to their immunosuppressive properties, ability to migrate to areas of injury, and demonstration of colonic healing, including fistulizing tracts. The results from ongoing clinical trials will provide a valuable understanding of the future of stem-cell therapy as a treatment option in refractory cases of IBD, a disease whose pathogenesis remains unknown, and is notoriously difficult to treat.

Embryonic stem cells and prospects for their use in regenerative medicine approaches to motor neurone disease.

PubMed

Christou, Y A; Moore, H D; Shaw, P J; Monk, P N

2007-10-01

Human embryonic stem cells are pluripotent cells with the potential to differentiate into any cell type in the presence of appropriate stimulatory factors and environmental cues. Their broad developmental potential has led to valuable insights into the principles of developmental and cell biology and to the proposed use of human embryonic stem cells or their differentiated progeny in regenerative medicine. This review focuses on the prospects for the use of embryonic stem cells in cell-based therapy for motor neurone disease or amyotrophic lateral sclerosis, a progressive neurodegenerative disease that specifically affects upper and lower motor neurones and leads ultimately to death from respiratory failure. Stem cell-derived motor neurones could conceivably be used to replace the degenerated cells, to provide authentic substrates for drug development and screening and for furthering our understanding of disease mechanisms. However, to reliably and accurately culture motor neurones, the complex pathways by which differentiation occurs in vivo must be understood and reiterated in vitro by embryonic stem cells. Here we discuss the need for new therapeutic strategies in the treatment of motor neurone disease, the developmental processes that result in motor neurone formation in vivo, a number of experimental approaches to motor neurone production in vitro and recent progress in the application of stem cells to the treatment and understanding of motor neurone disease.

Urine-derived induced pluripotent stem cells as a modeling tool to study rare human diseases

PubMed Central

Shi, Liang; Cui, Yazhou; Luan, Jing; Zhou, Xiaoyan; Han, Jinxiang

2016-01-01

Summary Rare diseases with a low prevalence are a key public health issue because the causes of those diseases are difficult to determine and those diseases lack a clearly established or curative treatment. Thus, investigating the molecular mechanisms that underlie the pathology of rare diseases and facilitating the development of novel therapies using disease models is crucial. Human induced pluripotent stem cells (iPSCs) are well suited to modeling rare diseases since they have the capacity for self-renewal and pluripotency. In addition, iPSC technology provides a valuable tool to generate patient-specific iPSCs. These cells can be differentiated into cell types that have been affected by a disease. These cells would circumvent ethical concerns and avoid immunological rejection, so they could be used in cell replacement therapy or regenerative medicine. To date, human iPSCs could have been generated from multiple donor sources, such as skin, adipose tissue, and peripheral blood. However, these cells are obtained via invasive procedures. In contrast, several groups of researchers have found that urine may be a better source for producing iPSCs from normal individuals or patients. This review discusses urinary iPSC (UiPSC) as a candidate for modeling rare diseases. Cells obtained from urine have overwhelming advantages compared to other donor sources since they are safely, affordably, and frequently obtained and they are readily obtained from patients. The use of iPSC-based models is also discussed. UiPSCs may prove to be a key means of modeling rare diseases and they may facilitate the treatment of those diseases in the future. PMID:27672542

[Management of sickle cells disease by households in Bamako].

PubMed

Sangho, Hamadoun; Keïta, Haoua Dembélé; Keïta, Assan Sidibé; Diarra, Fatoumata Y; Belemou, Boureyma; Dia, Amadou; Traoré, Mahamadou; Keïta, Fatoumata Danfaga; Diarra, Assa; Diakité, Baye; Diallo, Dapa; Sidibé, Toumani

2009-01-01

The sickle cell disease constitutes a major problem of public health. We find 5% to 20% of carriers of this disease in West Africa and 40% among some populations in central Africa (Congo, Zaire) and Nigeria (Beguè). In Mali prevalence is estimated to 12% with 3% for the homozygote form. It is a known disease and well documented on the scientific plan and its management is better and better codified nowadays, which contributes to the improvement of life quality. For this reason, Centre for Research and Documentation on Child Survival (CREDOS) lead this study. The aim was to assess the knowledge of the mothers for a best management of sickle cell disease in the households. We conducted a cross-sectional study with single passage realized in the households in 6 communes of Bamako district. We inquired 360 parents of children less than 5 years, according to the method of cluster sampling. The study found that 95.8% of mothers know the sickle cell disease. In addition 63.9% of the mothers didn't know the complications of the sickle cell disease and 58% the causes. In the event of discovered sickle cell disease, 58.3% of the mothers stated to want to resort to a medical structure in first intention, 18.3% with self medication and 13.9% with the traditional practitioner. In front of a sickle cell disease crisis, 56% stated to have recourse to modern medicine against 15.2% with the traditional practitioner. Household's implication in the management of the child sickle cell disease suffers a low knowledge of cause, clinical signs, and complications of this disease by the parents. For a better knowledge of this pathology by the families, information and education of the populations through messages BCC are necessary.

B cells flying solo.

PubMed

Groom, Joanna; Mackay, Fabienne

2008-01-01

Systemic autoimmunity such as systemic lupus erythematosus (SLE) is associated with the loss of B-cell tolerance, B-cell dysregulation and autoantibody production. While some autoantibodies may contribute to the pathology seen with SLE, numerous studies have shown that dysregulation of T-cell function is another critical aspect driving disease. The positive results obtained in clinical trials using T-cell- or B-cell-specific treatments have suggested that cooperation between T and B cells probably underlies disease progression in many patients. A similar cooperative mechanism seemed to explain SLE developing in mice overexpressing the B-cell-activating factor from the tumor necrosis factor family (BAFF). However, surprisingly, T-cell-deficient BAFF transgenic (Tg) mice develop SLE similar to T-cell-sufficient BAFF Tg mice, and the disease was linked to innate activation of B cells and production of proinflammatory autoantibody isotypes. In conclusion, dysregulated innate activation of B cells alone can drive disease independently of T cells, and as such this aspect represents a new pathogenic mechanism in autoimmunity.

Induced neural stem cells as a means of treatment in Huntington's disease.

PubMed

Choi, Kyung-Ah; Hong, Sunghoi

2017-11-01

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by chorea, dementia, and depression caused by progressive nerve cell degeneration, which is triggered by expanded CAG repeats in the huntingtin (Htt) gene. Currently, there is no cure for this disease, nor is there an effective medicine available to delay or improve the physical, mental, and behavioral severities caused by it. Areas covered: In this review, the authors describe the use of induced neural stem cells (iNSCs) by direct conversion technology, which offers great advantages as a therapeutic cell type to treat HD. Expert opinion: Cell conversion of somatic cells into a desired stem cell type is one of the most promising treatments for HD because it could be facilitated for the generation of patient-specific neural stem cells. The induced pluripotent stem cells (iPSCs) have a powerful potential for differentiation into neurons, but they may cause teratoma formation due to an undifferentiated pluripotent stem cell after transplantation Therefore, direct conversion of somatic cells into iNSCs is a promising alternative technology in regenerative medicine and the iNSCs may be provided as a therapeutic cell source for Huntington's disease.

Self-Organized Cerebellar Tissue from Human Pluripotent Stem Cells and Disease Modeling with Patient-Derived iPSCs.

PubMed

Muguruma, Keiko

2018-02-01

Recent advances in the techniques that differentiate induced pluripotent stem cells (iPSCs) into specific types of cells enabled us to establish in vitro cell-based models as a platform for drug discovery. iPSC-derived disease models are advantageous to generation of a large number of cells required for high-throughput screening. Furthermore, disease-relevant cells differentiated from patient-derived iPSCs are expected to recapitulate the disorder-specific pathogenesis and physiology in vitro. Such disease-relevant cells will be useful for developing effective therapies. We demonstrated that cerebellar tissues are generated from human PSCs (hPSCs) in 3D culture systems that recapitulate the in vivo microenvironments associated with the isthmic organizer. Recently, we have succeeded in generation of spinocerebellar ataxia (SCA) patient-derived Purkinje cells by combining the iPSC technology and the self-organizing stem cell 3D culture technology. We demonstrated that SCA6-derived Purkinje cells exhibit vulnerability to triiodothyronine depletion, which is suppressed by treatment with thyrotropin-releasing hormone and Riluzole. We further discuss applications of patient-specific iPSCs to intractable cerebellar disease.

Mast cell inflammasome activity in the meninges regulates EAE disease severity.

PubMed

Russi, Abigail E; Walker-Caulfield, Margaret E; Brown, Melissa A

2018-04-01

Inflammasomes are multiprotein complexes that assemble in response to microbial and other danger signals and regulate the secretion of biologically active IL-1β and IL-18. Although they are important in protective immunity against bacterial, viral and parasitic infections, aberrant inflammasome activity promotes chronic inflammation associated with autoimmune disease. Inflammasomes have been described in many immune cells, but the majority of studies have focused on their activity in macrophages. Here we discuss an important role for mast cell-inflammasome activity in EAE, the rodent model of multiple sclerosis, a CNS demyelinating disease. We review our evidence that mast cells in the meninges, tissues that surround the brain and spinal cord, interact with infiltrating myelin-specific T cells in early disease. This interaction elicits IL-1β expression by mast cells, which in turn, promotes GM-CSF expression by T cells. In view of the essential role that GM-CSF plays in T cell encephalitogenicity, we propose this mast cell-T cell crosstalk in the meninges is critical for EAE disease development. Copyright © 2016 Elsevier Inc. All rights reserved.

Concise Review: Stem Cell Trials Using Companion Animal Disease Models.

PubMed

Hoffman, Andrew M; Dow, Steven W

2016-07-01

Studies to evaluate the therapeutic potential of stem cells in humans would benefit from more realistic animal models. In veterinary medicine, companion animals naturally develop many diseases that resemble human conditions, therefore, representing a novel source of preclinical models. To understand how companion animal disease models are being studied for this purpose, we reviewed the literature between 2008 and 2015 for reports on stem cell therapies in dogs and cats, excluding laboratory animals, induced disease models, cancer, and case reports. Disease models included osteoarthritis, intervertebral disc degeneration, dilated cardiomyopathy, inflammatory bowel diseases, Crohn's fistulas, meningoencephalomyelitis (multiple sclerosis-like), keratoconjunctivitis sicca (Sjogren's syndrome-like), atopic dermatitis, and chronic (end-stage) kidney disease. Stem cells evaluated in these studies included mesenchymal stem-stromal cells (MSC, 17/19 trials), olfactory ensheathing cells (OEC, 1 trial), or neural lineage cells derived from bone marrow MSC (1 trial), and 16/19 studies were performed in dogs. The MSC studies (13/17) used adipose tissue-derived MSC from either allogeneic (8/13) or autologous (5/13) sources. The majority of studies were open label, uncontrolled studies. Endpoints and protocols were feasible, and the stem cell therapies were reportedly safe and elicited beneficial patient responses in all but two of the trials. In conclusion, companion animals with naturally occurring diseases analogous to human conditions can be recruited into clinical trials and provide realistic insight into feasibility, safety, and biologic activity of novel stem cell therapies. However, improvements in the rigor of manufacturing, study design, and regulatory compliance will be needed to better utilize these models. Stem Cells 2016;34:1709-1729. © 2016 AlphaMed Press.

RON kinase inhibition reduces renal endothelial injury in sickle cell disease mice

PubMed Central

Khaibullina, Alfia; Adjei, Elena A.; Afangbedji, Nowah; Ivanov, Andrey; Kumari, Namita; Almeida, Luis E.F.; Quezado, Zenaide M.N.; Nekhai, Sergei; Jerebtsova, Marina

2018-01-01

Sickle cell disease patients are at increased risk of developing a chronic kidney disease. Endothelial dysfunction and inflammation associated with hemolysis lead to vasculopathy and contribute to the development of renal disease. Here we used a Townes sickle cell disease mouse model to examine renal endothelial injury. Renal disease in Townes mice was associated with glomerular hypertrophy, capillary dilation and congestion, and significant endothelial injury. We also detected substantial renal macrophage infiltration, and accumulation of macrophage stimulating protein 1 in glomerular capillary. Treatment of human cultured macrophages with hemin or red blood cell lysates significantly increased expression of macrophage membrane-associated protease that might cleave and activate circulating macrophage stimulating protein 1 precursor. Macrophage stimulating protein 1 binds to and activates RON kinase, a cell surface receptor tyrosine kinase. In cultured human renal glomerular endothelial cells, macrophage stimulating protein 1 induced RON downstream signaling, resulting in increased phosphorylation of ERK and AKT kinases, expression of Von Willebrand factor, increased cell motility, and re-organization of F-actin. Specificity of macrophage stimulating protein 1 function was confirmed by treatment with RON kinase inhibitor BMS-777607 that significantly reduced downstream signaling. Moreover, treatment of sickle cell mice with BMS-777607 significantly reduced glomerular hypertrophy, capillary dilation and congestion, and endothelial injury. Taken together, our findings demonstrated that RON kinase is involved in the induction of renal endothelial injury in sickle cell mice. Inhibition of RON kinase activation may provide a novel approach for prevention of the development of renal disease in sickle cell disease. PMID:29519868

Transcriptomic Analyses Reveal Differential Gene Expression of Immune and Cell Death Pathways in the Brains of Mice Infected with West Nile Virus and Chikungunya Virus

PubMed Central

Lim, Stephanie M.; van den Ham, Henk-Jan; Oduber, Minoushka; Martina, Eurydice; Zaaraoui-Boutahar, Fatiha; Roose, Jeroen M.; van IJcken, Wilfred F. J.; Osterhaus, Albert D. M. E.; Andeweg, Arno C.; Koraka, Penelope; Martina, Byron E. E.

2017-01-01

West Nile virus (WNV) and chikungunya virus (CHIKV) are arboviruses that are constantly (re-)emerging and expanding their territory. Both viruses often cause a mild form of disease, but severe forms of the disease can consist of neurological symptoms, most often observed in the elderly and young children, respectively, for which the mechanisms are poorly understood. To further elucidate the mechanisms responsible for end-stage WNV and CHIKV neuroinvasive disease, we used transcriptomics to compare the induction of effector pathways in the brain during the early and late stage of disease in young mice. In addition to the more commonly described cell death pathways such as apoptosis and autophagy, we also found evidence for the differential expression of pyroptosis and necroptosis cell death markers during both WNV and CHIKV neuroinvasive disease. In contrast, no evidence of cell dysfunction was observed, indicating that cell death may be the most important mechanism of disease. Interestingly, there was overlap when comparing immune markers involved in neuroinvasive disease to those seen in neurodegenerative diseases. Nonetheless, further validation studies are needed to determine the activation and involvement of these effector pathways at the end stage of disease. Furthermore, evidence for a strong inflammatory response was found in mice infected with WNV and CHIKV. The transcriptomics profile measured in mice with WNV and CHIKV neuroinvasive disease in our study showed strong overlap with the mRNA profile described in the literature for other viral neuroinvasive diseases. More studies are warranted to decipher the role of cell inflammation and cell death in viral neuroinvasive disease and whether common mechanisms are active in both neurodegenerative and brain infectious diseases. PMID:28861067

Transcriptomic Analyses Reveal Differential Gene Expression of Immune and Cell Death Pathways in the Brains of Mice Infected with West Nile Virus and Chikungunya Virus.

PubMed

Lim, Stephanie M; van den Ham, Henk-Jan; Oduber, Minoushka; Martina, Eurydice; Zaaraoui-Boutahar, Fatiha; Roose, Jeroen M; van IJcken, Wilfred F J; Osterhaus, Albert D M E; Andeweg, Arno C; Koraka, Penelope; Martina, Byron E E

2017-01-01

West Nile virus (WNV) and chikungunya virus (CHIKV) are arboviruses that are constantly (re-)emerging and expanding their territory. Both viruses often cause a mild form of disease, but severe forms of the disease can consist of neurological symptoms, most often observed in the elderly and young children, respectively, for which the mechanisms are poorly understood. To further elucidate the mechanisms responsible for end-stage WNV and CHIKV neuroinvasive disease, we used transcriptomics to compare the induction of effector pathways in the brain during the early and late stage of disease in young mice. In addition to the more commonly described cell death pathways such as apoptosis and autophagy, we also found evidence for the differential expression of pyroptosis and necroptosis cell death markers during both WNV and CHIKV neuroinvasive disease. In contrast, no evidence of cell dysfunction was observed, indicating that cell death may be the most important mechanism of disease. Interestingly, there was overlap when comparing immune markers involved in neuroinvasive disease to those seen in neurodegenerative diseases. Nonetheless, further validation studies are needed to determine the activation and involvement of these effector pathways at the end stage of disease. Furthermore, evidence for a strong inflammatory response was found in mice infected with WNV and CHIKV. The transcriptomics profile measured in mice with WNV and CHIKV neuroinvasive disease in our study showed strong overlap with the mRNA profile described in the literature for other viral neuroinvasive diseases. More studies are warranted to decipher the role of cell inflammation and cell death in viral neuroinvasive disease and whether common mechanisms are active in both neurodegenerative and brain infectious diseases.

Interaction between allergic asthma and atherosclerosis

PubMed Central

Liu, Conglin; Zhang, Jingying; Shi, Guo-Ping

2015-01-01

Prior studies have established an essential role of mast cells in allergic asthma and atherosclerosis. Mast cell deficiency or inactivation protects mice from allergen-induced airway hyper-responsiveness and diet-induced atherosclerosis, suggesting that mast cells share pathologic activities in both diseases. Allergic asthma and atherosclerosis are inflammatory diseases that contain similar sets of elevated numbers of inflammatory cells in addition to mast cells in the airway and arterial wall, such as macrophages, monocytes, T cells, eosinophils, and smooth muscle cells. Emerging evidence from experimental models and human studies points to a potential interaction between the two seemingly unrelated diseases. Patients or mice with allergic asthma have a high risk of developing atherosclerosis or vice versa, despite the fact that asthma is a Th2-oriented disease, whereas Th1 immunity promotes atherosclerosis. In addition to the preferred Th1/Th2 responses that may differentiate the two diseases, mast cells and many other inflammatory cells also contribute to their pathogenesis by much more than just T cell immunity. Here we summarize the different roles of airway and arterial wall inflammatory cells and vascular cells in asthma and atherosclerosis, and propose an interaction between the two diseases, although limited investigations are available to delineate the molecular and cellular mechanisms by which one disease increases the risk of the other. Results from mouse allergic asthma and atherosclerosis models and from human population studies lead to the hypothesis that patients with atherosclerosis may benefit from anti-asthmatic medications, or that the therapeutic regimens targeting atherosclerosis may also alleviate allergic asthma. PMID:26608212

Transcriptomic Analysis of Host Immune Response in the Skin of Chickens Infected with Marek's Disease Virus

USDA-ARS?s Scientific Manuscript database

Marek’s disease virus, a highly cell-associated oncogenic 'alpha-herpesvirus, is the causative agent of a T cell lymphoma and neuropathic disease called Marek’s disease. The skin is the only anatomical site where infectious enveloped cell-free virions are produced and shed into the environment. Stud...

Poultry Allele-Specific Expression (ASE) of CD4+ T Cells in Response to Marek’s Disease Virus Infection

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a T cell lymphoma disease of poultry induced by Marek’s disease virus (MDV), a highly oncogenic alphaherpesvirus. To identify high-confidence candidate genes of MD genetic resistance, transcriptomic data in CD4+ T cells were obtained from MDV infected and non-infected groups ...

Mast cells as effectors in atherosclerosis

PubMed Central

Bot, Ilze; Shi, Guo-Ping; Kovanen, Petri T.

2014-01-01

The mast cell is a potent immune cell known for its functions in host defense responses and diseases such as asthma and allergies. In the past years, accumulating evidence established the contribution of the mast cell to cardiovascular diseases as well, in particular by its effects on atherosclerotic plaque progression and destabilization. Through its release of mediators, such as the mast cell-specific proteases chymase and tryptase, but also of growth factors, histamine and chemokines, activated mast cells can have detrimental effects on its immediate surroundings in the vessel wall. This results in matrix degradation, apoptosis and enhanced recruitment of inflammatory cells, thereby actively contributing to cardiovascular diseases. In this review, we will discuss the current knowledge on mast cell function in cardiovascular diseases and speculate on potential novel therapeutic strategies to prevent acute cardiovascular syndromes via targeting of mast cells. PMID:25104798

Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression.

PubMed

Peeters, Janneke G C; Vervoort, Stephin J; Tan, Sander C; Mijnheer, Gerdien; de Roock, Sytze; Vastert, Sebastiaan J; Nieuwenhuis, Edward E S; van Wijk, Femke; Prakken, Berent J; Creyghton, Menno P; Coffer, Paul J; Mokry, Michal; van Loosdregt, Jorg

2015-09-29

The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

The Implications of the Cancer Stem Cell Hypothesis for Neuro-Oncology and Neurology.

PubMed

Rich, Jeremy N

2008-05-01

The cancer stem cell hypothesis posits that cancers contain a subset of neoplastic cells that propagate and maintain tumors through sustained self-renewal and potent tumorigenecity. Recent excitement has been generated by a number of reports that have demonstrated the existence of cancer stem cells in several types of brain tumors. Brain cancer stem cells - also called tumor initiating cells or tumor propagating cells - share features with normal neural stem cells but do not necessarily originate from stem cells. Although most cancers have only a small fraction of cancer stem cells, these tumor cells have been shown in laboratory studies to contribute to therapeutic resistance, formation of new blood vessels to supply the tumor, and tumor spread. As malignant brain tumors rank among the deadliest of all neurologic diseases, the identification of new cellular targets may have profound implications in neuro-oncology. Novel drugs that target stem cell pathways active in brain tumors have been efficacious against cancer stem cells suggesting that anti-cancer stem cell therapies may advance brain tumor therapy. The cancer stem cell hypothesis may have several implications for other neurologic diseases as caution must be exercised in activating stem cell maintenance pathways in cellular therapies for neurodegenerative diseases. The ability for a small fraction of cells to determine the overall course of a disease may also inform new paradigms of disease that may translate into improved patient outcomes.

MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells.

PubMed

Ito, Keisuke; Eguchi, Yutaka; Imagawa, Yusuke; Akai, Shuji; Mochizuki, Hideki; Tsujimoto, Yoshihide

2017-01-01

Regulation of cell death is potentially a powerful treatment modality for intractable diseases such as neurodegenerative diseases. Although there have been many reports about the possible involvement of various types of cell death in neurodegenerative diseases, it is still unclear exactly how neurons die in patients with these diseases, thus treatment strategies based on cell death regulation have not been established yet. To obtain some insight into the mechanisms of cell death involved in neurodegenerative diseases, we studied the effect of 1-methyl-4-phenylpyridinium (MPP+) on the human neuroblastoma cell line SH-SY5Y (a widely used model of Parkinson's disease). We found that MPP+ predominantly induced non-apoptotic death of neuronally differentiated SH-SY5Y cells. This cell death was strongly inhibited by necrostatin-1 (Nec-1), a necroptosis inhibitor, and by an indole-containing compound (3,3'-diindolylmethane: DIM). However, it occurred independently of receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3), indicating that this form of cell death was not necroptosis. MPP+-induced cell death was also inhibited by several inhibitors of ferroptosis, including ferrostatin-1 (Fer-1). Although MPP+-induced death and ferroptosis shared some features, such as occurrence of lipid peroxidation and inhibition by Fer-1, MPP+-induced death seemed to be distinct from ferroptosis because MPP+-induced death (but not ferroptosis) was inhibited by Nec-1, was independent of p53, and was accompanied by ATP depletion and mitochondrial swelling. Further investigation of MPP+-induced non-apoptotic cell death may be useful for understanding the mechanisms of neuronal loss and for treatment of neurodegenerative diseases such as Parkinson's disease.

MPP+ induces necrostatin-1- and ferrostatin-1-sensitive necrotic death of neuronal SH-SY5Y cells

PubMed Central

Ito, Keisuke; Eguchi, Yutaka; Imagawa, Yusuke; Akai, Shuji; Mochizuki, Hideki; Tsujimoto, Yoshihide

2017-01-01

Regulation of cell death is potentially a powerful treatment modality for intractable diseases such as neurodegenerative diseases. Although there have been many reports about the possible involvement of various types of cell death in neurodegenerative diseases, it is still unclear exactly how neurons die in patients with these diseases, thus treatment strategies based on cell death regulation have not been established yet. To obtain some insight into the mechanisms of cell death involved in neurodegenerative diseases, we studied the effect of 1-methyl-4-phenylpyridinium (MPP+) on the human neuroblastoma cell line SH-SY5Y (a widely used model of Parkinson’s disease). We found that MPP+ predominantly induced non-apoptotic death of neuronally differentiated SH-SY5Y cells. This cell death was strongly inhibited by necrostatin-1 (Nec-1), a necroptosis inhibitor, and by an indole-containing compound (3,3′-diindolylmethane: DIM). However, it occurred independently of receptor-interacting serine/threonine-protein kinase 1/3 (RIP1/RIP3), indicating that this form of cell death was not necroptosis. MPP+-induced cell death was also inhibited by several inhibitors of ferroptosis, including ferrostatin-1 (Fer-1). Although MPP+-induced death and ferroptosis shared some features, such as occurrence of lipid peroxidation and inhibition by Fer-1, MPP+-induced death seemed to be distinct from ferroptosis because MPP+-induced death (but not ferroptosis) was inhibited by Nec-1, was independent of p53, and was accompanied by ATP depletion and mitochondrial swelling. Further investigation of MPP+-induced non-apoptotic cell death may be useful for understanding the mechanisms of neuronal loss and for treatment of neurodegenerative diseases such as Parkinson’s disease. PMID:28250973

Sickle Cell Disease (SCD)

MedlinePlus

... del paciente Transplant process Diseases treated by transplant Acute myeloid leukemia Adrenoleukodystrophy (ALD) Chronic Lymphocytic Leukemia (CLL) ... SCID) Sickle cell disease (SCD) Wiskott-Aldrich syndrome Acute lymphoblastic leukemia (ALL) Other diseases Treatment decisions Learn ...

Myeloid-derived suppressor cells regulate T cell and B cell responses during autoimmune disease.

PubMed

Crook, Kristen R; Jin, Mengyao; Weeks, Michael F; Rampersad, Rishi R; Baldi, Robert M; Glekas, Amy S; Shen, Yajuan; Esserman, Denise A; Little, Paul; Schwartz, Todd A; Liu, Peng

2015-03-01

MDSCs are a heterogeneous group of myeloid cells that suppress T cell activity in cancer and autoimmune disease. The effect of MDSCs on B cell function is not clear. Using the CIA model of autoimmune disease, we found an increase in M-MDSCs in the periphery of WT mice with CIA compared with naïve mice. These MDSCs were absent from the periphery of CCR2(-/-) mice that developed exacerbated disease. M-MDSCs, isolated from immunized mice, inhibited autologous CD4(+) T cell proliferation. The M-MDSC-mediated suppression of T cell proliferation was NO and IFN-γ dependent but IL-17 independent. Furthermore, we demonstrated for the first time that M-MDSCs from CIA mice also inhibited autologous B cell proliferation and antibody production. The suppression of B cells by M-MDSCs was dependent on the production of NO and PGE2 and required cell-cell contact. Administration of M-MDSCs rescued CCR2(-/-) mice from the exacerbated CIA phenotype and ameliorated disease in WT mice. Furthermore, adoptive transfer of M-MDSCs reduced autoantibody production by CCR2(-/-) and WT mice. In summary, M-MDSCs inhibit T cell and B cell function in CIA and may serve as a therapeutic approach in the treatment of autoimmune arthritis. © Society for Leukocyte Biology.

Th17 cells in human disease

PubMed Central

Tesmer, Laura A.; Lundy, Steven K.; Sarkar, Sujata; Fox, David A.

2012-01-01

Summary Our understanding of the role of T cells in human disease is undergoing revision as a result of the discovery of T-helper 17 (Th17) cells, a unique CD4+ T-cell subset characterized by production of interleukin-17 (IL-17). IL-17 is a highly inflammatory cytokine with robust effects on stromal cells in many tissues. Recent data in humans and mice suggest that Th17 cells play an important role in the pathogenesis of a diverse group of immune-mediated diseases, including psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma. Initial reports also propose a role for Th17 cells in tumorigenesis and transplant rejection. Important differences, as well as many similarities, are emerging when the biology of Th17 cells in the mouse is compared with corresponding phenomena in humans. As our understanding of human Th17 biology grows, the mechanisms underlying many diseases are becoming more apparent, resulting in a new appreciation for both previously known and more recently discovered cytokines, chemokines, and feedback mechanisms. Given the strong association between excessive Th17 activity and human disease, new therapeutic approaches targeting Th17 cells are highly promising, but the potential safety of such treatments may be limited by the role of these cells in normal host defenses against infection. PMID:18613831

Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease

PubMed Central

Jison, Maria L.; Munson, Peter J.; Barb, Jennifer J.; Suffredini, Anthony F.; Talwar, Shefali; Logun, Carolea; Raghavachari, Nalini; Beigel, John H.; Shelhamer, James H.; Danner, Robert L.; Gladwin, Mark T.

2016-01-01

In sickle cell disease, deoxygenation of intra-erythrocytic hemoglobin S leads to hemoglobin polymerization, erythrocyte rigidity, hemolysis, and microvascular occlusion. Ischemia-reperfusion injury, plasma hemoglobin-mediated nitric oxide consumption, and free radical generation activate systemic inflammatory responses. To characterize the role of circulating leukocytes in sickle cell pathogenesis we performed global transcriptional analysis of blood mononuclear cells from 27 patients in steady-state sickle cell disease (10 patients treated and 17 patients untreated with hydroxyurea) compared with 13 control subjects. We used gender-specific gene expression to validate human microarray experiments. Patients with sickle cell disease demonstrated differential gene expression of 112 genes involved in heme metabolism, cell-cycle regulation, antioxidant and stress responses, inflammation, and angiogenesis. Inducible heme oxygenase-1 and downstream proteins biliverdin reductase and p21, a cyclin-dependent kinase, were up-regulated, potentially contributing to phenotypic heterogeneity and absence of atherosclerosis in patients with sickle cell disease despite endothelial dysfunction and vascular inflammation. Hydroxyurea therapy did not significantly affect leukocyte gene expression, suggesting that such therapy has limited direct anti-inflammatory activity beyond leukoreduction. Global transcriptional analysis of circulating leukocytes highlights the intense oxidant and inflammatory nature of steady-state sickle cell disease and provides insight into the broad compensatory responses to vascular injury. PMID:15031206

A Phase I Study of iPS Cell Generation From Patients With COPD

ClinicalTrials.gov

2018-03-20

Thoracic Diseases; Respiratory Tract Diseases; Cancer of Lung; Cancer of the Lung; Lung Cancer; Lung Diseases, Obstructive; COPD; Pulmonary Emphysema; Neoplasms, Lung; Neoplasms, Pulmonary; Pulmonary Cancer; Pulmonary Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell

Blood and Diversity

MedlinePlus

... blood. About Sickle Cell Disease Sickle cell disease is a common, inherited red blood disorder. Throughout their lives, sickle cell disease patients ... more time, consider a Power Red donation . Power Red is similar to a whole blood donation, except a special machine is used to ...

Concise review: current status of stem cells and regenerative medicine in lung biology and diseases.

PubMed

Weiss, Daniel J

2014-01-01

Lung diseases remain a significant and devastating cause of morbidity and mortality worldwide. In contrast to many other major diseases, lung diseases notably chronic obstructive pulmonary diseases (COPDs), including both asthma and emphysema, are increasing in prevalence and COPD is expected to become the third leading cause of disease mortality worldwide by 2020. New therapeutic options are desperately needed. A rapidly growing number of investigations of stem cells and cell therapies in lung biology and diseases as well as in ex vivo lung bioengineering have offered exciting new avenues for advancing knowledge of lung biology as well as providing novel potential therapeutic approaches for lung diseases. These initial observations have led to a growing exploration of endothelial progenitor cells and mesenchymal stem (stromal) cells in clinical trials of pulmonary hypertension and COPD with other clinical investigations planned. Ex vivo bioengineering of the trachea, larynx, diaphragm, and the lung itself with both biosynthetic constructs as well as decellularized tissues have been used to explore engineering both airway and vascular systems of the lung. Lung is thus a ripe organ for a variety of cell therapy and regenerative medicine approaches. Current state-of-the-art progress for each of the above areas will be presented as will discussion of current considerations for cell therapy-based clinical trials in lung diseases. © AlphaMed Press.

Potential Use of Autologous Renal Cells from Diseased Kidneys for the Treatment of Renal Failure.

PubMed

George, Sunil K; Abolbashari, Mehran; Jackson, John D; Aboushwareb, Tamer; Atala, Anthony; Yoo, James J

2016-01-01

Chronic kidney disease (CKD) occurs when certain conditions cause the kidneys to gradually lose function. For patients with CKD, renal transplantation is the only treatment option that restores kidney function. In this study, we evaluated primary renal cells obtained from diseased kidneys to determine whether their normal phenotypic and functional characteristics are retained, and could be used for cell therapy. Primary renal cells isolated from both normal kidneys (NK) and diseased kidneys (CKD) showed similar phenotypic characteristics and growth kinetics. The expression levels of renal tubular cell markers, Aquaporin-1 and E-Cadherin, and podocyte-specific markers, WT-1 and Nephrin, were similar in both NK and CKD kidney derived cells. Using fluorescence- activated cell sorting (FACS), specific renal cell populations were identified and included proximal tubular cells (83.1% from NK and 80.3% from CKD kidneys); distal tubular cells (11.03% from NK and 10.9% from CKD kidneys); and podocytes (1.91% from NK and 1.78% from CKD kidneys). Ultra-structural analysis using scanning electron microscopy (SEM) revealed microvilli on the apical surface of cultured cells from NK and CKD samples. Moreover, transmission electron microscopy (TEM) analysis showed a similar organization of tight junctions, desmosomes, and other intracellular structures. The Na+ uptake characteristics of NK and CKD derived renal cells were also similar (24.4 mmol/L and 25 mmol/L, respectively) and no significant differences were observed in the protein uptake and transport characteristics of these two cell isolates. These results show that primary renal cells derived from diseased kidneys such as CKD have similar structural and functional characteristics to their counterparts from a normal healthy kidney (NK) when grown in vitro. This study suggests that cells derived from diseased kidney may be used as an autologous cell source for renal cell therapy, particularly in patients with CKD or end-stage renal disease (ESRD).

Using Human Induced Pluripotent Stem Cells to Model Skeletal Diseases.

PubMed

Barruet, Emilie; Hsiao, Edward C

2016-01-01

Musculoskeletal disorders affecting the bones and joints are major health problems among children and adults. Major challenges such as the genetic origins or poor diagnostics of severe skeletal disease hinder our understanding of human skeletal diseases. The recent advent of human induced pluripotent stem cells (human iPS cells) provides an unparalleled opportunity to create human-specific models of human skeletal diseases. iPS cells have the ability to self-renew, allowing us to obtain large amounts of starting material, and have the potential to differentiate into any cell types in the body. In addition, they can carry one or more mutations responsible for the disease of interest or be genetically corrected to create isogenic controls. Our work has focused on modeling rare musculoskeletal disorders including fibrodysplasia ossificans progressive (FOP), a congenital disease of increased heterotopic ossification. In this review, we will discuss our experiences and protocols differentiating human iPS cells toward the osteogenic lineage and their application to model skeletal diseases. A number of critical challenges and exciting new approaches are also discussed, which will allow the skeletal biology field to harness the potential of human iPS cells as a critical model system for understanding diseases of abnormal skeletal formation and bone regeneration.

The emerging role of myeloid-derived suppressor cells in lung diseases.

PubMed

Kolahian, Saeed; Öz, Hasan Halit; Zhou, Benyuan; Griessinger, Christoph M; Rieber, Nikolaus; Hartl, Dominik

2016-03-01

Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterised by their potential to control T-cell responses and to dampen inflammation. While the role of MDSCs in cancer has been studied in depth, our understanding of their relevance for infectious and inflammatory disease conditions has just begun to evolve. Recent studies highlight an emerging and complex role for MDSCs in pulmonary diseases. In this review, we discuss the potential contribution of MDSCs as biomarkers and therapeutic targets in lung diseases, particularly lung cancer, tuberculosis, chronic obstructive pulmonary disease, asthma and cystic fibrosis. Copyright ©ERS 2016.

Excess Circulating Alternatively Activated Myeloid (M2) Cells Accelerate ALS Progression While Inhibiting Experimental Autoimmune Encephalomyelitis

PubMed Central

Miller, Omer; Butovsky, Oleg; Bukshpan, Shay; Beers, David R.; Henkel, Jenny S.; Yoles, Eti; Appel, Stanley H.; Schwartz, Michal

2011-01-01

Background Circulating immune cells including autoreactive T cells and monocytes have been documented as key players in maintaining, protecting and repairing the central nervous system (CNS) in health and disease. Here, we hypothesized that neurodegenerative diseases might be associated, similarly to tumors, with increased levels of circulating peripheral myeloid derived suppressor cells (MDSCs), representing a subset of suppressor cells that often expand under pathological conditions and inhibit possible recruitment of helper T cells needed for fighting off the disease. Methods and Findings We tested this working hypothesis in amyotrophic lateral sclerosis (ALS) and its mouse model, which are characterized by a rapid progression once clinical symptoms are evident. Adaptive transfer of alternatively activated myeloid (M2) cells, which homed to the spleen and exhibited immune suppressive activity in G93A mutant superoxide dismutase-1 (mSOD1) mice at a stage before emergence of disease symptoms, resulted in earlier appearance of disease symptoms and shorter life expectancy. The same protocol mitigated the inflammation-induced disease model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), which requires circulating T cells for disease induction. Analysis of whole peripheral blood samples obtained from 28 patients suffering from sporadic ALS (sALS), revealed a two-fold increase in the percentage of circulating MDSCs (LIN−/LowHLA-DR−CD33+) compared to controls. Conclusions Taken together, these results emphasize the distinct requirements for fighting the inflammatory neurodegenerative disease, multiple sclerosis, and the neurodegenerative disease, ALS, though both share a local inflammatory component. Moreover, the increased levels of circulating MDSCs in ALS patients indicates the operation of systemic mechanisms that might lead to an impairment of T cell reactivity needed to overcome the disease conditions within the CNS. This high level of suppressive immune cells might represent a risk factor and a novel target for therapeutic intervention in ALS at least at the early stage. PMID:22073221

Modeling Alzheimer’s disease with human induced pluripotent stem (iPS) cells

PubMed Central

Mungenast, Alison E.; Siegert, Sandra; Tsai, Li-Huei

2018-01-01

In the last decade, induced pluripotent stem (iPS) cells have revolutionized the utility of human in vitro models of neurological disease. The iPS-derived and differentiated cells allow researchers to study the impact of a distinct cell type in health and disease as well as performing therapeutic drug screens on a human genetic background. In particular, clinical trials for Alzheimer’s disease (AD) have been often failing. Two of the potential reasons are first, the species gap involved in proceeding from initial discoveries in rodent models to human studies, and second, an unsatisfying patient stratification, meaning subgrouping patients based on the disease severity due to the lack of phenotypic and genetic markers. iPS cells overcome this obstacles and will improve our understanding of disease subtypes in AD. They allow researchers conducting in depth characterization of neural cells from both familial and sporadic AD patients as well as preclinical screens on human cells. In this review, we briefly outline the status quo of iPS cell research in neurological diseases along with the general advantages and pitfalls of these models. We summarize how genome-editing techniques such as CRISPR/Cas will allow researchers to reduce the problem of genomic variability inherent to human studies, followed by recent iPS cell studies relevant to AD. We then focus on current techniques for the differentiation of iPS cells into neural cell types that are relevant to AD research. Finally, we discuss how the generation of three-dimensional cell culture systems will be important for understanding AD phenotypes in a complex cellular milieu, and how both two- and three-dimensional iPS cell models can provide platforms for drug discovery and translational studies into the treatment of AD. PMID:26657644

Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells.

PubMed

Mungenast, Alison E; Siegert, Sandra; Tsai, Li-Huei

2016-06-01

In the last decade, induced pluripotent stem (iPS) cells have revolutionized the utility of human in vitro models of neurological disease. The iPS-derived and differentiated cells allow researchers to study the impact of a distinct cell type in health and disease as well as performing therapeutic drug screens on a human genetic background. In particular, clinical trials for Alzheimer's disease (AD) have been failing. Two of the potential reasons are first, the species gap involved in proceeding from initial discoveries in rodent models to human studies, and second, an unsatisfying patient stratification, meaning subgrouping patients based on the disease severity due to the lack of phenotypic and genetic markers. iPS cells overcome this obstacles and will improve our understanding of disease subtypes in AD. They allow researchers conducting in depth characterization of neural cells from both familial and sporadic AD patients as well as preclinical screens on human cells. In this review, we briefly outline the status quo of iPS cell research in neurological diseases along with the general advantages and pitfalls of these models. We summarize how genome-editing techniques such as CRISPR/Cas9 will allow researchers to reduce the problem of genomic variability inherent to human studies, followed by recent iPS cell studies relevant to AD. We then focus on current techniques for the differentiation of iPS cells into neural cell types that are relevant to AD research. Finally, we discuss how the generation of three-dimensional cell culture systems will be important for understanding AD phenotypes in a complex cellular milieu, and how both two- and three-dimensional iPS cell models can provide platforms for drug discovery and translational studies into the treatment of AD. Copyright © 2015 Elsevier Inc. All rights reserved.

The therapeutic potential of cell identity reprogramming for the treatment of aging-related neurodegenerative disorders.

PubMed

Smith, Derek K; He, Miao; Zhang, Chun-Li; Zheng, Jialin C

2017-10-01

Neural cell identity reprogramming strategies aim to treat age-related neurodegenerative disorders with newly induced neurons that regenerate neural architecture and functional circuits in vivo. The isolation and neural differentiation of pluripotent embryonic stem cells provided the first in vitro models of human neurodegenerative disease. Investigation into the molecular mechanisms underlying stem cell pluripotency revealed that somatic cells could be reprogrammed to induced pluripotent stem cells (iPSCs) and these cells could be used to model Alzheimer disease, amyotrophic lateral sclerosis, Huntington disease, and Parkinson disease. Additional neural precursor and direct transdifferentiation strategies further enabled the induction of diverse neural linages and neuron subtypes both in vitro and in vivo. In this review, we highlight neural induction strategies that utilize stem cells, iPSCs, and lineage reprogramming to model or treat age-related neurodegenerative diseases, as well as, the clinical challenges related to neural transplantation and in vivo reprogramming strategies. Copyright © 2016. Published by Elsevier Ltd.

Cell Therapy for Lung Diseases. Report from an NIH–NHLBI Workshop, November 13–14, 2012

PubMed Central

Matthay, Michael A.; Anversa, Piero; Bhattacharya, Jahar; Burnett, Bruce K.; Chapman, Harold A.; Hare, Joshua M.; Hei, Derek J.; Hoffman, Andrew M.; Kourembanas, Stella; McKenna, David H.; Ortiz, Luis A.; Ott, Harald C.; Tente, William; Thébaud, Bernard; Trapnell, Bruce C.; Weiss, Daniel J.; Yuan, Jason X.-J.

2013-01-01

The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened the Cell Therapy for Lung Disease Working Group on November 13–14, 2012, to review and formulate recommendations for future research directions. The workshop brought together investigators studying basic mechanisms and the roles of cell therapy in preclinical models of lung injury and pulmonary vascular disease, with clinical trial experts in cell therapy for cardiovascular diseases and experts from the NHLBI Production Assistance for Cell Therapy program. The purpose of the workshop was to discuss the current status of basic investigations in lung cell therapy, to identify some of the scientific gaps in current knowledge regarding the potential roles and mechanisms of cell therapy in the treatment of lung diseases, and to develop recommendations to the NHLBI and the research community on scientific priorities and practical steps that would lead to first-in-human trials of lung cell therapy. PMID:23713908

[Using cell technologies to treat urologic diseases].

PubMed

Glybochko, P V; Olefir, Yu V; Alyaev, Yu G; Butnaru, D V; Bezrukov, E A; Chaplenko, A A; Zharikova, T M

2016-08-01

Stem and progenitor cells being introduced into the body have the ability to stimulate regeneration of tissues and organs by differentiating into specialized cells. Stem cell therapy is used in urology to treat various disorders, including erectile dysfunction, urinary incontinence, Peyronies disease, and male infertility. This review presents the results of international preclinical and clinical research on stem cell based medications for treating the above diseases. The most promising appears to be the use of adipose tissue-derived mesenchymal stem cells.

Potentials of single-cell biology in identification and validation of disease biomarkers.

PubMed

Niu, Furong; Wang, Diane C; Lu, Jiapei; Wu, Wei; Wang, Xiangdong

2016-09-01

Single-cell biology is considered a new approach to identify and validate disease-specific biomarkers. However, the concern raised by clinicians is how to apply single-cell measurements for clinical practice, translate the message of single-cell systems biology into clinical phenotype or explain alterations of single-cell gene sequencing and function in patient response to therapies. This study is to address the importance and necessity of single-cell gene sequencing in the identification and development of disease-specific biomarkers, the definition and significance of single-cell biology and single-cell systems biology in the understanding of single-cell full picture, the development and establishment of whole-cell models in the validation of targeted biological function and the figure and meaning of single-molecule imaging in single cell to trace intra-single-cell molecule expression, signal, interaction and location. We headline the important role of single-cell biology in the discovery and development of disease-specific biomarkers with a special emphasis on understanding single-cell biological functions, e.g. mechanical phenotypes, single-cell biology, heterogeneity and organization of genome function. We have reason to believe that such multi-dimensional, multi-layer, multi-crossing and stereoscopic single-cell biology definitely benefits the discovery and development of disease-specific biomarkers. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Applications of patient-specific induced pluripotent stem cells; focused on disease modeling, drug screening and therapeutic potentials for liver disease.

PubMed

Chun, Yong Soon; Chaudhari, Pooja; Jang, Yoon-Young

2010-12-14

The recent advances in the induced pluripotent stem cell (iPSC) research have significantly changed our perspectives on regenerative medicine by providing researchers with a unique tool to derive disease-specific stem cells for study. In this review, we describe the human iPSC generation from developmentally diverse origins (i.e. endoderm-, mesoderm-, and ectoderm- tissue derived human iPSCs) and multistage hepatic differentiation protocols, and discuss both basic and clinical applications of these cells including disease modeling, drug toxicity screening/drug discovery, gene therapy and cell replacement therapy.

Changes in B cell immunophenotype in common variable immunodeficiency: cause or effect – is bronchiectasis indicative of undiagnosed immunodeficiency?

PubMed Central

Bright, P; Grigoriadou, S; Kamperidis, P; Buckland, M; Hickey, A; Longhurst, H J

2013-01-01

Common variable immunodeficiency (CVID) is the most common severe primary immunodeficiency, but the pathology of this condition is poorly understood. CVID involves a defect in the production of immunoglobulin from B cells, with a subsequent predisposition to infections. Approximately 10–20% of cases are inherited, but even in families with a genetic defect the penetrance is far from complete. A classification system for CVID has been suggested (EUROclass) based on B cell immunophenotyping, but it has not been shown that altered B cell immunophenotype is not a consequence of the complications and treatment of CVID. This study compares the EUROclass B cell immunophenotype of CVID patients (n = 30) with suitable disease controls with bronchiectasis (n = 11), granulomatous disease (Crohn's disease) (n = 9) and neurological patients on immunoglobulin treatment (n = 6). The results of this study correlate with previous literature, that alterations in B cell immunophenotype are associated strongly with CVID. Interestingly, three of the 11 bronchiectasis patients without known immunodeficiency had an altered B cell immunophenotype, suggesting the possibility of undiagnosed immunodeficiency, or that bronchiectasis may cause a secondary alteration in B cell immunophenotype. This study showed a significant difference in B cell immunophenotype between CVID patients compared to disease control groups of granulomatous disease and immunoglobulin treatment. This suggests that granulomatous disease (in Crohn's disease) and immunoglobulin treatment (for chronic neurological conditions) are not causal of an altered B cell immunophenotype in these control populations. PMID:23286946

Gastro-intestinal autoimmunity: preclinical experiences and successful therapy of fistulizing bowel diseases and gut Graft versus host disease by mesenchymal stromal cells.

PubMed

Voswinkel, Jan; Francois, Sabine; Gorin, Norbert-Claude; Chapel, Alain

2013-07-01

Mesenchymal stromal cells (MSC) are multipotent adult stem cells with the potential to regenerate tissue damage and inhibit inflammation and fibrosis in parallel. As they are non-immunogenic, MSC can be safely auto- and allotransplanted and consequently represent a therapeutic option for refractory connective tissue diseases and fistulizing colitis like Crohn's disease. Actually, there are more than 200 registered clinical trial sites for evaluating MSC therapy, 22 are on autoimmune diseases and 27 are actually recruiting bowel disease' patients. More than 1,500 patients with bowel diseases like Crohn's disease were treated in clinical trials by local as well as systemic MSC therapy. Phase I and II trials on fistula documented the feasibility and safety of MSC therapy, and a significant superiority compared to fibrin glue in fistulizing bowel diseases was demonstrated. Autologous as well as allogeneic use of Bone marrow as well as of adipose tissue-derived MSC are feasible. In refractory Graft versus host disease, especially in refractory gut Graft versus host diseases, encouraging results were reported using MSC. Systemic MSC therapy of refractory irradiation-induced colitis was safe and effective on pain, diarrhea, hemorrhage, inflammation and fistulization accompanied by modulation of the lymphocyte subsets toward an increase in T regulatory cells and a decrease in activated effector T cells. Mesenchymal stem cells represent a safe therapy for patients with refractory inflammatory bowel diseases.

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility

PubMed Central

Sehgal, Anuj; Rios, Daniel

2016-01-01

Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer’s patches is essential for the efficient spread of disease to the brain. To replicate within Peyer’s patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer’s patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer’s patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases. PMID:27973593

Increased Abundance of M Cells in the Gut Epithelium Dramatically Enhances Oral Prion Disease Susceptibility.

PubMed

Donaldson, David S; Sehgal, Anuj; Rios, Daniel; Williams, Ifor R; Mabbott, Neil A

2016-12-01

Many natural prion diseases of humans and animals are considered to be acquired through oral consumption of contaminated food or pasture. Determining the route by which prions establish host infection will identify the important factors that influence oral prion disease susceptibility and to which intervention strategies can be developed. After exposure, the early accumulation and replication of prions within small intestinal Peyer's patches is essential for the efficient spread of disease to the brain. To replicate within Peyer's patches, the prions must first cross the gut epithelium. M cells are specialised epithelial cells within the epithelia covering Peyer's patches that transcytose particulate antigens and microorganisms. M cell-development is dependent upon RANKL-RANK-signalling, and mice in which RANK is deleted only in the gut epithelium completely lack M cells. In the specific absence of M cells in these mice, the accumulation of prions within Peyer's patches and the spread of disease to the brain was blocked, demonstrating a critical role for M cells in the initial transfer of prions across the gut epithelium in order to establish host infection. Since pathogens, inflammatory stimuli and aging can modify M cell-density in the gut, these factors may also influence oral prion disease susceptibility. Mice were therefore treated with RANKL to enhance M cell density in the gut. We show that prion uptake from the gut lumen was enhanced in RANKL-treated mice, resulting in shortened survival times and increased disease susceptibility, equivalent to a 10-fold higher infectious titre of prions. Together these data demonstrate that M cells are the critical gatekeepers of oral prion infection, whose density in the gut epithelium directly limits or enhances disease susceptibility. Our data suggest that factors which alter M cell-density in the gut epithelium may be important risk factors which influence host susceptibility to orally acquired prion diseases.

B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

PubMed Central

Shen, Ping; Brown, Sheila; Lampropoulou, Vicky; Roch, Toralf; Lawrie, Sarah; Fan, Boli; O’Connor, Richard A.; Anderton, Stephen M.; Bar-Or, Amit; Fillatreau, Simon; Gray, David

2012-01-01

B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6–secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell–specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6–sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6–producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell–driven pathogenesis in T cell–mediated autoimmune disease such as EAE and MS. PMID:22547654

Modelling human disease with pluripotent stem cells.

PubMed

Siller, Richard; Greenhough, Sebastian; Park, In-Hyun; Sullivan, Gareth J

2013-04-01

Recent progress in the field of cellular reprogramming has opened up the doors to a new era of disease modelling, as pluripotent stem cells representing a myriad of genetic diseases can now be produced from patient tissue. These cells can be expanded and differentiated to produce a potentially limitless supply of the affected cell type, which can then be used as a tool to improve understanding of disease mechanisms and test therapeutic interventions. This process requires high levels of scrutiny and validation at every stage, but international standards for the characterisation of pluripotent cells and their progeny have yet to be established. Here we discuss the current state of the art with regard to modelling diseases affecting the ectodermal, mesodermal and endodermal lineages, focussing on studies which have demonstrated a disease phenotype in the tissue of interest. We also discuss the utility of pluripotent cell technology for the modelling of cancer and infectious disease. Finally, we spell out the technical and scientific challenges which must be addressed if the field is to deliver on its potential and produce improved patient outcomes in the clinic.

Type two innate lymphoid cells: the Janus cells in health and disease.

PubMed

Maazi, Hadi; Akbari, Omid

2017-07-01

Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2, and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity, and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by co-stimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Necroptosis in neurodegenerative diseases: a potential therapeutic target

PubMed Central

Zhang, Shuo; Tang, Mi-bo; Luo, Hai-yang; Shi, Chang-he; Xu, Yu-ming

2017-01-01

Neurodegenerative diseases are a group of chronic progressive disorders characterized by neuronal loss. Necroptosis, a recently discovered form of programmed cell death, is a cell death mechanism that has necrosis-like morphological characteristics. Necroptosis activation relies on the receptor-interacting protein (RIP) homology interaction motif (RHIM). A variety of RHIM-containing proteins transduce necroptotic signals from the cell trigger to the cell death mediators RIP3 and mixed lineage kinase domain-like protein (MLKL). RIP1 plays a particularly important and complex role in necroptotic cell death regulation ranging from cell death activation to inhibition, and these functions are often cell type and context dependent. Increasing evidence suggests that necroptosis plays an important role in the pathogenesis of neurodegenerative diseases. Moreover, small molecules such as necrostatin-1 are thought inhibit necroptotic signaling pathway. Understanding the precise mechanisms underlying necroptosis and its interactions with other cell death pathways in neurodegenerative diseases could provide significant therapeutic insights. The present review is aimed at summarizing the molecular mechanisms of necroptosis and highlighting the emerging evidence on necroptosis as a major driver of neuron cell death in neurodegenerative diseases. PMID:28661482

Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer's Disease.

PubMed

Del Cerro, Patricia; Alquézar, Carolina; Bartolomé, Fernando; González-Naranjo, Pedro; Pérez, Concepción; Carro, Eva; Páez, Juan A; Campillo, Nuria E; Martín-Requero, Ángeles

2018-05-07

Alzheimer's disease is a multifactorial disorder for which there is no disease-modifying treatment yet. CB2 receptors have emerged as a promising therapeutic target for Alzheimer's disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects. The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer's disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer's disease, contributing to the instigation of the disease. Lymphoblastoid cell lines from patients with Alzheimer's disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in β-amyloid-treated neuronal cells. We report here that PGN33 normalized the increased proliferative activity of Alzheimer's disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented β-amyloid-induced cell death in neuronal cells. Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer's disease.

Mast cells as effectors in atherosclerosis.

PubMed

Bot, Ilze; Shi, Guo-Ping; Kovanen, Petri T

2015-02-01

The mast cell is a potent immune cell known for its functions in host defense responses and diseases, such as asthma and allergies. In the past years, accumulating evidence established the contribution of the mast cell to cardiovascular diseases as well, in particular, by its effects on atherosclerotic plaque progression and destabilization. Through its release not only of mediators, such as the mast cell-specific proteases chymase and tryptase, but also of growth factors, histamine, and chemokines, activated mast cells can have detrimental effects on its immediate surroundings in the vessel wall. This results in matrix degradation, apoptosis, and enhanced recruitment of inflammatory cells, thereby actively contributing to cardiovascular diseases. In this review, we will discuss the current knowledge on mast cell function in cardiovascular diseases and speculate on potential novel therapeutic strategies to prevent acute cardiovascular syndromes via targeting of mast cells. © 2014 American Heart Association, Inc.

Treating atherosclerosis with regulatory T cells.

PubMed

Foks, Amanda C; Lichtman, Andrew H; Kuiper, Johan

2015-02-01

Regulatory T cells (Tregs) play an important role in the regulation of T-cell-mediated immune responses through suppression of T-cell proliferation and secretion of inhibitory cytokines, such as interleukin-10 and transforming growth factor-β. Impaired Treg numbers and function have been associated with numerous diseases, and an imbalance between proinflammatory/proatherogenic cells and Tregs promotes atherosclerotic disease. Restoration of this balance by inducing Tregs has great therapeutic potential to prevent cardiovascular disease. In addition to suppressing differentiation and function of effector T cells, Tregs have been shown to induce anti-inflammatory macrophages, inhibit foam cell formation and to influence cholesterol metabolism. Furthermore, Tregs suppress immune responses of endothelial cells and innate lymphoid cells. In this review, we focus on the recent knowledge on Treg subsets, their activity and function in atherosclerosis, and discuss promising strategies to use Tregs as a therapeutic tool to prevent cardiovascular disease. © 2014 American Heart Association, Inc.

Cellular Models: HD Patient-Derived Pluripotent Stem Cells.

PubMed

Geater, Charlene; Hernandez, Sarah; Thompson, Leslie; Mattis, Virginia B

2018-01-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded polyglutamine (polyQ)-encoding repeats in the Huntingtin (HTT) gene. Traditionally, HD cellular models consisted of either patient cells not affected by disease or rodent neurons expressing expanded polyQ repeats in HTT. As these models can be limited in their disease manifestation or proper genetic context, respectively, human HD pluripotent stem cells (PSCs) are currently under investigation as a way to model disease in patient-derived neurons and other neural cell types. This chapter reviews embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) models of disease, including published differentiation paradigms for neurons and their associated phenotypes, as well as current challenges to the field such as validation of the PSCs and PSC-derived cells. Highlighted are potential future technical advances to HD PSC modeling, including transdifferentiation, complex in vitro multiorgan/system reconstruction, and personalized medicine. Using a human HD patient model of the central nervous system, hopefully one day researchers can tease out the consequences of mutant HTT (mHTT) expression on specific cell types within the brain in order to identify and test novel therapies for disease.

The era of immunogenomics/immunopharmacogenomics.

PubMed

Zewde, Makda; Kiyotani, Kazuma; Park, Jae-Hyun; Fang, Hua; Yap, Kai Lee; Yew, Poh Yin; Alachkar, Houda; Kato, Taigo; Mai, Tu H; Ikeda, Yuji; Matsuda, Tatsuo; Liu, Xiao; Ren, Lili; Deng, Boya; Harada, Makiko; Nakamura, Yusuke

2018-05-21

Although germline alterations and somatic mutations in disease cells have been extensively analyzed, molecular changes in immune cells associated with disease conditions have not been characterized in depth. It is clear that our immune system has a critical role in various biological and pathological conditions, such as infectious diseases, autoimmune diseases, drug-induced skin and liver toxicity, food allergy, and rejection of transplanted organs. The recent development of cancer immunotherapies, particularly drugs modulating the immune checkpoint molecules, has clearly demonstrated the importance of host immune cells in cancer treatments. However, the molecular mechanisms by which these new therapies kill tumor cells are still not fully understood. In this regard, we have begun to explore the role of newly developed tools such as next-generation sequencing in the genetic characterization of both cancer cells and host immune cells, a field that is called immunogenomics/ immunopharmacogenomics. This new field has enormous potential to help us better understand changes in our immune system during the course of various disease conditions. Here we report the potential of deep sequencing of T-cell and B-cell receptors in capturing the molecular contribution of the immune system, which we believe plays critical roles in the pathogenesis of various human diseases.

Nanotechnology and stem cell therapy for cardiovascular diseases: potential applications.

PubMed

La Francesca, Saverio

2012-01-01

The use of stem cell therapy for the treatment of cardiovascular diseases has generated significant interest in recent years. Limitations to the clinical application of this therapy center on issues of stem cell delivery, engraftment, and fate. Nanotechnology-based cell labeling and imaging techniques facilitate stem cell tracking and engraftment studies. Nanotechnology also brings exciting new opportunities to translational stem cell research as it enables the controlled engineering of nanoparticles and nanomaterials that can properly relate to the physical scale of cell-cell and cell-niche interactions. This review summarizes the most relevant potential applications of nanoscale technologies to the field of stem cell therapy for the treatment of cardiovascular diseases.

Reducing FLI1 Levels in the MRL/lpr Lupus Mouse Model Impacts T Cell Function by Modulating Glycosphingolipid Metabolism

PubMed Central

Richard, Erin Morris; Thiyagarajan, Thirumagal; Bunni, Marlene A.; Basher, Fahmin; Roddy, Patrick O.; Siskind, Leah J.; Nietert, Paul J.; Nowling, Tamara K.

2013-01-01

Systemic Lupus erythematosus (SLE) is an autoimmune disease caused, in part, by abnormalities in cells of the immune system including B and T cells. Genetically reducing globally the expression of the ETS transcription factor FLI1 by 50% in two lupus mouse models significantly improves disease measures and survival through an unknown mechanism. In this study we analyze the effects of reducing FLI1 in the MRL/lpr lupus prone model on T cell function. We demonstrate that adoptive transfer of MRL/lpr Fli1 +/+ or Fli1 +/- T cells and B cells into Rag1-deficient mice results in significantly decreased serum immunoglobulin levels in animals receiving Fli1 +/- lupus T cells compared to animals receiving Fli1 +/+ lupus T cells regardless of the genotype of co-transferred lupus B cells. Ex vivo analyses of MRL/lpr T cells demonstrated that Fli1 +/- T cells produce significantly less IL-4 during early and late disease and exhibited significantly decreased TCR-specific activation during early disease compared to Fli1 +/+ T cells. Moreover, the Fli1 +/- T cells expressed significantly less neuraminidase 1 (Neu1) message and decreased NEU activity during early disease and significantly decreased levels of glycosphingolipids during late disease compared to Fli1 +/+ T cells. FLI1 dose-dependently activated the Neu1 promoter in mouse and human T cell lines. Together, our results suggest reducing FLI1 in lupus decreases the pathogenicity of T cells by decreasing TCR-specific activation and IL-4 production in part through the modulation of glycosphingolipid metabolism. Reducing the expression of FLI1 or targeting the glycosphingolipid metabolic pathway in lupus may serve as a therapeutic approach to treating lupus. PMID:24040398

Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism.

PubMed

Richard, Erin Morris; Thiyagarajan, Thirumagal; Bunni, Marlene A; Basher, Fahmin; Roddy, Patrick O; Siskind, Leah J; Nietert, Paul J; Nowling, Tamara K

2013-01-01

Systemic Lupus erythematosus (SLE) is an autoimmune disease caused, in part, by abnormalities in cells of the immune system including B and T cells. Genetically reducing globally the expression of the ETS transcription factor FLI1 by 50% in two lupus mouse models significantly improves disease measures and survival through an unknown mechanism. In this study we analyze the effects of reducing FLI1 in the MRL/lpr lupus prone model on T cell function. We demonstrate that adoptive transfer of MRL/lpr Fli1(+/+) or Fli1(+/-) T cells and B cells into Rag1-deficient mice results in significantly decreased serum immunoglobulin levels in animals receiving Fli1(+/-) lupus T cells compared to animals receiving Fli1(+/+) lupus T cells regardless of the genotype of co-transferred lupus B cells. Ex vivo analyses of MRL/lpr T cells demonstrated that Fli1(+/-) T cells produce significantly less IL-4 during early and late disease and exhibited significantly decreased TCR-specific activation during early disease compared to Fli1(+/+) T cells. Moreover, the Fli1(+/-) T cells expressed significantly less neuraminidase 1 (Neu1) message and decreased NEU activity during early disease and significantly decreased levels of glycosphingolipids during late disease compared to Fli1(+/+) T cells. FLI1 dose-dependently activated the Neu1 promoter in mouse and human T cell lines. Together, our results suggest reducing FLI1 in lupus decreases the pathogenicity of T cells by decreasing TCR-specific activation and IL-4 production in part through the modulation of glycosphingolipid metabolism. Reducing the expression of FLI1 or targeting the glycosphingolipid metabolic pathway in lupus may serve as a therapeutic approach to treating lupus.

GATA2 Deficiency and Epstein-Barr Virus Disease.

PubMed

Cohen, Jeffrey I

2017-01-01

GATA2 is a transcription factor that binds to the promoter of hematopoietic genes. Mutations in one copy of the gene are associated with haploinsufficiency and reduced levels of protein. This results in reduced numbers of several cell types important for immune surveillance including dendritic cells, monocytes, CD4, and NK cells, as well as impaired NK cell function. Recently, GATA2 has been associated with several different presentations of severe Epstein-Barr virus (EBV) disease including primary infection requiring repeated hospitalizations, chronic active EBV disease, EBV-associated hydroa vacciniforme with hemophagocytosis, and EBV-positive smooth muscle tumors. EBV was found predominantly in B cells in each of the cases in which it was studied, unlike most cases of chronic active EBV disease in which the virus is usually present in T or NK cells. The variety of EBV-associated diseases seen in patients with GATA2 deficiency suggest that additional forms of severe EBV disease may be found in patients with GATA2 deficiency in the future.

Y-chromosome R-M343 African Lineages and Sickle Cell Disease reveal structured assimilation in Lebanon

PubMed Central

Haber, Marc; Platt, Daniel E; Khoury, Simon; Badro, Danielle A; Abboud, Miguel; Smith, Chris Tyler; Zalloua, Pierre A

2012-01-01

We have sought to identify signals of assimilation of African male lines in Lebanon by exploring the association of sickle cell disease in Lebanon with Y-chromosome haplogroups that are informative of the disease origin and its exclusivity to the Muslim community. A total of 732 samples were analyzed including 33 sickle cell disease patients from Lebanon genotyped for 28 binary markers and 19 short tandem repeats on the non-recombinant segment of the Y chromosome. Genetic organization was identified using populations known to have influenced the genetic structure of the Lebanese population, in addition to African populations with high incidence of sickle cell disease. Y-chromosome haplogroup R-M343 sub-lineages distinguish between sub-Saharan African and Lebanese Y chromosomes. We detected a limited penetration of sickle cell disease into Lebanese R-M343 carriers, restricted to Lebanese Muslims. We suggest that this penetration brought the sickle cell gene along with the African R-M343, probably with the Saharan caravan slave trade. PMID:20981037

EXPLORING PARENT-SIBLING COMMUNICATION IN FAMILIES OF CHILDREN WITH SICKLE CELL DISEASE

PubMed Central

Graff, J. Carolyn; Hankins, Jane S.; Hardy, Belinda T.; Hall, Heather R.; Roberts, Ruth J.; Neely-Barnes, Susan L.

2011-01-01

Focus group interviews were conducted with parents of children with sickle cell disease to explore parent-sibling communication about sickle cell disease. Communication was influenced by attributes and behaviors of the parent, the child with sickle cell disease, and the sibling; extended family, neighbors, friends, and church members or social networks; and available, accessible resources related to the child’s health, child’s school, and parent employment. Outcomes that influenced and were influenced by factors within and outside the parent-sibling dyad and nuclear family included parent satisfaction, parent roles, family intactness, and status attainment. These findings support previous research with African American families and expand our views of the importance of educating parents, family members, and others about sickle cell disease. The findings suggest a need to explore sibling perception of this communication, parent and sibling perception of the impact of frequent hospitalizations and clinic visits on the sibling and family, and variations within families of children with sickle cell disease. PMID:20384476

Environmentally Induced Epigenetic Transgenerational Inheritance of Altered Sertoli Cell Transcriptome and Epigenome: Molecular Etiology of Male Infertility

PubMed Central

Guerrero-Bosagna, Carlos; Savenkova, Marina; Haque, Md. Muksitul; Nilsson, Eric; Skinner, Michael K.

2013-01-01

Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, enhanced spermatogenic cell apoptosis was observed. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific cellular pathways were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that correlates with adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility. PMID:23555832

Fibrillar Structure and Charge Determine the Interaction of Polyglutamine Protein Aggregates with the Cell Surface*

PubMed Central

Trevino, R. Sean; Lauckner, Jane E.; Sourigues, Yannick; Pearce, Margaret M.; Bousset, Luc; Melki, Ronald; Kopito, Ron R.

2012-01-01

The pathogenesis of most neurodegenerative diseases, including transmissible diseases like prion encephalopathy, inherited disorders like Huntington disease, and sporadic diseases like Alzheimer and Parkinson diseases, is intimately linked to the formation of fibrillar protein aggregates. It is becoming increasingly appreciated that prion-like intercellular transmission of protein aggregates can contribute to the stereotypical spread of disease pathology within the brain, but the mechanisms underlying the binding and uptake of protein aggregates by mammalian cells are largely uninvestigated. We have investigated the properties of polyglutamine (polyQ) aggregates that endow them with the ability to bind to mammalian cells in culture and the properties of the cell surface that facilitate such uptake. Binding and internalization of polyQ aggregates are common features of mammalian cells and depend upon both trypsin-sensitive and trypsin-resistant saturable sites on the cell surface, suggesting the involvement of cell surface proteins in this process. polyQ aggregate binding depends upon the presence of a fibrillar amyloid-like structure and does not depend upon electrostatic interaction of fibrils with the cell surface. Sequences in the huntingtin protein that flank the amyloid-forming polyQ tract also influence the extent to which aggregates are able to bind to cell surfaces. PMID:22753412

Seamless correction of the sickle cell disease mutation of the HBB gene in human induced pluripotent stem cells using TALENs.

PubMed

Sun, Ning; Zhao, Huimin

2014-05-01

Sickle cell disease (SCD) is the most common human genetic disease which is caused by a single mutation of human β-globin (HBB) gene. The lack of long-term treatment makes the development of reliable cell and gene therapies highly desirable. Disease-specific patient-derived human induced pluripotent stem cells (hiPSCs) have great potential for developing novel cell and gene therapies. With the disease-causing mutations corrected in situ, patient-derived hiPSCs can restore normal cell functions and serve as a renewable autologous cell source for the treatment of genetic disorders. Here we successfully utilized transcription activator-like effector nucleases (TALENs), a recently emerged novel genome editing tool, to correct the SCD mutation in patient-derived hiPSCs. The TALENs we have engineered are highly specific and generate minimal off-target effects. In combination with piggyBac transposon, TALEN-mediated gene targeting leaves no residual ectopic sequences at the site of correction and the corrected hiPSCs retain full pluripotency and a normal karyotype. Our study demonstrates an important first step of using TALENs for the treatment of genetic diseases such as SCD, which represents a significant advance toward hiPSC-based cell and gene therapies. © 2013 Wiley Periodicals, Inc.

Cation Homeostasis in Red Cells From Patients With Sickle Cell Disease Heterologous for HbS and HbC (HbSC Genotype).

PubMed

Hannemann, A; Rees, D C; Tewari, S; Gibson, J S

2015-11-01

Sickle cell disease (SCD) in patients of HbSC genotype is considered similar, albeit milder, to that in homozygous HbSS individuals--but with little justification. In SCD, elevated red cell cation permeability is critical as increased solute loss causes dehydration and encourages sickling. Recently, we showed that the KCl cotransporter (KCC) activity in red cells from HbSC patients correlated significantly with disease severity, but that in HbSS patients did not. Two transporters involved in red cell dehydration, the conductive channels Psickle and the Gardos channel, behaved similarly in red cells from the two genotypes, but were significantly less active in HbSC patients. By contrast, KCC activity was quantitatively greater in HbSC red cells. Results suggest that KCC is likely to have greater involvement in red cell dehydration in HbSC patients, which could explain its association with disease severity in this genotype. This work supports the hypothesis that SCD in HbSC patients is a distinct disease entity to that in HbSS patients. Results suggest the possibility of designing specific treatments of particular benefit to HbSC patients and a rationale for the development of prognostic markers, to inform early treatment of children likely to develop more severe complications of the disease.

Role of IL-22– and TNF-α–Producing Th22 Cells in Uveitis Patients with Behçet’s Disease

PubMed Central

Kawazoe, Yuko; Imai, Ayano; Kawaguchi, Tatsushi; Horie, Shintaro; Keino, Hiroshi; Takahashi, Masayo; Mochizuki, Manabu

2013-01-01

Behçet’s disease is a systemic inflammatory disorder with recurrent episodes of oral ulceration, skin lesions, genital ulceration, and intraocular inflammation (uveitis). The intraocular inflammation is strictly associated with Th effector cells. IL-22 is a member of the IL-10 cytokine family that is involved in inflammatory processes. Recently, Th22 cells were identified as a Th cell population that produces IL-22 and TNF-α and are distinct from Th1, Th2, and Th17 cells. In this study, we established Th22-type T cell clones from ocular samples taken from Behçet’s disease patients with active uveitis. These clones produced large amounts of IL-22 and TNF-α but not the Th1 cytokine IFN-γ and the Th17 cytokine IL-17. CD4+ T cells from the peripheral blood of Behçet’s disease patients differentiated into Th22 cells in the presence of IL-6 and TNF-α in vitro. The polarized Th22 cell lines produced large amounts of IL-22, and the polarized Th1 and Th17 cells also produced IL-22. In the presence of anti–TNF-α– and anti–IL-6–blocking Abs, Behçet’s disease Th22-type T cells failed to produce IL-22. In addition, infliximab-pretreated Th22 cells and Th22-type ocular T cells produced less IL-22 and TNF-α. Moreover, IL-22–producing T cells were isolated from mice with experimental autoimmune uveitis, an animal model of Behçet’s disease, and the intraocular T cells from uveitis models produced large amounts of IL-22 in the presence of retinal Ags. Our results suggest that inflammatory cytokines IL-22 and TNF-α may play a key role in the ocular immune response in Behçet’s disease. PMID:23630362

Human Embryonic Stem Cell Therapy in Crohn’s Disease: A Case Report

PubMed Central

Shroff, Geeta

2016-01-01

Patient: Male, 21 Final Diagnosis: Crohn’s disease Symptoms: Intolerance to specific foods • abdominal pain and diarrhea Medication: Human embryonic stem cell therapy Clinical Procedure: Human embryonic stem cell transplantation Specialty: Gastroenterology Objective: Unusual or unexpected effect of treatment Background: Crohn’s disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565 000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn’s disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn’s disease. Case Report: A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Conclusions: Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn’s disease. PMID:26923312

Can Tissue Cilia Lengths and Urine Cilia Proteins Be Markers of Kidney Diseases?

PubMed

Park, Kwon Moo

2018-05-01

The primary cilium is an organelle which consists of a microtubule in the core and a surrounding cilia membrane, and has long been recognized as a "vestigial organelle". However, new evidence demonstrates that the primary cilium has a notable effect on signal transduction in the cell and is associated with some genetic and non-genetic diseases. In the kidney, the primary cilium protrudes into the Bowman's space and the tubular lumen from the apical side of epithelial cells. The length of primary cilia is dynamically altered during the normal cell cycle, being shortened by retraction into the cell body at the entry of cell division and elongated at differentiation. Furthermore, the length of primary cilia is also dynamically changed in the cells, as a result and/or cause, during the progression of various kidney diseases including acute kidney injury and chronic kidney disease. Notably, recent data has demonstrated that the shortening of the primary cilium in the cell is associated with fragmentation, apart from retraction into the cell body, in the progression of diseases and that the fragmented primary cilia are released into the urine. This data reveals that the alteration of primary cilia length could be related to the progression of diseases. This review will consider if primary cilia length alteration is associated with the progression of kidney diseases and if the length of tissue primary cilia and the presence or increase of cilia proteins in the urine is indicative of kidney diseases.

Follicular T helper cells and IL-21 in rheumatic diseases.

PubMed

Rasmussen, Tue Kruse

2016-10-01

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are lifelong diseases with increased mortality and chronic pains. They are both characterized by immunological imbalances causing the immune system attack and destroy the bodies own tissues (called autoimmune disease). The best treatment, we are currently able to offer these patients, cause significant side-effects and can not prevent significant loss of quality of life. At the heart of the disease mechanisms in RA and SLE are subsets of immune cells called T and B cells. These cell types produce proteins (called antibodies), which under normal circumstances protect the body against disease. In RA and SLE these cells produce antibodies that are directed at the bodies own tissues (called autoantibodies), causing inflammation and tissue damage. The cause of this loss of tolerance is still unknown. Interleukin 21 (IL-21) is thought to exert key functions in controlling and directing the T and B cell responses leading to formation of antibodies and autoantibodies alike. IL-21 is a signaling molecule secreted by a subpopulation of T cells called follicular T helper (Tfh) cells. IFNα is another signaling molecule of key importance in autoimmune disease. Stratification of SLE patients by their responsiveness to IFNα has proven a crucial tool in stratifying patients in terms of disease development and treatment response. The aim of this PhD study is to investigate the role of IL-21 and IFNα, and their effects on Tfh cells and B cells and the formation of autoantibodies in RA and SLE. The first part of this study addresses whether plasma levels of IL-21 influence disease activity in rheumatic disease. We further investigate the distribution of IL-21-producing Tfh cells in these patients. We find that IL-21 plasma levels correlate to disease activity and radiological progression in RA, and that the IL-21-producing Tfh cell are increased in the blood and synovial fluid of these patients. These findings support the idea that IL-21 and Tfh cells are linked to the development and perpetuation of these diseases. In the second part of this we investigate how small RNA molecules, called microRNAs, can regulate immunological processes. We find that microRNA-155 can regulate IL-21's capacity to signal, while microRNA-21 is important for survival of T cells. The third, and last part of this, concerns IFNα signaling and its impact on the development of SLE and the formation of autoantibodies. We find that IFNα signaling is altered in a murine model of SLE, and that inhibition of this signaling pathway leads to severe kidney disease. The latter is of key importance as inhibition of IFNα is currently in early trial as a new treatment form for SLE patients. In SLE patients, we find that IFNα responsiveness, as measured by a so-called IFN signature, is crucial in terms of development of the disease as well as serious complications such as kidney disease and involvement of the central nervous system. Interferon alpha does this by affecting intracellular signaling responses and the formation of autoantibodies. The data presented in this thesis supports that IL-21 and Tfh cells have a key role in the disease processes characterizing RA and SLE. We further describe a novel mechanism for microRNA-155 and microRNA-21 in regulating immunological processes in these diseases. Finally we show, that IFNα has important functions in the formation of autoantibodies in SLE. In conclusion, this thesis adds new and important knowledge on the interplay between Tfh cells and B cells and their formation of autoantibodies in rheumatic disease. This knowledge will guide and further the development of new treatment strategies to better patient outcome.

Persistent Changes in Circulating and Intestinal γδ T Cell Subsets, Invariant Natural Killer T Cells and Mucosal-Associated Invariant T Cells in Children and Adults with Coeliac Disease

PubMed Central

Dunne, Margaret R.; Elliott, Louise; Hussey, Seamus; Mahmud, Nasir; Kelly, Jacinta; Doherty, Derek G.; Feighery, Conleth F.

2013-01-01

Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets), natural killer cells, CD56+ T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity. PMID:24124528

Persistent changes in circulating and intestinal γδ T cell subsets, invariant natural killer T cells and mucosal-associated invariant T cells in children and adults with coeliac disease.

PubMed

Dunne, Margaret R; Elliott, Louise; Hussey, Seamus; Mahmud, Nasir; Kelly, Jacinta; Doherty, Derek G; Feighery, Conleth F

2013-01-01

Coeliac disease is a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals. The only current therapy is a lifelong gluten free diet. While much work has focused on the gliadin-specific adaptive immune response in coeliac disease, little is understood about the involvement of the innate immune system. Here we used multi-colour flow cytometry to determine the number and frequency of γδ T cells (Vδ1, Vδ2 and Vδ3 subsets), natural killer cells, CD56(+) T cells, invariant NKT cells, and mucosal associated invariant T cells, in blood and duodenum from adults and children with coeliac disease and healthy matched controls. All circulating innate lymphocyte populations were significantly decreased in adult, but not paediatric coeliac donors, when compared with healthy controls. Within the normal small intestine, we noted that Vδ3 cells were the most abundant γδ T cell type in the adult epithelium and lamina propria, and in the paediatric lamina propria. In contrast, patients with coeliac disease showed skewing toward a predominant Vδ1 profile, observed for both adult and paediatric coeliac disease cohorts, particularly within the gut epithelium. This was concurrent with decreases in all other gut lymphocyte subsets, suggesting a specific involvement of Vδ1 cells in coeliac disease pathogenesis. Further analysis showed that γδ T cells isolated from the coeliac gut display an activated, effector memory phenotype, and retain the ability to rapidly respond to in vitro stimulation. A profound loss of CD56 expression in all lymphocyte populations was noted in the coeliac gut. These findings demonstrate a sustained aberrant innate lymphocyte profile in coeliac disease patients of all ages, persisting even after elimination of gluten from the diet. This may lead to impaired immunity, and could potentially account for the increased incidence of autoimmune co-morbidity.

Fully-human Heavy-chain-only Anti-B-cell Maturation Antigen (BCMA) Chimeric Antigen Receptors (CARs) | NCI Technology Transfer Center | TTC

Cancer.gov

Chimeric Antigen Receptor T cell (CAR-T) therapies that specifically target B-cell maturation antigen (BCMA) are strong therapeutic candidates for patients with plasma cell malignancy diseases such as, multiple myeloma (MM), as well as for patients with Hodgkin’s lymphoma. BCMA is a cell surface protein preferentially expressed on a subset of B cells and mature plasma cells, but not on other cells in the body. The limited expression of BCMA on B and plasma cells makes BCMA an attractive therapeutic target for B cell and plasma cell malignancy diseases. The 12 anti-BCMA CARs described are fully human CARS and have the potential to treat patients with various plasma cell and B cell malignancy diseases.

Alemtuzumab and Glucocorticoids in Treating Newly Diagnosed Acute Graft-Versus-Host Disease in Patients Who Have Undergone a Donor Stem Cell Transplant

ClinicalTrials.gov

2010-05-12

Breast Cancer; Chronic Myeloproliferative Disorders; Gestational Trophoblastic Tumor; Graft Versus Host Disease; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Neuroblastoma; Ovarian Cancer; Testicular Germ Cell Tumor

Cell therapies for Chagas disease.

PubMed

Carvalho, Adriana Bastos; Goldenberg, Regina Coeli Dos Santos; Campos de Carvalho, Antonio Carlos

2017-11-01

In this review of cell therapies in Chagas disease, we cover aspects related to the disease, its treatment and world demographics, before proceeding to describe the preclinical and clinical trials performed using cell therapies in the search for an alternative therapy for the most severe and lethal form of this disease, chronic chagasic cardiomyopathy. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Coexistence of sickle cell disease and severe congenital neutropenia: first impressions can be deceiving.

PubMed

Wali, Yasser; Beshlawi, Ismail; Fawaz, Naglaa; Alkhayat, Aisha; Zalabany, Mahmoud; Elshinawy, Mohamed; Al-Kindi, Salam; Al-Rawas, Abdul Hakim A; Klein, Christoph

2012-09-01

We report an Omani family in whom the propositus had a rare coexistence of sickle cell disease and severe congenital neutropenia associated with a mutation in ELANE. In contrast to his siblings with sickle cell disease, the severity of HbSS-associated complications such as painful crises and acute chest syndrome was significantly reduced. His course of the disease had markedly worsened after initiating G-CSF therapy. These clinical observations suggest that neutropenia may ameliorate inflammatory responses and thus display a modulating factor with respect to the clinical course of sickle cell disease. © 2012 John Wiley & Sons A/S.

Immunological Cells and Functions in Gaucher Disease

PubMed Central

Pandey, Manoj Kumar; Grabowski, Gregory A.

2013-01-01

The macrophage (MΦ) has been the focus of causality, research, and therapy of Gaucher disease, but recent evidence casts doubt its solitary role in the disease pathogenesis. The excess of glucosylceramide (GC) in such cells accounts for some of the disease manifestations. Evidence of increased expression of C-C and C-X-C chemokines (i.e., CCL2,CXCL1, CXCL8) in Gaucher disease could be critical for monocytes (MOs) transformation to inflammatory subsets of (MΦs) and dendritic cells (DCs) as well as neutrophil (PMNs) recruitment to visceral organs. These immune responses could be essential for activation of T- and B-cell subsets, and the induction of numerous cytokines and chemokines that participate in the initiation and propagation of the molecular pathogenesis of Gaucher disease. The association of Gaucher disease with a variety of cellular and humoral immune responses is reviewed here to provide a potential foundation for expanding the complex pathophysiology of Gaucher disease. PMID:23510064

Stem Cell Research: Unlocking the Mystery of Disease

MedlinePlus

... Issue Past Issues From the Director: Stem Cell Research: Unlocking the Mystery of Disease Past Issues / Summer ... Director, described the need for expanding stem cell research. Recently, he spoke about stem cell research with ...

Tay-Sachs disease

MedlinePlus

GM2 gangliosidosis - Tay-Sachs; Lysosomal storage disease - Tay-Sachs disease ... called gangliosides. Without this protein, gangliosides, particularly ganglioside GM2, build up in cells, often nerve cells in ...

A Case Report of NK-Cell Lymphoproliferative Disease With a Wide Involvement of Digestive Tract Develop Into Epstein-Barr Virus Associated NK/T Cell Lymphoma in an Immunocompetent Patient.

PubMed

Chen, Haotian; Zhang, Yu; Jiang, Zhinong; Zhou, Wei; Cao, Qian

2016-03-01

Epstein-Barr virus (EBV) plays an important role in various diseases. EBV-associated lymphoproliferative disease (LPD) is a rare disease with a canceration tendency. It is difficult to differentiate LPD with involvement of digestive tract from Crohn disease due to similar clinical and endoscopic manifestations. We present a case report of multiple ulcers with esophagus, small bowel and the entire colon involved, proved to be NK-Cell LPD, developed into EBV-associated NK/T Cell lymphoma, in an immunocompetent man who was initially misdiagnosed as Crohn disease.This report underscores that intestinal ulcers should be cautiously diagnosed, for it sometimes could be a precancerous lesion.

A comparison study of children with sickle cell disease and their non-diseased siblings on hopelessness, depression, and perceived competence.

PubMed

Lee, E J; Phoenix, D; Brown, W; Jackson, B S

1997-01-01

The purpose of this comparison study was to explore the extent to which hopelessness and self-perceptions of competence are associated with depression in a community population of children with sickle cell disease compared to their non-diseased siblings. Subjects were African-American children drawn randomly from the case management programme at the L.D. Barksdale Sickle Cell Anemia Foundation. Depression scores were higher for the non-diseased siblings. The children with sickle cell disease scored lower on the perceived physical competence scale. Recommendations for practice include increasing hope, improving relationships, monitoring depression in patients and their siblings, and monitoring perceptions of cognitive, social, physical, and general self-worth.

Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders.

PubMed

Park, Sanghui; Ko, Young H

2014-01-01

Primary infection with Epstein-Barr virus (EBV) is usually asymptomatic and, in a normal host, EBV remains latent in B cells after primary infection for the remainder of life. Uncommonly, EBV can infect T or natural killer (NK) cells in a person with a defect in innate immunity, and EBV infection can cause unique systemic lymphoproliferative diseases (LPD) of childhood. Primary infection in young children can be complicated by hemophagocytic lymphohistiocytosis or fulminant systemic T-cell LPD of childhood. Uncommonly, patients can develop chronic active EBV (CAEBV) disease-type T/NK LPD, which includes CAEBV infection of the systemic form, hydroa vacciniforme-like T-cell LPD, and mosquito-bite hypersensitivity. The clinical course of CAEBV disease-type T/NK LPD can be smoldering, persistent or progressive, depending on the balance between viral factors and host immunity. Aggressive NK-cell leukemia, hydroa vacciniforme-like T-cell lymphoma, or uncommonly extranodal NK/T-cell lymphoma can develop in children and young adults with CAEBV disease-type T/NK-cell LPD. Extranodal T/NK-cell lymphoma is a disease of adults, and its incidence begins to increase in the third decade and comprises the major subtype of T/NK LPD throughout life. Aggressive NK-cell leukemia and nodal T/NK-cell lymphoma of the elderly are fulminant diseases, and immune senescence may be an important pathogenetic factor. This review describes the current progress in identifying different types of EBV-associated T/NK-cell LPD and includes a brief presentation of data from Korea. © 2014 Japanese Dermatological Association.

Regenerative Medicine: Solution in Sight.

PubMed

Wang, Qingjie; Stern, Jeffrey H; Temple, Sally

2016-01-01

The retina, like other central nervous system tissues, has poor regenerative properties in humans. Therefore, diseases that cause retinal cell loss, such as Age-related macular degeneration (AMD), retinitis pigmentosa (RP), Leber congenital amaurosis, Usher syndrome, glaucoma, and diabetic retinopathy, typically result in permanent visual impairment. Stem cell technologies have revolutionized our ability to produce neural cells in abundant supply. Much stem cell research effort is focused on producing the required cell types for cell replacement, or to generate disease-in-a-dish models to elucidate novel disease mechanisms for therapeutic development. Here we review the recent advances in stem cell studies relevant to producing RPE and retinal cells, and highlight future directions.

Gaucher cell, photomicrograph (image)

MedlinePlus

Gaucher disease is called a "lipid storage disease" where abnormal amounts of lipids called "glycosphingolipids" are stored in special cells called reticuloendothelial cells. Classically, the nucleus is ...

Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio.

PubMed

Ryu, Do-Yeal; Rahman, Md Saidur; Pang, Myung-Geol

2017-09-06

Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose-6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases.

Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio

PubMed Central

Ryu, Do-Yeal

2017-01-01

Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose-6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases. PMID:28878155

Brazilian Guidelines for transcranial doppler in children and adolescents with sickle cell disease

PubMed Central

Lobo, Clarisse Lopes de Castro; Cançado, Rodolfo Delfini; Leite, Ana Claudia Celestino Bezerra; dos Anjos, Ana Claudia Mendonça; Pinto, Ana Cristina Silva; Matta, Andre Palma da Cunha; Silva, Célia Maria; Silva, Gisele Sampaio; Friedrisch, João Ricardo; Braga, Josefina Aparecida Pellegrini; Lange, Marcos Christiano; Figueiredo, Maria Stella; Rugani, Marília Álvares; Veloso, Orlando; Moura, Patrícia Gomes; Cortez, Paulo Ivo; Adams, Robert; Gualandro, Sandra Fátima Menosi; de Castilho, Shirley Lopes; Thomé, Ursula; Zetola, Viviane Flumignan

2011-01-01

Background Sickle cell disease is the most common monogenic hereditary disease in Brazil. Although strokes are one of the main causes of morbidity and mortality in these patients, the use of transcranial Doppler to identify children at risk is not universally used. Objective To develop Brazilian guidelines for the use of transcranial Doppler in sickle cell disease children and adolescents, so that related health policies can be expanded, and thus contribute to reduce morbidity and mortality. Methods The guidelines were formulated in a consensus meeting of experts in transcranial Doppler and sickle cell disease. The issues discussed were previously formulated and scientific articles in databases (MEDLINE, SciELO and Cochrane) were carefully analyzed. The consensus for each question was obtained by a vote of experts on the specific theme. Results Recommendations were made, including indications for the use of transcranial Doppler according to the sickle cell disease genotype and patients age; the necessary conditions to perform the exam and its periodicity depending on exam results; the criteria for the indication of blood transfusions and iron chelation therapy; the indication of hydroxyurea; and the therapeutic approach in cases of conditional transcranial Doppler. Conclusion The Brazilian guidelines on the use of transcranial doppler in sickle cell disease patients may reduce the risk of strokes, and thus reduce the morbidity and mortality and improve the quality of life of sickle cell disease patients. PMID:23284243

Insights into neurogenesis and aging: potential therapy for degenerative disease?

PubMed Central

Marr, Robert A; Thomas, Rosanne M; Peterson, Daniel A

2010-01-01

Neurogenesis is the process by which new neural cells are generated from a small population of multipotent stem cells in the adult CNS. This natural generation of new cells is limited in its regenerative capabilities and also declines with age. The use of stem cells in the treatment of neurodegenerative disease may hold great potential; however, the age-related incidence of many CNS diseases coincides with reduced neurogenesis. This review concisely summarizes current knowledge related to adult neurogenesis and its alteration with aging and examines the feasibility of using stem cell and gene therapies to combat diseases of the CNS with advancing age. PMID:20806052

Evolving locally appropriate models of care for Indian sickle cell disease

PubMed Central

Serjeant, Graham R.

2016-01-01

The sickle cell gene in India represents a separate occurrence of the HbS mutations from those in Africa. Sickle cell disease in India occurs against different genetic and environmental backgrounds from those seen in African patients and there is evidence of clinical differences between the populations. Knowledge of the clinical features of African disease was drawn from the Jamaican Cohort Study, based on prospective follow up of all cases of sickle cell disease detected by the screening of 100,000 consecutive newborns in Kingston, Jamaica, and supplemented by observations from the Cooperative Study of Sickle Cell Disease in the US. Defining the principal causes of early morbidity in African sickle cell disease led to successful interventions including pneumococcal prophylaxis, parental education in the early diagnosis of acute splenic sequestration, and the early detection by trans-cranial Doppler of cerebral vessel stenosis predictive of stroke but their success depended on early diagnosis, ideally at birth. Although reducing mortality among patients with African forms of SS disease, the question remains whether these interventions are appropriate or justified in Indian patients. This dilemma is approached by comparing the available data in African and Indian forms of SS disease seeking to highlight the similarities and differences and to identify the deficiencies in knowledge of Indian disease. These deficiencies could be most readily addressed by cohort studies based on newborn screening and since much of the morbidity of African disease occurs in the first five years of life, these need not be a daunting prospect for Indian health care personnel. Newborn screening programmes for sickle cell disease are already underway in India and appropriate protocols and therapeutic trials could quickly answer many of these questions. Without this knowledge, Indian physicians may continue to use possibly unnecessary and expensive models of care. PMID:27377495

Microbiota-specific Th17 Cells: Yin and Yang in Regulation of Inflammatory Bowel Disease.

PubMed

Wu, Wei; Chen, Feidi; Liu, Zhanju; Cong, Yingzi

2016-06-01

Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the intestinal lamina propria under steady conditions. Many studies have demonstrated that microbiota-reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-interleukin-17A or anti-interleukin-17RA antibodies in patients with Crohn's Disease show no improvement or even exacerbation of disease. Accumulating data has also indicated that Th17 cells may provide a protective effect as well to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both proinflammatory and anti-inflammatory functions of intestinal Th17 cells have emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis and in the pathogenesis of inflammatory bowel diseases.

Pathophysiological insights in sickle cell disease.

PubMed

Odièvre, Marie-Hélène; Verger, Emmanuelle; Silva-Pinto, Ana Cristina; Elion, Jacques

2011-10-01

The first coherent pathophysiological scheme for sickle cell disease (SCD) emerged in the sixties-seventies based on an extremely detailed description of the molecular mechanism by which HbS in its deoxy-form polymerises and forms long fibres within the red blood cell that deform it and make it fragile. This scheme explains the haemolytic anaemia, and the mechanistic aspects of the vaso-occlusive crises (VOCs), but, even though it constitutes the basic mechanism of the disease, it does not account for the processes that actually trigger VOCs. This paper reviews recent data which imply: red blood cell dehydration, its abnormal adhesion properties to the endothelium, the participation of inflammatory phenomenon and of a global activation of all the cells present in the vessel, and finally, abnormalities of the vascular tone and of nitric oxide metabolism. These data altogether have shed a new light on the pathophysiology of the first molecular disease i.e. sickle cell disease.

Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases?

PubMed

Iida, Tomoya; Wagatsuma, Kohei; Hirayama, Daisuke; Nakase, Hiroshi

2017-12-21

Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.

Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities.

PubMed

Roybal, Kole T; Lim, Wendell A

2017-04-26

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.

The Vascular Wall: a Plastic Hub of Activity in Cardiovascular Homeostasis and Disease.

PubMed

Awgulewitsch, Cassandra P; Trinh, Linh T; Hatzopoulos, Antonis K

2017-06-01

This review aims to summarize recent findings regarding the plasticity and fate switching among somatic and progenitor cells residing in the vascular wall of blood vessels in health and disease. Cell lineage tracing methods have identified multiple origins of stem cells, macrophages, and matrix-producing cells that become mobilized after acute or chronic injury of cardiovascular tissues. These studies also revealed that in the disease environment, resident somatic cells become plastic, thereby changing their stereotypical identities to adopt proinflammatory and profibrotic phenotypes. Currently, the functional significance of this heterogeneity among reparative cells is unknown. Furthermore, mechanisms that control cellular plasticity and fate decisions in the disease environment are poorly understood. Cardiovascular diseases are responsible for the majority of deaths worldwide. From a therapeutic perspective, these novel discoveries may identify new targets to improve the repair and regeneration of the cardiovascular system.

The potential role of adult stem cells in the management of the rheumatic diseases

PubMed Central

Franceschetti, Tiziana; De Bari, Cosimo

2017-01-01

Adult stem cells are considered as appealing therapeutic candidates for inflammatory and degenerative musculoskeletal diseases. A large body of preclinical research has contributed to describing their immune-modulating properties and regenerative potential. Additionally, increasing evidence suggests that stem cell differentiation and function are disrupted in the pathogenesis of rheumatic diseases. Clinical studies have been limited, for the most part, to the application of adult stem cell-based treatments on small numbers of patients or as a ‘salvage’ therapy in life-threatening disease cases. Nevertheless, these preliminary studies indicate that adult stem cells are promising tools for the long-term treatment of rheumatic diseases. This review highlights recent knowledge acquired in the fields of hematopoietic and mesenchymal stem cell therapy for the management of systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and osteoarthritis (OA) and the potential mechanisms mediating their function. PMID:28717403

Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities

PubMed Central

Roybal, Kole T.; Lim, Wendell A.

2017-01-01

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases. PMID:28446063

Hematopoietic Gene Therapies for Metabolic and Neurologic Diseases.

PubMed

Biffi, Alessandra

2017-10-01

Increasingly, patients affected by metabolic diseases affecting the central nervous system and neuroinflammatory disorders receive hematopoietic cell transplantation (HCT) in the attempt to slow the course of their disease, delay or attenuate symptoms, and improve pathologic findings. The possible replacement of brain-resident myeloid cells by the transplanted cell progeny contributes to clinical benefit. Genetic engineering of the cells to be transplanted (hematopoietic stem cell) may endow the brain myeloid progeny of these cells with enhanced or novel functions, contributing to therapeutic effects. Copyright © 2017 Elsevier Inc. All rights reserved.

An Hepatic Abscess in a Patient With Sickle Cell Anemia.

PubMed

Marolf, Marissa D; Chaudhary, Manu; Kaplan, Sheldon L

2016-11-01

We present a case of hepatic abscess in a transfusion-dependent 16-year-old patient with sickle cell disease. There have been 10 such cases in sickle cell disease patients reported, with the last report published greater than a decade ago. The diagnosis of hepatic abscess merits consideration in sickle cell disease patients presenting with fever without a source and/or abdominal pain.

Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery.

PubMed

Corti, Stefania; Faravelli, Irene; Cardano, Marina; Conti, Luciano

2015-06-01

Although intensive efforts have been made, effective treatments for neurodegenerative and neurodevelopmental diseases have not been yet discovered. Possible reasons for this include the lack of appropriate disease models of human neurons and a limited understanding of the etiological and neurobiological mechanisms. Recent advances in pluripotent stem cell (PSC) research have now opened the path to the generation of induced pluripotent stem cells (iPSCs) starting from somatic cells, thus offering an unlimited source of patient-specific disease-relevant neuronal cells. In this review, the authors focus on the use of human PSC-derived cells in modeling neurological disorders and discovering of new drugs and provide their expert perspectives on the field. The advent of human iPSC-based disease models has fuelled renewed enthusiasm and enormous expectations for insights of disease mechanisms and identification of more disease-relevant and novel molecular targets. Human PSCs offer a unique tool that is being profitably exploited for high-throughput screening (HTS) platforms. This process can lead to the identification and optimization of molecules/drugs and thus move forward new pharmacological therapies for a wide range of neurodegenerative and neurodevelopmental conditions. It is predicted that improvements in the production of mature neuronal subtypes, from patient-specific human-induced pluripotent stem cells and their adaptation to culture, to HTS platforms will allow the increased exploitation of human pluripotent stem cells in drug discovery programs.

Programmed cell death 1 (PD-1) regulates the effector function of CD8 T cells via PD-L1 expressed on target keratinocytes.

PubMed

Okiyama, Naoko; Katz, Stephen I

2014-09-01

Programmed cell death 1 (PD-1) is an inhibitory molecule expressed by activated T cells. Its ligands (PD-L1 and -L2; PD-Ls) are expressed not only by a variety of leukocytes but also by stromal cells. To assess the role of PD-1 in CD8 T cell-mediated diseases, we used PD-1-knockout (KO) OVA-specific T cell-receptor transgenic (Tg) CD8 T cells (OT-I cells) in a murine model of mucocutaneous graft-versus-host disease (GVHD). We found that mice expressing OVA on epidermal keratinocytes (K14-mOVA mice) developed markedly enhanced GVHD-like disease after transfer of PD-1-KO OT-I cells as compared to those mice transferred with wild-type OT-I cells. In addition, K14-mOVA × OT-I double Tg (DTg) mice do not develop GVHD-like disease after adoptive transfer of OT-I cells, while transfer of PD-1-KO OT-I cells caused GVHD-like disease in a Fas/Fas-L independent manner. These results suggest that PD-1/PD-Ls-interactions have stronger inhibitory effects on pathogenic CD8 T cells than does Fas/Fas-L-interactions. Keratinocytes from K14-mOVA mice with GVHD-like skin lesions express PD-L1, while those from mice without the disease do not. These findings reflect the fact that primary keratinocytes express PD-L1 when stimulated by interferon-γ in vitro. When co-cultured with K14-mOVA keratinocytes for 2 days, PD-1-KO OT-I cells exhibited enhanced proliferation and activation compared to wild-type OT-I cells. In addition, knockdown of 50% PD-L1 expression on the keratinocytes with transfection of PD-L1-siRNA enhanced OT-I cell proliferation. In aggregate, our data strongly suggest that PD-L1, expressed on activated target keratinocytes presenting autoantigens, regulates autoaggressive CD8 T cells, and inhibits the development of mucocutaneous autoimmune diseases. Published by Elsevier Ltd.

The Use of Stem Cells to Model Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: From Basic Research to Regenerative Medicine.

PubMed

Hedges, Erin C; Mehler, Vera J; Nishimura, Agnes L

2016-01-01

In recent years several genes have linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as a spectrum disease; however little is known about what triggers their onset. With the ability to generate patient specific stem cell lines from somatic cells, it is possible to model disease without the need to transfect cells with exogenous DNA. These pluripotent stem cells have opened new avenues for identification of disease phenotypes and their relation to specific molecular pathways. Thus, as never before, compounds with potential applications for regenerative medicine can be specifically tailored in patient derived cultures. In this review, we discuss how patient specific induced pluripotent stem cells (iPSCs) have been used to model ALS and FTD and the most recent drug screening targets for these diseases. We also discuss how an iPSC bank would improve the quality of the available cell lines and how it would increase knowledge about the ALS/FTD disease spectrum.

Induced Pluripotent Stem Cells in Huntington's Disease: Disease Modeling and the Potential for Cell-Based Therapy.

PubMed

Liu, Ling; Huang, Jin-Sha; Han, Chao; Zhang, Guo-Xin; Xu, Xiao-Yun; Shen, Yan; Li, Jie; Jiang, Hai-Yang; Lin, Zhi-Cheng; Xiong, Nian; Wang, Tao

2016-12-01

Huntington's disease (HD) is an incurable neurodegenerative disorder that is characterized by motor dysfunction, cognitive impairment, and behavioral abnormalities. It is an autosomal dominant disorder caused by a CAG repeat expansion in the huntingtin gene, resulting in progressive neuronal loss predominately in the striatum and cortex. Despite the discovery of the causative gene in 1993, the exact mechanisms underlying HD pathogenesis have yet to be elucidated. Treatments that slow or halt the disease process are currently unavailable. Recent advances in induced pluripotent stem cell (iPSC) technologies have transformed our ability to study disease in human neural cells. Here, we firstly review the progress made to model HD in vitro using patient-derived iPSCs, which reveal unique insights into illuminating molecular mechanisms and provide a novel human cell-based platform for drug discovery. We then highlight the promises and challenges for pluripotent stem cells that might be used as a therapeutic source for cell replacement therapy of the lost neurons in HD brains.

Human induced pluripotent stem cells in Parkinson's disease: A novel cell source of cell therapy and disease modeling.

PubMed

Li, Wen; Chen, Shengdi; Li, Jia-Yi

2015-11-01

Human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) are two novel cell sources for studying neurodegenerative diseases. Dopaminergic neurons derived from hiPSCs/hESCs have been implicated to be very useful in Parkinson's disease (PD) research, including cell replacement therapy, disease modeling and drug screening. Recently, great efforts have been made to improve the application of hiPSCs/hESCs in PD research. Considerable advances have been made in recent years, including advanced reprogramming strategies without the use of viruses or using fewer transcriptional factors, optimized methods for generating highly homogeneous neural progenitors with a larger proportion of mature dopaminergic neurons and better survival and integration after transplantation. Here we outline the progress that has been made in these aspects in recent years, particularly during the last year, and also discuss existing issues that need to be addressed. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Comprehensive, Ethnically Diverse Library of Sickle Cell Disease-Specific Induced Pluripotent Stem Cells.

PubMed

Park, Seonmi; Gianotti-Sommer, Andreia; Molina-Estevez, Francisco Javier; Vanuytsel, Kim; Skvir, Nick; Leung, Amy; Rozelle, Sarah S; Shaikho, Elmutaz Mohammed; Weir, Isabelle; Jiang, Zhihua; Luo, Hong-Yuan; Chui, David H K; Figueiredo, Maria Stella; Alsultan, Abdulraham; Al-Ali, Amein; Sebastiani, Paola; Steinberg, Martin H; Mostoslavsky, Gustavo; Murphy, George J

2017-04-11

Sickle cell anemia affects millions of people worldwide and is an emerging global health burden. As part of a large NIH-funded NextGen Consortium, we generated a diverse, comprehensive, and fully characterized library of sickle-cell-disease-specific induced pluripotent stem cells (iPSCs) from patients of different ethnicities, β-globin gene (HBB) haplotypes, and fetal hemoglobin (HbF) levels. iPSCs stand to revolutionize the way we study human development, model disease, and perhaps eventually, treat patients. Here, we describe this unique resource for the study of sickle cell disease, including novel haplotype-specific polymorphisms that affect disease severity, as well as for the development of patient-specific therapeutics for this phenotypically diverse disorder. As a complement to this library, and as proof of principle for future cell- and gene-based therapies, we also designed and employed CRISPR/Cas gene editing tools to correct the sickle hemoglobin (HbS) mutation. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Incidence and Predictors of Bacterial infection in Febrile Children with Sickle Cell Disease.

PubMed

Morrissey, Benita J; Bycroft, Thomas P; Almossawi, Ofran; Wilkey, Olufunke B; Daniels, Justin G

2015-01-01

Children with sickle cell disease are at increased risk of developing bacteremia and other serious bacterial infections. Fever is a common symptom in sickle cell disease and can also occur with sickle cell crises and viral infections. We aimed to evaluate the incidence and predictors of bacteremia and bacterial infection in children with sickle cell disease presenting with fever to a district hospital and sickle cell center in London. A retrospective analysis was performed on all attendances of children (aged under 16 years) with sickle cell disease presenting with a fever of 38.5 °C or higher over a 1-year period. Confirmed bacterial infection was defined as bacteremia, bacterial meningitis, urinary tract infection (UTI), pneumonia, osteomyelitis or other bacterial infection with positive identification of organism. Children were defined as having a suspected bacterial infection if a bacterial infection was suspected clinically, but no organism was identified. Over a 1-year period there were 88 episodes analyzed in 59 children. Bacteremia occurred in 3.4% of episodes and confirmed bacterial infection in 7.0%. Suspected bacterial infection occurred in 33.0%. One death occurred from Salmonella typhirium septicemia. C-reactive protein (CRP) level and white blood cell (WBC) count were both significantly associated with bacterial infection (p = 0.004 and 0.02, respectively.) In conclusion, bacterial infections continue to be a significant problem in children with sickle cell disease. C-reactive protein was significantly associated with bacterial infections, and could be included in clinical risk criteria for febrile children with sickle cell disease.

Presence of Epstein-Barr virus-infected B lymphocytes with thyrotropin receptor antibodies on their surface in Graves' disease patients and in healthy individuals.

PubMed

Nagata, Keiko; Higaki, Katsumi; Nakayama, Yuji; Miyauchi, Hiromi; Kiritani, Yui; Kanai, Kyosuke; Matsushita, Michiko; Iwasaki, Takeshi; Sugihara, Hirotsugu; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Nanba, Eiji; Kimura, Hiroshi; Hayashi, Kazuhiko

2014-05-01

Graves' disease is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies (TRAbs). Because Epstein-Barr virus (EBV) persists in B cells and is occasionally reactivated, we hypothesized that EBV contributes to TRAbs production in Graves' disease patients by stimulating the TRAbs-producing B cells. In order for EBV to stimulate antibody-producing cells, EBV must be present in those cells but that have not yet been observed. We examined whether EBV-infected (EBV(+)) B cells with TRAbs on their surface (TRAbs(+)) as membrane immunoglobulin were present in peripheral blood of Graves' disease patients. We analyzed cultured or non-cultured peripheral blood mononuclear cells (PBMCs) from 13 patients and 11 healthy controls by flow-cytometry and confocal laser microscopy, and confirmed all cultured PBMCs from 8 patients really had TRAbs(+) EBV(+) double positive cells. We unexpectedly detected TRAbs(+) cells in all healthy controls, and TRAbs(+) EBV(+) double positive cells in all cultured PBMC from eight healthy controls. The frequency of TRAbs(+) cells in cultured PBMCs was significantly higher in patients than in controls (p = 0.021). In this study, we indicated the presence of EBV-infected B lymphocytes with TRAbs on their surface, a possible player of the production of excessive TRAbs, the causative autoantibody for Graves' disease. This is a basic evidence for our hypothesis that EBV contributes to TRAbs production in Graves' disease patients. Our results further suggest that healthy controls have the potential for TRAbs production. This gives us an important insight into the pathogenesis of Graves' disease.

Presence of Epstein–Barr virus-infected B lymphocytes with thyrotropin receptor antibodies on their surface in Graves’ disease patients and in healthy individuals

PubMed Central

Nagata, Keiko; Higaki, Katsumi; Nakayama, Yuji; Miyauchi, Hiromi; Kiritani, Yui; Kanai, Kyosuke; Matsushita, Michiko; Iwasaki, Takeshi; Sugihara, Hirotsugu; Kuwamoto, Satoshi; Kato, Masako; Murakami, Ichiro; Nanba, Eiji; Kimura, Hiroshi; Hayashi, Kazuhiko

2014-01-01

Abstract Graves’ disease is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies (TRAbs). Because Epstein–Barr virus (EBV) persists in B cells and is occasionally reactivated, we hypothesized that EBV contributes to TRAbs production in Graves’ disease patients by stimulating the TRAbs-producing B cells. In order for EBV to stimulate antibody-producing cells, EBV must be present in those cells but that have not yet been observed. We examined whether EBV-infected (EBV(+)) B cells with TRAbs on their surface (TRAbs(+)) as membrane immunoglobulin were present in peripheral blood of Graves’ disease patients. We analyzed cultured or non-cultured peripheral blood mononuclear cells (PBMCs) from 13 patients and 11 healthy controls by flow-cytometry and confocal laser microscopy, and confirmed all cultured PBMCs from 8 patients really had TRAbs(+) EBV(+) double positive cells. We unexpectedly detected TRAbs(+) cells in all healthy controls, and TRAbs(+) EBV(+) double positive cells in all cultured PBMC from eight healthy controls. The frequency of TRAbs(+) cells in cultured PBMCs was significantly higher in patients than in controls (p = 0.021). In this study, we indicated the presence of EBV-infected B lymphocytes with TRAbs on their surface, a possible player of the production of excessive TRAbs, the causative autoantibody for Graves’ disease. This is a basic evidence for our hypothesis that EBV contributes to TRAbs production in Graves’ disease patients. Our results further suggest that healthy controls have the potential for TRAbs production. This gives us an important insight into the pathogenesis of Graves’ disease. PMID:24467196

Mucosal-associated invariant T cells in autoimmunity, immune-mediated diseases and airways disease.

PubMed

Hinks, Timothy S C

2016-05-01

Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T cells, expressing a semi-invariant T-cell receptor (TCR) and able to recognize small molecules presented on the non-polymorphic MHC-related protein 1. Their intrinsic effector-memory phenotype, enabling secretion of pro-inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune-mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation-induced down-regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR-independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers. © 2016 The Authors. Immunology published by John Wiley & Sons Ltd.

Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment?

PubMed

Sayed, Blayne A; Christy, Alison L; Walker, Margaret E; Brown, Melissa A

2010-06-15

Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.

Langerhans Cells and Their Role in Oral Mucosal Diseases

PubMed Central

Upadhyay, Juhi; Upadhyay, Ram B; Agrawal, Pankaj; Jaitley, Shweta; Shekhar, Rhitu

2013-01-01

Dendritic cells are arguably the most potent antigen-presenting cells and may be the only cells capable of initiating the adaptive immune response. The epithelial residents of dendritic cells are Langerhans cells, which serve as the “sentinels” of the mucosa, altering the immune system not only to pathogen entry but also of tolerance to self antigen and commensal microbes. Oral mucosal Langerhans cells are capable of engaging and internalizing a wide variety of pathogens and have been found responsive to nickel in patients with nickel allergies, oral Candida species, oral lichen planus, lichenoid drug eruptions, graft versus host diseases, periodontal diseases median rhomboid glossitis, human immunodeficiency virus infection, hairy leukoplakia of the tongue, and oral squamous cell carcinoma. Review focuses on the role of antigen-presenting cells in particular Langerhans cells to better understand the mechanisms underlying immune responses. In this review, comprehensive detail about mucosal diseases has been compiled using the PubMed database and through textbooks. PMID:24251267

Gaucher cell, photomicrograph #2 (image)

MedlinePlus

Gaucher disease is called a "lipid storage disease" where abnormal amounts of lipids called "glycosphingolipids" are stored in special cells called reticuloendothelial cells. Classically, the nucleus is ...

The Measure of Sickle Cell Stigma: Initial findings from the Improving Patient Outcomes through Respect and Trust study.

PubMed

Bediako, Shawn M; Lanzkron, Sophie; Diener-West, Marie; Onojobi, Gladys; Beach, Mary C; Haywood, Carlton

2016-05-01

Research about the influence of stigma on health outcomes in sickle cell disease is limited. We administered the recently developed Measure of Sickle Cell Stigma to 262 patients in the United States. The Measure of Sickle Cell Stigma yielded very good internal consistency and four interpretable factors. Significant associations among stigma, pain-related healthcare utilization, and perceived disease severity were observed for three of the four stigma factors (F range = 2.78-5.44). The Measure of Sickle Cell Stigma appears to be a useful tool for measuring disease-specific stigma among adults living with sickle cell disease, and further assessment of its clinical utility is warranted. © The Author(s) 2014.

Stem cells and cellular therapy: potential treatment for cardiovascular diseases.

PubMed

Zavos, Panayiotis M

2006-02-08

This paper reviews the current status of cloning and stem cell research and its application to treating various diseases, particularly cardiovascular disease. Recently new techniques have been developed to isolate embryonic stem cells from preimplantation embryos. These cells are undifferentiated and are therefore able to develop into the cells of whichever organ it is in contact with. These cells would be especially beneficial for the treatment of ischemia and various other cardiovascular diseases. There are a variety of various issues that need to be discussed before this technology can be applied safely, including government regulations to ensure the clinical safety and effectiveness of the procedures, as well as the prevention of improper handling or the use of contaminated tissues.

Measuring dynamic membrane fluctuations in cell membrane using quantitative phase imaging (Conference Presentation)

NASA Astrophysics Data System (ADS)

Lee, SangYun; Kim, Kyoohyun; Park, YongKeun

2017-02-01

There is a strong correlation between the dynamic membrane fluctuations and the biomechanical properties of living cells. The dynamic membrane fluctuation consists of submicron displacements, and can be altered by changing the cells' pathophysiological conditions. These results have significant relevance to the understanding of RBC biophysics and pathology, as follows. RBCs must withstand large mechanical deformations during repeated passages through the microvasculature and the fenestrated walls of the splenic sinusoids. This essential ability is diminished with senescence, resulting in physiological destruction of the aging RBCs. Pathological destruction of the red cells, however, occurs in cells affected by a host of diseases such as spherocytosis, malaria, and Sickle cell disease, as RBCs depart from their normal discoid shape and lose their deformability. Therefore, quantifying the RBC deformability insight into a variety of problems regarding the interplay of cell structure, dynamics, and function. Furthermore, the ability to monitor mechanical properties of RBCs is of vital interest in monitoring disease progression or response to treatment as molecular and pharmaceutical approaches for treatment of chronic diseases. Here, we present the measurements of dynamic membrane fluctuations in live cells using quantitative phase imaging techniques. Measuring both the 3-D refractive index maps and the dynamic phase images of live cells are simultaneously measured, from which dynamic membrane fluctuation and deformability of cells are precisely calculated. We also present its applications to various diseases ranging from sickle cell diseases, babesiosis, and to diabetes.

Natural killer cell subsets in cerebrospinal fluid of patients with multiple sclerosis

PubMed Central

Rodríguez-Martín, E; Picón, C; Costa-Frossard, L; Alenda, R; Sainz de la Maza, S; Roldán, E; Espiño, M; Villar, L M; Álvarez-Cermeño, J C

2015-01-01

Changes in blood natural killer (NK) cells, important players of the immune innate system, have been described in multiple sclerosis (MS). We studied percentages and total cell counts of different effector and regulatory NK cells in cerebrospinal fluid (CSF) of MS patients and other neurological diseases to gain clearer knowledge of the role of these cells in neuroinflammation. NK cell subsets were assessed by flow cytometry in CSF of 85 consecutive MS patients (33 with active disease and 52 with stable MS), 16 with other inflammatory diseases of the central nervous system (IND) and 17 with non-inflammatory neurological diseases (NIND). MS patients showed a decrease in percentages of different CSF NK subpopulations compared to the NIND group. However, absolute cell counts showed a significant increase of all NK subsets in MS and IND patients, revealing that the decrease in percentages does not reflect a real reduction of these immune cells. Remarkably, MS patients showed a significant increase of regulatory/effector (CD56bright/CD56dim) NK ratio compared to IND and NIND groups. In addition, MS activity associated with an expansion of NK T cells. These data show that NK cell subsets do not increase uniformly in all inflammatory neurological disease and suggest strongly that regulatory CD56bright and NK T cells may arise in CSF of MS patients as an attempt to counteract the CNS immune activation characteristic of the disease. PMID:25565222

African American Students' Awareness of Sickle Cell Disease.

ERIC Educational Resources Information Center

Ogamdi, Simon O.

1994-01-01

Reports a study that investigated knowledge level about sickle cell disease among students at a predominantly black university. Survey results indicated the students most directly concerned did not well understand the basic facts about sickle cell disease. Most students could not recall whether they had ever been tested. (SM)

76 FR 74067 - Agency Forms Undergoing Paperwork Reduction Act Review

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-30

... Project Formative Research to Support the Development of Sickle Cell Disease Educational Messages and... seeks to improve the quality of life of people living with sickle cell disease (SCD). To accomplish this... associated with sickle cell disease. To develop valuable messages and materials, CDC will conduct formative...

Early immune responses to Marek’s disease vaccines

USDA-ARS?s Scientific Manuscript database

Marek’s disease virus (MDV), a highly cell-associated lymphotropic 'alpha-herpesvirus, is the causative agent of Marek’s disease (MD) in domestic chickens. MDV replicates in chicken lymphocytes and establishes a latent infection within CD4+ T cells. The latently infected CD4+ T cells carry the vir...

Bone-Immune Cell Crosstalk: Bone Diseases

PubMed Central

Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta

2015-01-01

Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma. PMID:26000310

Bone-immune cell crosstalk: bone diseases.

PubMed

Mori, Giorgio; D'Amelio, Patrizia; Faccio, Roberta; Brunetti, Giacomina

2015-01-01

Bone diseases are associated with great morbidity; thus, the understanding of the mechanisms leading to their development represents a great challenge to improve bone health. Recent reports suggest that a large number of molecules produced by immune cells affect bone cell activity. However, the mechanisms are incompletely understood. This review aims to shed new lights into the mechanisms of bone diseases involving immune cells. In particular, we focused our attention on the major pathogenic mechanism underlying periodontal disease, psoriatic arthritis, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, metastatic solid tumors, and multiple myeloma.

Re-education begins at home: an overview of the discovery of in vivo-active small molecule modulators of endogenous stem cells.

PubMed

Um, JungIn; Lee, Ji-Hyung; Jung, Da-Woon; Williams, Darren R

2018-04-01

Degenerative diseases, such as Alzheimer's disease, heart disease and arthritis cause great suffering and are major socioeconomic burdens. An attractive treatment approach is stem cell transplantation to regenerate damaged or destroyed tissues. However, this can be problematic. For example, donor cells may not functionally integrate into the host tissue. An alternative methodology is to deliver bioactive agents, such as small molecules, directly into the diseased tissue to enhance the regenerative potential of endogenous stem cells. Areas covered: In this review, the authors discuss the necessity of developing these small molecules to treat degenerative diseases and survey progress in their application as therapeutics. They describe both the successes and caveats of developing small molecules that target endogenous stem cells to induce tissue regeneration. This article is based on literature searches which encompass databases for biomedical research and clinical trials. These small molecules are also categorized per their target disease and mechanism of action. Expert opinion: The development of small molecules targeting endogenous stem cells is a high-profile research area. Some compounds have made the successful transition to the clinic. Novel approaches, such as modulating the stem cell niche or targeted delivery to disease sites, should increase the likelihood of future successes in this field.

Relationship between pulmonary and cardiac abnormalities in sickle cell disease: implications for the management of patients

PubMed Central

Maioli, Maria Christina Paixão; Soares, Andrea Ribeiro; Bedirian, Ricardo; Alves, Ursula David; de Lima Marinho, Cirlene; Lopes, Agnaldo José

2015-01-01

Objective To evaluate the association between clinical, pulmonary, and cardiovascular findings in patients with sickle cell disease and, secondarily, to compare these findings between sickle cell anemia patients and those with other sickle cell diseases. Methods Fifty-nine adults were included in this cross-sectional study; 47 had sickle cell anemia, and 12 had other sickle cell diseases. All patients underwent pulmonary function tests, chest computed tomography, and echocardiography. Results Abnormalities on computed tomography, echocardiography, and pulmonary function tests were observed in 93.5%, 75.0%; and 70.2% of patients, respectively. A higher frequency of restrictive abnormalities was observed in patients with a history of acute chest syndrome (85% vs. 21.6%; p-value < 0.0001) and among patients with increased left ventricle size (48.2% vs. 22.2%; p-value = 0.036), and a higher frequency of reduced respiratory muscle strength was observed in patients with a ground-glass pattern (33.3% vs. 4.3%; p-value = 0.016). Moreover, a higher frequency of mosaic attenuation was observed in patients with elevated tricuspid regurgitation velocity (61.1% vs. 24%; p-value = 0.014). Compared to patients with other sickle cell diseases, sickle cell anemia patients had suffered increased frequencies of acute pain episodes, and acute chest syndrome, and exhibited mosaic attenuation on computed tomography, and abnormalities on echocardiography. Conclusion A significant interrelation between abnormalities of the pulmonary and cardiovascular systems was observed in sickle cell disease patients. Furthermore, the severity of the cardiopulmonary parameters among patients with sickle cell anemia was greater than that of patients with other sickle cell diseases. PMID:26969771

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis.

PubMed

Pender, Michael P

2012-01-01

CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.

CD8+ T-Cell Deficiency, Epstein-Barr Virus Infection, Vitamin D Deficiency, and Steps to Autoimmunity: A Unifying Hypothesis

PubMed Central

Pender, Michael P.

2012-01-01

CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection. PMID:22312480

Mesenchymal stem cells for bone repair and metabolic bone diseases.

PubMed

Undale, Anita H; Westendorf, Jennifer J; Yaszemski, Michael J; Khosla, Sundeep

2009-10-01

Human mesenchymal stem cells offer a potential alternative to embryonic stem cells in clinical applications. The ability of these cells to self-renew and differentiate into multiple tissues, including bone, cartilage, fat, and other tissues of mesenchymal origin, makes them an attractive candidate for clinical applications. Patients who experience fracture nonunion and metabolic bone diseases, such as osteogenesis imperfecta and hypophosphatasia, have benefited from human mesenchymal stem cell therapy. Because of their ability to modulate immune responses, allogeneic transplant of these cells may be feasible without a substantial risk of immune rejection. The field of regenerative medicine is still facing considerable challenges; however, with the progress achieved thus far, the promise of stem cell therapy as a viable option for fracture nonunion and metabolic bone diseases is closer to reality. In this review, we update the biology and clinical applicability of human mesenchymal stem cells for bone repair and metabolic bone diseases.

Cardiac Biomarkers: a Focus on Cardiac Regeneration

PubMed Central

Forough, Reza; Scarcello, Catherine; Perkins, Matthew

2011-01-01

Historically, biomarkers have been used in two major ways to maintain and improve better health status: first, for diagnostic purposes, and second, as specific targets to treat various diseases. A new era in treatment and even cure for the some diseases using reprograming of somatic cells is about to be born. In this approach, scientists are successfully taking human skin cells (previously considered terminally-differentiated cells) and re-programming them into functional cardiac myocytes and other cell types in vitro. A cell reprograming approach for treatment of cardiovascular diseases will revolutionize the field of medicine and significantly expand the human lifetime. Availability of a comprehensive catalogue for cardiac biomarkers is necessary for developing cell reprograming modalities to treat cardiac diseases, as well as for determining the progress of reprogrammed cells as they become cardiac cells. In this review, we present a comprehensive survey of the cardiac biomarkers currently known. PMID:23074366

Clinical potentials of human pluripotent stem cells in lung diseases

PubMed Central

2014-01-01

Lung possesses very limited regenerative capacity. Failure to maintain homeostasis of lung epithelial cell populations has been implicated in the development of many life-threatening pulmonary diseases leading to substantial morbidity and mortality worldwide, and currently there is no known cure for these end-stage pulmonary diseases. Embryonic stem cells (ESCs) and somatic cell-derived induced pluripotent stem cells (iPSCs) possess unlimited self-renewal capacity and great potential to differentiate to various cell types of three embryonic germ layers (ectodermal, mesodermal, and endodermal). Therapeutic use of human ESC/iPSC-derived lung progenitor cells for regeneration of injured or diseased lungs will have an enormous clinical impact. This article provides an overview of recent advances in research on pluripotent stem cells in lung tissue regeneration and discusses technical challenges that must be overcome for their clinical applications in the future. PMID:24995122

The impact of mast cells on cardiovascular diseases.

PubMed

Kritikou, Eva; Kuiper, Johan; Kovanen, Petri T; Bot, Ilze

2016-05-05

Mast cells comprise an innate immune cell population, which accumulates in tissues proximal to the outside environment and, upon activation, augments the progression of immunological reactions through the release and diffusion of either pre-formed or newly generated mediators. The released products of mast cells include histamine, proteases, as well as a variety of cytokines, chemokines and growth factors, which act on the surrounding microenvironment thereby shaping the immune responses triggered in various diseased states. Mast cells have also been detected in the arterial wall and are implicated in the onset and progression of numerous cardiovascular diseases. Notably, modulation of distinct mast cell actions using genetic and pharmacological approaches highlights the crucial role of this cell type in cardiovascular syndromes. The acquired evidence renders mast cells and their mediators as potential prognostic markers and therapeutic targets in a broad spectrum of pathophysiological conditions related to cardiovascular diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

Different subsets of natural killer T cells may vary in their roles in health and disease

PubMed Central

Kumar, Vipin; Delovitch, Terry L

2014-01-01

Natural killer T cells (NKT) can regulate innate and adaptive immune responses. Type I and type II NKT cell subsets recognize different lipid antigens presented by CD1d, an MHC class-I-like molecule. Most type I NKT cells express a semi-invariant T-cell receptor (TCR), but a major subset of type II NKT cells reactive to a self antigen sulphatide use an oligoclonal TCR. Whereas TCR-α dominates CD1d-lipid recognition by type I NKT cells, TCR-α and TCR-β contribute equally to CD1d-lipid recognition by type II NKT cells. These variable modes of NKT cell recognition of lipid–CD1d complexes activate a host of cytokine-dependent responses that can either exacerbate or protect from disease. Recent studies of chronic inflammatory and autoimmune diseases have led to a hypothesis that: (i) although type I NKT cells can promote pathogenic and regulatory responses, they are more frequently pathogenic, and (ii) type II NKT cells are predominantly inhibitory and protective from such responses and diseases. This review focuses on a further test of this hypothesis by the use of recently developed techniques, intravital imaging and mass cytometry, to analyse the molecular and cellular dynamics of type I and type II NKT cell antigen-presenting cell motility, interaction, activation and immunoregulation that promote immune responses leading to health versus disease outcomes. PMID:24428389

Stem cell treatment of degenerative eye disease.

PubMed

Mead, Ben; Berry, Martin; Logan, Ann; Scott, Robert A H; Leadbeater, Wendy; Scheven, Ben A

2015-05-01

Stem cell therapies are being explored extensively as treatments for degenerative eye disease, either for replacing lost neurons, restoring neural circuits or, based on more recent evidence, as paracrine-mediated therapies in which stem cell-derived trophic factors protect compromised endogenous retinal neurons from death and induce the growth of new connections. Retinal progenitor phenotypes induced from embryonic stem cells/induced pluripotent stem cells (ESCs/iPSCs) and endogenous retinal stem cells may replace lost photoreceptors and retinal pigment epithelial (RPE) cells and restore vision in the diseased eye, whereas treatment of injured retinal ganglion cells (RGCs) has so far been reliant on mesenchymal stem cells (MSC). Here, we review the properties of non-retinal-derived adult stem cells, in particular neural stem cells (NSCs), MSC derived from bone marrow (BMSC), adipose tissues (ADSC) and dental pulp (DPSC), together with ESC/iPSC and discuss and compare their potential advantages as therapies designed to provide trophic support, repair and replacement of retinal neurons, RPE and glia in degenerative retinal diseases. We conclude that ESCs/iPSCs have the potential to replace lost retinal cells, whereas MSC may be a useful source of paracrine factors that protect RGC and stimulate regeneration of their axons in the optic nerve in degenerate eye disease. NSC may have potential as both a source of replacement cells and also as mediators of paracrine treatment. Copyright © 2015. Published by Elsevier B.V.

Endothelial and circulating progenitor cells in hematological diseases and allogeneic hematopoietic stem cell transplantation.

PubMed

Ruggeri, Annalisa; Paviglianiti, Annalisa; Volt, Fernanda; Kenzey, Chantal; Rafii, Hanadi; Rocha, Vanderson; Gluckman, Eliane

2017-10-12

Circulating endothelial cells (CECs), originated form endothelial progenitors (EPCs) are mature cells which are not associated with vessel walls, and that are detached from the endothelium. Normally, they are present in insignificant amounts in the peripheral blood of healthy individuals. On the other hand, elevated CECs and EPCs levels have been reported in the peripheral blood of patients with different types of cancers and some other diseases. Consequently, CECs and EPCs represent a potential biomarker in several clinical conditions involving endothelial turnover and remodeling, such as hematological diseases. These cells may be involved in disease progression and the neoplastic angiogenesis process. Moreover, CESs and EPCs are probably involved in endothelial damage that is a marker of several complications following allogeneic hematopoietic stem cell transplantation. This review aims to provide an overview on the characterization of CECs and EPCs, describe isolation methods and to identify the potential role of these cells in hematological diseases and hematopoietic stem cell transplantation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Mitochondrial cyclophilin D regulates T cell metabolic responses and disease tolerance to tuberculosis.

PubMed

Tzelepis, Fanny; Blagih, Julianna; Khan, Nargis; Gillard, Joshua; Mendonca, Laura; Roy, Dominic G; Ma, Eric H; Joubert, Philippe; Jones, Russell G; Divangahi, Maziar

2018-05-11

Mycobacterium tuberculosis ( Mtb ) is one of the most ancient human pathogens, yet the exact mechanism(s) of host defense against Mtb remains unclear. Although one-third of the world's population is chronically infected with Mtb , only 5 to 10% develop active disease. This indicates that, in addition to resistance mechanisms that control bacterial burden, the host has also evolved strategies to tolerate the presence of Mtb to limit disease severity. We identify mitochondrial cyclophilin D (CypD) as a critical checkpoint of T cell metabolism that controls the expansion of activated T cells. Although loss of CypD function in T cells led to enhanced Mtb antigen-specific T cell responses, this increased T cell response had no impact on bacterial burden. Rather, mice containing CypD-deficient T cells exhibited substantially compromised disease tolerance and succumbed to Mtb infection. This study establishes a mechanistic link between T cell-mediated immunity and disease tolerance during Mtb infection. Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Parkinson disease

MedlinePlus

... this page: //medlineplus.gov/ency/article/000755.htm Parkinson disease To use the sharing features on this page, please enable JavaScript. Parkinson disease results from certain brain cells dying. These cells ...

Amelioration of Sickle Cell Pain after Parathyroidectomy in Two Patients with Concurrent Hyperparathyroidism: An Interesting Finding.

PubMed

Muthu, John; Ali, Mir

2016-01-01

Patients with sickle cell disease have high morbidity and healthcare utilization due to repeated painful crises. Some coexisting conditions which cause pain similar to sickle cell disease may go undiagnosed in these patients. We report two adults with concurrent hyperparathyroidism who experienced significant improvement in sickle cell pain following parathyroidectomy thereby pointing to hyperparathyroidism as the principal causative factor for their pain. Meticulous evaluation for parathyroid disorders can be rewarding in sickle cell disease.

Amelioration of Sickle Cell Pain after Parathyroidectomy in Two Patients with Concurrent Hyperparathyroidism: An Interesting Finding

PubMed Central

Muthu, John

2016-01-01

Patients with sickle cell disease have high morbidity and healthcare utilization due to repeated painful crises. Some coexisting conditions which cause pain similar to sickle cell disease may go undiagnosed in these patients. We report two adults with concurrent hyperparathyroidism who experienced significant improvement in sickle cell pain following parathyroidectomy thereby pointing to hyperparathyroidism as the principal causative factor for their pain. Meticulous evaluation for parathyroid disorders can be rewarding in sickle cell disease. PMID:27579039

Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation[S

PubMed Central

Allende, Maria L.; Cook, Emily K.; Larman, Bridget C.; Nugent, Adrienne; Brady, Jacqueline M.; Golebiowski, Diane; Sena-Esteves, Miguel; Tifft, Cynthia J.

2018-01-01

Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses. PMID:29358305

Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation.

PubMed

Allende, Maria L; Cook, Emily K; Larman, Bridget C; Nugent, Adrienne; Brady, Jacqueline M; Golebiowski, Diane; Sena-Esteves, Miguel; Tifft, Cynthia J; Proia, Richard L

2018-03-01

Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate, GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of Sandhoff disease, we first generated iPS cells from the fibroblasts of an infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental Sandhoff disease iPS cells and isogenic HEXB -corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The Sandhoff disease organoids, but not the HEXB -corrected organoids, accumulated GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB -corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the GM2 gangliosidoses.

Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

PubMed Central

Pessoa de Magalhães, Roberto J.; Vidriales, María-Belén; Paiva, Bruno; Fernandez-Gimenez, Carlos; García-Sanz, Ramón; Mateos, Maria-Victoria; Gutierrez, Norma C.; Lecrevisse, Quentin; Blanco, Juan F; Hernández, Jose; de las Heras, Natalia; Martinez-Lopez, Joaquin; Roig, Monica; Costa, Elaine Sobral; Ocio, Enrique M.; Perez-Andres, Martin; Maiolino, Angelo; Nucci, Marcio; De La Rubia, Javier; Lahuerta, Juan-Jose; San-Miguel, Jesús F.; Orfao, Alberto

2013-01-01

Multiple myeloma remains largely incurable. However, a few patients experience more than 10 years of relapse-free survival and can be considered as operationally cured. Interestingly, long-term disease control in multiple myeloma is not restricted to patients with a complete response, since some patients revert to having a profile of monoclonal gammopathy of undetermined significance. We compared the distribution of multiple compartments of lymphocytes and dendritic cells in the bone marrow and peripheral blood of multiple myeloma patients with long-term disease control (n=28), patients with newly diagnosed monoclonal gammopathy of undetermined significance (n=23), patients with symptomatic multiple myeloma (n=23), and age-matched healthy adults (n=10). Similarly to the patients with monoclonal gammopathy of undetermined significance and symptomatic multiple myeloma, patients with long-term disease control showed an expansion of cytotoxic CD8+ T cells and natural killer cells. However, the numbers of bone marrow T-regulatory cells were lower in patients with long-term disease control than in those with symptomatic multiple myeloma. It is noteworthy that B cells were depleted in patients with monoclonal gammopathy of undetermined significance and in those with symptomatic multiple myeloma, but recovered in both the bone marrow and peripheral blood of patients with long-term disease control, due to an increase in normal bone marrow B-cell precursors and plasma cells, as well as pre-germinal center peripheral blood B cells. The number of bone marrow dendritic cells and tissue macrophages differed significantly between patients with long-term disease control and those with symptomatic multiple myeloma, with a trend to cell count recovering in the former group of patients towards levels similar to those found in healthy adults. In summary, our results indicate that multiple myeloma patients with long-term disease control have a constellation of unique immune changes favoring both immune cytotoxicity and recovery of B-cell production and homing, suggesting improved immune surveillance. PMID:22773604

Effect of high-glucose conditions on human periodontal ligament endothelial cells: in vitro analysis.

PubMed

Maruyama, Kosuke; Sato, Soh

2017-01-01

Endothelial cells participate in key aspects of vascular biology, such as maintenance of capillary permeability and regulation of inflammation. According to previous reports, endothelial cells have revealed highly specific characteristics depending on the organs and tissues. In particular, periodontal endothelial cells have a higher permeability than vascular endothelial cells of other types of tissue. Periodontal disease is not only a chronic disease in oral, but also affect the entire body. Diabetes and periodontal disease are closely related, with periodontal disease even been referred to as the sixth complication of disease. However, no reports have investigated the pathophysiology of microvascular in periodontal tissue once diabetes has developed. Therefore, the aim of the present study is to investigate changes in the properties of human periodontal endothelial cells (HPDLECs) that were cultured under high-glucose conditions. We isolated HPDLECs from human periodontal ligament cells. HPDLECs were cultured under high-glucose (5.5, 11.0, 22.0 mM) and investigated proliferation, apoptosis, tube formation and the expression of cell adhesion molecules. A 5.5 mM (100 mg/dl) control was used in this study. HPDLECs stimulated with high glucose concentration exhibited suppression of cell proliferation and an increased percentage of apoptosis-positive cells. This results suggested that apoptosis was caused by TNF-α expression. The expression levels cell adhesion molecules increased. These results suggest that when HPDLECs are stimulated with a high glucose concentrations, PKC in the intracellular cell substrate is activated, increasing the expression of intercellular and vascular adhesion molecules. Thus, the results of this study demonstrate that diabetes exacerbates periodontal disease.

Therapeutics with SPION-labeled stem cells for the main diseases related to brain aging: a systematic review.

PubMed

Alvarim, Larissa T; Nucci, Leopoldo P; Mamani, Javier B; Marti, Luciana C; Aguiar, Marina F; Silva, Helio R; Silva, Gisele S; Nucci-da-Silva, Mariana P; DelBel, Elaine A; Gamarra, Lionel F

2014-01-01

The increase in clinical trials assessing the efficacy of cell therapy for structural and functional regeneration of the nervous system in diseases related to the aging brain is well known. However, the results are inconclusive as to the best cell type to be used or the best methodology for the homing of these stem cells. This systematic review analyzed published data on SPION (superparamagnetic iron oxide nanoparticle)-labeled stem cells as a therapy for brain diseases, such as ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and dementia. This review highlights the therapeutic role of stem cells in reversing the aging process and the pathophysiology of brain aging, as well as emphasizing nanotechnology as an important tool to monitor stem cell migration in affected regions of the brain.

Human Embryonic Stem Cell Therapy in Crohn's Disease: A Case Report.

PubMed

Shroff, Geeta

2016-02-29

Crohn's disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565,000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn's disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn's disease. A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn's disease.

IL-33: biological properties, functions, and roles in airway disease.

PubMed

Drake, Li Yin; Kita, Hirohito

2017-07-01

Interleukin (IL)-33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL-33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL-33 and group 2 innate lymphoid cells (ILC2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL-33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL-33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL-33 and ILC2 levels are elevated in patients with allergic airway diseases suggest that IL-33 plays an important role in the pathogenesis of these diseases. IL-33 and ILC2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL-33 and discussed the roles of the IL-33 in regulating airway immune responses and allergic airway diseases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cell therapy for basement membrane-linked diseases.

PubMed

Nyström, Alexander; Bornert, Olivier; Kühl, Tobias

2017-01-01

For most disorders caused by mutations in genes encoding basement membrane (BM) proteins, there are at present only limited treatment options available. Genetic BM-linked disorders can be viewed as especially suited for treatment with cell-based therapy approaches because the proteins that need to be restored are located in the extracellular space. In consequence, complete and permanent engraftment of cells does not necessarily have to occur to achieve substantial causal therapeutic effects. For these disorders cells can be used as transient vehicles for protein replacement. In addition, it is becoming evident that BM-linked genetic disorders are modified by secondary diseases mechanisms. Cell-based therapies have also the ability to target such disease modifying mechanisms. Thus, cell therapies can simultaneously provide causal treatment and symptomatic relief, and accordingly hold great potential for treatment of BM-linked disorders. However, this potential has for most applications and diseases so far not been realized. Here, we will present the state of cell therapies for BM-linked diseases. We will discuss use of both pluripotent and differentiated cells, the limitation of the approaches, their challenges, and the way forward to potential wider implementation of cell therapies in the clinics. Copyright © 2016 Elsevier B.V. All rights reserved.

Mesenchymal Stem Cells as a Source of Dopaminergic Neurons: A Potential Cell Based Therapy for Parkinson's Disease.

PubMed

Venkatesh, Katari; Sen, Dwaipayan

2017-01-01

Cell repair/replacing strategies for neurodegenerative diseases such as Parkinson's disease depend on well-characterized dopaminergic neuronal candidates that are healthy and show promising effect on the rejuvenation of degenerated area of the brain. Therefore, it is imperative to develop innovative therapeutic strategies that replace damaged neurons with new/functional dopaminergic neurons. Although several research groups have reported the generation of neural precursors/neurons from human/ mouse embryonic stem cells and mesenchymal stem cells, the latter is considered to be an attractive therapeutic candidate because of its high capacity for self-renewable, no adverse effect to allogeneic versus autologous transplants, high ethical acceptance and no teratoma formation. Therefore, mesenchymal stem cells can be considered as an ideal source for replacing lost cells in degenerative diseases like Parkinson's. Hence, the use of these cells in the differentiation of dopaminergic neurons becomes significant and thrives as a therapeutic approach to treat Parkinson's disease. Here we highlight the basic biology of mesenchymal stem cells, their differentiation potential into dopaminergic neurons and potential use in the clinics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Epstein–Barr virus-positive T/NK-cell lymphoproliferative disorders

PubMed Central

Cai, Qingqing; Chen, Kailin; Young, Ken H

2015-01-01

Epstein–Barr virus, a ubiquitous human herpesvirus, can induce both lytic and latent infections that result in a variety of human diseases, including lymphoproliferative disorders. The oncogenic potential of Epstein–Barr virus is related to its ability to infect and transform B lymphocytes into continuously proliferating lymphoblastoid cells. However, Epstein–Barr virus has also been implicated in the development of T/natural killer cell lymphoproliferative diseases. Epstein–Barr virus encodes a series of products that mimic several growth, transcription and anti-apoptotic factors, thus usurping control of pathways that regulate diverse homeostatic cellular functions and the microenvironment. However, the exact mechanism by which Epstein–Barr virus promotes oncogenesis and inflammatory lesion development remains unclear. Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases often have overlapping clinical symptoms as well as histologic and immunophenotypic features because both lymphoid cell types derive from a common precursor. Accurate classification of Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases is a prerequisite for appropriate clinical management. Currently, the treatment of most T/natural killer cell lymphoproliferative diseases is less than satisfactory. Novel and targeted therapies are strongly required to satisfy clinical demands. This review describes our current knowledge of the genetics, oncogenesis, biology, diagnosis and treatment of Epstein–Barr virus-associated T/natural killer cell lymphoproliferative diseases. PMID:25613730

Skin Diseases: Skin Health and Skin Diseases

MedlinePlus

... The two most common types are basal cell cancer and squamous cell cancer. Melanoma, a more serious type of skin ... The two most common types are basal cell cancer and squamous cell cancer. They usually form on the head, face, ...

ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age-Related Diseases

PubMed Central

Davalli, Pierpaola; Mitic, Tijana; Caporali, Andrea; Lauriola, Angela; D'Arca, Domenico

2016-01-01

The aging process worsens the human body functions at multiple levels, thus causing its gradual decrease to resist stress, damage, and disease. Besides changes in gene expression and metabolic control, the aging rate has been associated with the production of high levels of Reactive Oxygen Species (ROS) and/or Reactive Nitrosative Species (RNS). Specific increases of ROS level have been demonstrated as potentially critical for induction and maintenance of cell senescence process. Causal connection between ROS, aging, age-related pathologies, and cell senescence is studied intensely. Senescent cells have been proposed as a target for interventions to delay the aging and its related diseases or to improve the diseases treatment. Therapeutic interventions towards senescent cells might allow restoring the health and curing the diseases that share basal processes, rather than curing each disease in separate and symptomatic way. Here, we review observations on ROS ability of inducing cell senescence through novel mechanisms that underpin aging processes. Particular emphasis is addressed to the novel mechanisms of ROS involvement in epigenetic regulation of cell senescence and aging, with the aim to individuate specific pathways, which might promote healthy lifespan and improve aging. PMID:27247702

Early induction of c-Myc is associated with neuronal cell death.

PubMed

Lee, Hyun-Pil; Kudo, Wataru; Zhu, Xiongwei; Smith, Mark A; Lee, Hyoung-gon

2011-11-14

Neuronal cell cycle activation has been implicated in neurodegenerative diseases such as Alzheimer's disease, while the initiating mechanism of cell cycle activation remains to be determined. Interestingly, our previous studies have shown that cell cycle activation by c-Myc (Myc) leads to neuronal cell death which suggests Myc might be a key regulator of cell cycle re-entry mediated neuronal cell death. However, the pattern of Myc expression in the process of neuronal cell death has not been addressed. To this end, we examined Myc induction by the neurotoxic agents camptothecin and amyloid-β peptide in a differentiated SH-SY5Y neuronal cell culture model. Myc expression was found to be significantly increased following either treatment and importantly, the induction of Myc preceded neuronal cell death suggesting it is an early event of neuronal cell death. Since ectopic expression of Myc in neurons causes the cell cycle activation and neurodegeneration in vivo, the current data suggest that induction of Myc by neurotoxic agents or other disease factors might be a key mediator in cell cycle activation and consequent cell death that is a feature of neurodegenerative diseases. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemokines and skin diseases.

PubMed

Sugaya, Makoto

2015-04-01

Chemokines are small molecules that induce chemotaxis and activation of certain subsets of leukocytes. The expression patterns of chemokines and chemokine receptors are specific to certain organs and cells. Therefore, chemokines are important to elucidate the mechanism of organ-specific human diseases. CCL17 expressed by Langerhans cells, blood endothelial cells, and fibroblasts plays a key role in attracting Th2 cells and tumor cells of adult T-cell leukemia/lymphoma and mycosis fungoides/Sézary syndrome into the skin, developing various Th2-type inflammatory skin diseases as well as cutaneous lymphoma. CCL11 and CCL26 expressed by skin-resident cells, such as fibroblasts, blood endothelial cells, and keratinocytes, induce infiltration of CCR3-expressing cells such as Th2 cells and eosinophils. CCL11 may also serve as an autocrine as well as a paracrine in anaplastic large cell lymphoma. CX3CL1 expressed on blood endothelial cells leads to infiltration of CX3CR1(+) immune cells, such as mast cells, neutrophils, and macrophages, playing important roles in wound healing, tumor immunity, and vasculitis. Biologics targeting chemokines and their receptors are promising strategies for various skin diseases that are resistant to the current therapy.

Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model

PubMed Central

Kobari, Ladan; Yates, Frank; Oudrhiri, Noufissa; Francina, Alain; Kiger, Laurent; Mazurier, Christelle; Rouzbeh, Shaghayegh; El-Nemer, Wassim; Hebert, Nicolas; Giarratana, Marie-Catherine; François, Sabine; Chapel, Alain; Lapillonne, Hélène; Luton, Dominique; Bennaceur-Griscelli, Annelise; Douay, Luc

2012-01-01

Background Human induced pluripotent stem cells offer perspectives for cell therapy and research models for diseases. We applied this approach to the normal and pathological erythroid differentiation model by establishing induced pluripotent stem cells from normal and homozygous sickle cell disease donors. Design and Methods We addressed the question as to whether these cells can reach complete erythroid terminal maturation notably with a complete switch from fetal to adult hemoglobin. Sickle cell disease induced pluripotent stem cells were differentiated in vitro into red blood cells and characterized for their terminal maturation in terms of hemoglobin content, oxygen transport capacity, deformability, sickling and adherence. Nucleated erythroblast populations generated from normal and pathological induced pluripotent stem cells were then injected into non-obese diabetic severe combined immunodeficiency mice to follow the in vivo hemoglobin maturation. Results We observed that in vitro erythroid differentiation results in predominance of fetal hemoglobin which rescues the functionality of red blood cells in the pathological model of sickle cell disease. We observed, in vivo, the switch from fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from either normal or pathological induced pluripotent stem cells into mice. Conclusions These results demonstrate that human induced pluripotent stem cells: i) can achieve complete terminal erythroid maturation, in vitro in terms of nucleus expulsion and in vivo in terms of hemoglobin maturation; and ii) open the way to generation of functionally corrected red blood cells from sickle cell disease induced pluripotent stem cells, without any genetic modification or drug treatment. PMID:22733021

Extracellular cell stress (heat shock) proteins-immune responses and disease: an overview.

PubMed

Pockley, A Graham; Henderson, Brian

2018-01-19

Extracellular cell stress proteins are highly conserved phylogenetically and have been shown to act as powerful signalling agonists and receptors for selected ligands in several different settings. They also act as immunostimulatory 'danger signals' for the innate and adaptive immune systems. Other studies have shown that cell stress proteins and the induction of immune reactivity to self-cell stress proteins can attenuate disease processes. Some proteins (e.g. Hsp60, Hsp70, gp96) exhibit both inflammatory and anti-inflammatory properties, depending on the context in which they encounter responding immune cells. The burgeoning literature reporting the presence of stress proteins in a range of biological fluids in healthy individuals/non-diseased settings, the association of extracellular stress protein levels with a plethora of clinical and pathological conditions and the selective expression of a membrane form of Hsp70 on cancer cells now supports the concept that extracellular cell stress proteins are involved in maintaining/regulating organismal homeostasis and in disease processes and phenotype. Cell stress proteins, therefore, form a biologically complex extracellular cell stress protein network having diverse biological, homeostatic and immunomodulatory properties, the understanding of which offers exciting opportunities for delivering novel approaches to predict, identify, diagnose, manage and treat disease.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'. © 2017 The Author(s).

Cation Homeostasis in Red Cells From Patients With Sickle Cell Disease Heterologous for HbS and HbC (HbSC Genotype)

PubMed Central

Hannemann, A.; Rees, D.C.; Tewari, S.; Gibson, J.S.

2015-01-01

Sickle cell disease (SCD) in patients of HbSC genotype is considered similar, albeit milder, to that in homozygous HbSS individuals — but with little justification. In SCD, elevated red cell cation permeability is critical as increased solute loss causes dehydration and encourages sickling. Recently, we showed that the KCl cotransporter (KCC) activity in red cells from HbSC patients correlated significantly with disease severity, but that in HbSS patients did not. Two transporters involved in red cell dehydration, the conductive channels Psickle and the Gardos channel, behaved similarly in red cells from the two genotypes, but were significantly less active in HbSC patients. By contrast, KCC activity was quantitatively greater in HbSC red cells. Results suggest that KCC is likely to have greater involvement in red cell dehydration in HbSC patients, which could explain its association with disease severity in this genotype. This work supports the hypothesis that SCD in HbSC patients is a distinct disease entity to that in HbSS patients. Results suggest the possibility of designing specific treatments of particular benefit to HbSC patients and a rationale for the development of prognostic markers, to inform early treatment of children likely to develop more severe complications of the disease. PMID:26870793

Characterisation of an epigenetically altered CD4+ CD28+ Kir+ T cell subset in autoimmune rheumatic diseases by multiparameter flow cytometry

PubMed Central

Strickland, Faith M; Patel, Dipak; Somers, Emily; Robida, Aaron M; Pihalja, Michael; Swartz, Richard; Marder, Wendy; Richardson, Bruce

2016-01-01

Objectives Antigen-specific CD4+ T cells epigenetically modified with DNA methylation inhibitors overexpress genes normally suppressed by this mechanism, including CD11a, CD70, CD40L and the KIR gene family. The altered cells become autoreactive, losing restriction for nominal antigen and responding to self-class II major histocompatibility complex (MHC) molecules without added antigen, and are sufficient to cause a lupus-like disease in syngeneic mice. T cells overexpressing the same genes are found in patients with active lupus. Whether these genes are co-overexpressed on the same or different cells is unknown. The goal of this study was to determine whether these genes are overexpressed on the same or different T cells and whether this subset of CD4+ T cells is also present in patients with lupus and other rheumatic diseases. Methods Multicolour flow cytometry was used to compare CD11a, CD70, CD40L and KIR expression on CD3+CD4+CD28+ T cells to their expression on experimentally demethylated CD3+CD4+CD28+ T cells and CD3+CD4+CD28+ T cells from patients with active lupus and other autoimmune diseases. Results Experimentally demethylated CD4+ T cells and T cells from patients with active lupus have a CD3+CD4+CD28+CD11ahiCD70+CD40LhiKIR+ subset, and the subset size is proportional to lupus flare severity. A similar subset is found in patients with other rheumatic diseases including rheumatoid arthritis, systemic sclerosis and Sjögren's syndrome but not retroperitoneal fibrosis. Conclusions Patients with active autoimmune rheumatic diseases have a previously undescribed CD3+CD4+CD28+CD11ahiCD70+CD40LhiKIR+ T cell subset. This subset may play an important role in flares of lupus and related autoimmune rheumatic diseases, provide a biomarker for disease activity and serve as a novel therapeutic target for the treatment of lupus flares. PMID:27099767

Altered peripheral profile of blood cells in Alzheimer disease

PubMed Central

Chen, Si-Han; Bu, Xian-Le; Jin, Wang-Sheng; Shen, Lin-Lin; Wang, Jun; Zhuang, Zheng-Qian; Zhang, Tao; Zeng, Fan; Yao, Xiu-Qing; Zhou, Hua-Dong; Wang, Yan-Jiang

2017-01-01

Abstract Alzheimer disease (AD) has been made a global priority for its multifactorial pathogenesis and lack of disease-modifying therapies. We sought to investigate the changes of profile of blood routine in AD and its correlation with the disease severity. In all, 92 AD patients and 84 age and sex-matched normal controls were enrolled and their profiles of blood routine were evaluated. Alzheimer disease patients had increased levels of mean corpuscular hemoglobin, mean corpuscular volume, red cell distribution width-standard deviation, mean platelet volume,and decreased levels of platelet distribution width, red blood cell, hematocrit, hemoglobin, lymphocyte, and basophil compared with normal controls. Alterations in quantity and quality of blood cells may be involved in the pathogenesis of AD and contribute to the disease progression. PMID:28538375

Sickle Cell Disease (For Teens)

MedlinePlus

... help relieve the pain of sickle cell crises. Penicillin or other antibiotics can help prevent infections, though doctors usually stop giving penicillin to kids who have sickle cell disease after ...

Clonal analysis of stem cells in differentiation and disease.

PubMed

Colom, Bartomeu; Jones, Philip H

2016-12-01

Tracking the fate of individual cells and their progeny by clonal analysis has redefined the concept of stem cells and their role in health and disease. The maintenance of cell turnover in adult tissues is achieved by the collective action of populations of stem cells with an equal likelihood of self-renewal or differentiation. Following injury stem cells exhibit striking plasticity, switching from homeostatic behavior in order to repair damaged tissues. The effects of disease states on stem cells are also being uncovered, with new insights into how somatic mutations trigger clonal expansion in early neoplasia. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

The molecular mechanism of serum microRNA124b induced coronary heart disease by inducing myocardial cell senescence.

PubMed

Guo, M-L; Guo, L-L; Qin, Q-J; Weng, Y-Q; Wang, Y-N; Yao, J; Wang, Y-B; Zhang, X-Z; Ge, Z-M

2018-04-01

The incidence and mortality of coronary heart disease are rapidly increasing in recent years. Myocardial cell dysfunction and cell senescence may play a role in coronary heart disease. MicroRNA controls a variety of biological processes, but leaving its role in coronary heart disease has yet to be explored. Patients with coronary heart disease were regarded as subjects, and healthy volunteers as the control, on both of which microRNA124b level of serum was studied by Real-time PCR, and the heart function of patients was detected by using ultrasound. The relationship between serum microRNA124b level and cardiac function was analyzed along with the model of rat coronary artery disease; the level of aging proteins P21 and P53 in cardiac muscle cells was also tested. MicroRNA124b in the serum of patients with coronary heart disease was increased, and the heart function of patients was decreased (p < 0.05). Serum level of microRNA124b in a rat model of coronary heart disease was increased, and the cardiac function was decreased (p < 0.05). When myocardial cell appeared ageing, the level of P21 and P53 was increased, and the level of microRNA124b was related with P53. The level of microRNA124b in the serum of coronary heart disease patients and rat model may be related to the occurrence of coronary heart disease; microRNA124b may lead to the occurrence of coronary heart disease by causing cell senescence.

ADH1B promotes mesothelial clearance and ovarian cancer infiltration.

PubMed

Gharpure, Kshipra M; Lara, Olivia D; Wen, Yunfei; Pradeep, Sunila; LaFargue, Chris; Ivan, Cristina; Rupaimoole, Rajesha; Hu, Wei; Mangala, Lingegowda S; Wu, Sherry Y; Nagaraja, Archana S; Baggerly, Keith; Sood, Anil K

2018-05-18

Primary debulking surgery followed by adjuvant chemotherapy is the standard treatment for ovarian cancer. Residual disease after primary surgery is associated with poor patient outcome. Previously, we discovered ADH1B to be a molecular biomarker of residual disease. In the current study, we investigated the functional role of ADH1B in promoting ovarian cancer cell invasiveness and contributing to residual disease. We discovered that ADH1B overexpression leads to a more infiltrative cancer cell phenotype, promotes metastasis, increases the adhesion of cancer cells to mesothelial cells, and increases extracellular matrix degradation. Live cell imaging revealed that ADH1B-overexpressing cancer cells efficiently cleared the mesothelial cell layer compared to control cells. Moreover, gene array analysis revealed that ADH1B affects several pathways related to the migration and invasion of cancer cells. We also discovered that hypoxia increases ADH1B expression in ovarian cancer cells. Collectively, these findings indicate that ADH1B plays an important role in the pathways that promote ovarian cancer cell infiltration and may increase the likelihood of residual disease following surgery.

Apoptosis and Vocal Fold Disease: Clinically Relevant Implications of Epithelial Cell Death

ERIC Educational Resources Information Center

Novaleski, Carolyn K.; Carter, Bruce D.; Sivasankar, M. Preeti; Ridner, Sheila H.; Dietrich, Mary S.; Rousseau, Bernard

2017-01-01

Purpose: Vocal fold diseases affecting the epithelium have a detrimental impact on vocal function. This review article provides an overview of apoptosis, the most commonly studied type of programmed cell death. Because apoptosis can damage epithelial cells, this article examines the implications of apoptosis on diseases affecting the vocal fold…

Management of sickle cell disease in patients undergoing cardiac surgery.

PubMed

Crawford, Todd C; Carter, Michael V; Patel, Rina K; Suarez-Pierre, Alejandro; Lin, Sophie Z; Magruder, Jonathan Trent; Grimm, Joshua C; Cameron, Duke E; Baumgartner, William A; Mandal, Kaushik

2017-02-01

Sickle cell disease is a life-limiting inherited hemoglobinopathy that poses inherent risk for surgical complications following cardiac operations. In this review, we discuss preoperative considerations, intraoperative decision-making, and postoperative strategies to optimize the care of a patient with sickle cell disease undergoing cardiac surgery. © 2017 Wiley Periodicals, Inc.

Human T-Cell Clones from Autoimmune Thyroid Glands: Specific Recognition of Autologous Thyroid Cells

NASA Astrophysics Data System (ADS)

Londei, Marco; Bottazzo, G. Franco; Feldmann, Marc

1985-04-01

The thyroid glands of patients with autoimmune diseases such as Graves' disease and certain forms of goiter contain infiltrating activated T lymphocytes and, unlike cells of normal glands, the epithelial follicular cells strongly express histocompatability antigens of the HLA-DR type. In a study of such autoimmune disorders, the infiltrating T cells from the thyroid glands of two patients with Graves' disease were cloned in mitogen-free interleukin-2 (T-cell growth factor). The clones were expanded and their specificity was tested. Three types of clones were found. One group, of T4 phenotype, specifically recognized autologous thyroid cells. Another, also of T4 phenotype, recognized autologous thyroid or blood cells and thus responded positively in the autologous mixed lymphocyte reaction. Other clones derived from cells that were activated in vivo were of no known specificity. These clones provide a model of a human autoimmune disease and their analysis should clarify mechanisms of pathogenesis and provide clues to abrogating these undesirable immune responses.

[TNF-α, diabetes type 1 and regulatory T cells].

PubMed

Ryba, Monika; Myśliwska, Jolanta

2010-01-01

Recent studies on animal models of diabetes as well as human regulatory T cells have shown that α impairs the ability of these cells to prevent the disease. NOD mice treated with α had decreased frequency of regulatory T cells, whereas anti-TNF administration induced the increase in the number of these cells and disease prevention. The action of α also influenced the suppressive potential of Tregs. Increased susceptibility of Tregs to the modulatory effects of α involves signaling through TNFR2 that is expressed on the surface of this cell population. It seems that α neutralization may rescue regulatory T cells and restore their function in several autoimmune and inflammatory diseases. This review describes recent data concerning regulatory T cells in the context of inflammation that is present during diabetes type 1. It describes how TNF contributes to the pathogenesis of type 1 diabetes, what is the impact of this cytokine on regulatory T cell population and therapeutic effects that result from its neutralization in several inflammatory and autoimmune diseases.

Cell mechanics as a marker for diseases: Biomedical applications of AFM

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rianna, Carmela; Radmacher, Manfred, E-mail: mr@biophysik.uni-bremen.de

Many diseases are related to changes in cell mechanics. Atomic Force Microscopy (AFM) is one of the most suitable techniques allowing the investigation of both topography and mechanical properties of adherent cells with high spatial resolution under physiological conditions. Over the years the use of this technique in medical and clinical applications has largely increased, resulting in the notion of cell mechanics as a biomarker to discriminate between different physiological and pathological states of cells. Cell mechanics has proven to be a biophysical fingerprint able discerning between cell phenotypes, unraveling processes in aging or diseases, or even detecting and diagnosingmore » cellular pathologies. We will review in this report some of the works on cell mechanics investigated by AFM with clinical and medical relevance in order to clarify the state of research in this field and to highlight the role of cell mechanics in the study of pathologies, focusing on cancer, blood and cardiovascular diseases.« less

Systematic Epstein-Barr virus-positive T-cell lymphoproliferative disease presenting as a persistent fever and cough: a case report.

PubMed

Ameli, Fereshteh; Ghafourian, Firouzeh; Masir, Noraidah

2014-08-27

Systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is an extremely rare disorder and classically arises following primary acute or chronic active Epstein-Barr virus infection. It is characterized by clonal proliferation of Epstein-Barr virus-infected T-cells with an activated cytotoxic phenotype. This disease has a rapid clinical course and is more frequent in Asia and South America, with relatively few cases being reported in Western countries. The clinical and pathological features of the disease overlap with other conditions including infectious mononucleosis, chronic active Epstein-Barr virus infection, hemophagocytic lymphohistiocytosis and natural killer cell malignancies. We describe the rare case of systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease in a 16-year-old Malay boy. He presented with a six-month history of fever and cough, with pulmonary and mediastinal lymphadenopathy and severe pancytopenia. Medium- to large-sized, CD8+ and Epstein-Barr virus-encoded RNA-positive atypical lymphoid cells were present in the bone marrow aspirate. He subsequently developed fatal virus-associated hemophagocytic syndrome and died due to sepsis and multiorgan failure. Although systemic Epstein-Barr virus-positive T-cell lymphoproliferative childhood disease is a disorder which is rarely encountered in clinical practice, our case report underlines the importance of a comprehensive diagnostic approach in the management of this disease. A high level of awareness of the disease throughout the diagnosis process for young patients who present with systemic illness and hemophagocytic syndrome may be of great help for the clinical diagnosis of this disease.

Immunomodulatory activity of interleukin-27 in human chronic periapical diseases.

PubMed

Li, Juan; Wang, Rong; Huang, Shi-Guang

2017-01-01

This study aims to observe expression of IL-27 on different cells in periapical tissues of different types of human chronic periapical diseases. Periapical tissue specimens of 60 donors, including healthy control (n=20), periapical granuloma group (n=20) and radicular cysts group (n=20), were fixed in 10% buffered formalin, stained with hematoxylin and eosin for histopathology. Then specimens were stained with double- immuno-fluorescence assay for identification of IL-27-tryptase (mast cells, MCs), IL-27-CD14 (mononuclear phagocyte cells, MPs) and IL-27-CD31 (endothelial cells, ECs) double-positive cells in periapical tissues. The results indicated that compared with healthy control, the densities (cells/mm 2 ) of IL-27-tryptase, IL-27-CD14 and IL-27-CD31 double-positive cells were significantly increased in human chronic periapical diseases (periapical granuloma group and radicular cysts group) ( P <0.001). The density of IL-27-tryptase double positive cells in radicular cysts group was significantly higher than those in periapical granuloma group ( P <0.001). Densities of IL-27-CD14 and IL-27-CD31 double-positive cells in periapical granuloma group had no significant difference with those in radicular cysts group ( P =0.170 and 0.138, respectively). IL-27-CD14 double positive cells density achieved to peak among three cell groups in radicular cysts groups. In conclusion, IL-27 expressed in MCs, MPs and ECs of human chronic periapical diseases with different degrees. IL-27-tryptase double-positive cells may participate in pathogenic mechanism of chronic periapical diseases, especially for formation of fibrous in periapical cysts. IL-27-CD14 and IL-27-CD31 double-positive cells may participate in immunologic response to resist periapical infection, and they may play an dual role in pathogenesis and localization of periapical diseases.

Awareness of Sickle Cell Trait Status: A Cross-Sectional Survey of Antenatal Women in Ghana.

PubMed

Obed, Samuel Amenyi; Asah-Opoku, Kwaku; Aboagye, Serwah; Torto, Magdalene; Oppong, Samuel Antwi; Nuamah, Mercy Anna

2017-03-01

AbstractThis study was conducted to evaluate pregnant women's awareness of sickle cell disease and sickle cell trait and the factors that contribute to it. Two hundred and six pregnant women with at least 20 weeks gestation answered a questionnaire regarding awareness of their trait status and questions to test their knowledge of sickle cell disease. Although the majority of patients were aware of their trait status (87.4%), only 29% of knowledge questions were answered correctly; patients who self-identified as having sickle cell trait did not do better. Patients who responded that they knew a good deal about sickle cell disease scored an average of 3.5 points (number of correct responses to nine questions) more than individuals who responded that they knew nothing ( P < 0.001). Individuals who knew they had been tested for the sickle cell trait scored approximately 2 points higher than those who did not know whether they had been tested ( P = 0.004). Respondents with at least secondary education scored on average 1 point higher on the knowledge test than those with less education ( P = 0.004). Knowing someone with sickle cell disease was associated with a mean score of 1.25 points higher than individuals who did not know any affected individual ( P = 0.000).There is a deficit in the knowledge of sickle cell disease among Ghanaian pregnant women. Therefore, there is the need for public education on sickle cell disease.

Temporal transcriptome changes induced by MDV in Marek's disease-resistant and -susceptible inbred chickens

USDA-ARS?s Scientific Manuscript database

Mareks disease (MD) is a lymphoproliferative disease in chickens caused by Marek's disease virus (MDV) and characterized by T cell lymphoma and infiltration of lymphoid cells into various organs such as liver, spleen, peripheral nerves and muscle. Resistance to MD and disease risk have long been tho...

Blood Disorders

MedlinePlus

... become hard, sticky, and shaped like a C. Thalassemia Red blood cell disorder. Von Willebrand Disease Blood ... Hemophilia Hereditary Hemorrhagic Telangiectasia (HHT) Sickle Cell Disease Thalassemia Vitamin K Deficiency Bleeding Von Willebrand Disease Women’s ...

Sickle Cell Disease with Cyanotic Congenital Heart Disease: Long-Term Outcomes in 5 Children.

PubMed

Iannucci, Glen J; Adisa, Olufolake A; Oster, Matthew E; McConnell, Michael; Mahle, William T

2016-12-01

Sickle cell disease is a risk factor for cerebrovascular accidents in the pediatric population. This risk is compounded by hypoxemia. Cyanotic congenital heart disease can expose patients to prolonged hypoxemia. To our knowledge, the long-term outcome of patients who have combined sickle cell and cyanotic congenital heart disease has not been reported. We retrospectively reviewed patient records at our institution and identified 5 patients (3 girls and 2 boys) who had both conditions. Their outcomes were uniformly poor: 4 died (age range, 12 mo-17 yr); 3 had documented cerebrovascular accidents; and 3 developed ventricular dysfunction. The surviving patient had developmental delays. On the basis of this series, we suggest mitigating hypoxemia, and thus the risk of stroke, in patients who have sickle cell disease and cyanotic congenital heart disease. Potential therapies include chronic blood transfusions, hydroxyurea, earlier surgical correction to reduce the duration of hypoxemia, and heart or bone marrow transplantation.

Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept.

PubMed

Altieri, Barbara; Muscogiuri, Giovanna; Barrea, Luigi; Mathieu, Chantal; Vallone, Carla V; Mascitelli, Luca; Bizzaro, Giorgia; Altieri, Vincenzo M; Tirabassi, Giacomo; Balercia, Giancarlo; Savastano, Silvia; Bizzaro, Nicola; Ronchi, Cristina L; Colao, Annamaria; Pontecorvi, Alfredo; Della Casa, Silvia

2017-09-01

In the last few years, more attention has been given to the "non-calcemic" effect of vitamin D. Several observational studies and meta-analyses demonstrated an association between circulating levels of vitamin D and outcome of many common diseases, including endocrine diseases, chronic diseases, cancer progression, and autoimmune diseases. In particular, cells of the immune system (B cells, T cells, and antigen presenting cells), due to the expression of 1α-hydroxylase (CYP27B1), are able to synthesize the active metabolite of vitamin D, which shows immunomodulatory properties. Moreover, the expression of the vitamin D receptor (VDR) in these cells suggests a local action of vitamin D in the immune response. These findings are supported by the correlation between the polymorphisms of the VDR or the CYP27B1 gene and the pathogenesis of several autoimmune diseases. Currently, the optimal plasma 25-hydroxyvitamin D concentration that is necessary to prevent or treat autoimmune diseases is still under debate. However, experimental studies in humans have suggested beneficial effects of vitamin D supplementation in reducing the severity of disease activity. In this review, we summarize the evidence regarding the role of vitamin D in the pathogenesis of autoimmune endocrine diseases, including type 1 diabetes mellitus, Addison's disease, Hashimoto's thyroiditis, Graves' disease and autoimmune polyendocrine syndromes. Furthermore, we discuss the supplementation with vitamin D to prevent or treat autoimmune diseases.

Unusual causes of abdominal pain: sickle cell anemia.

PubMed

Ahmed, Shahid; Shahid, Rabia K; Russo, Linda A

2005-04-01

Sickle cell disease is characterized by chronic hemolytic anemia and vaso-occlusive painful crises. The vascular occlusion in sickle cell disease is a complex process and accounts for the majority of the clinical manifestation of the disease. Abdominal pain is an important component of vaso-occlusive painful crises. It often represents a substantial diagnostic challenge in this population of patients. These episodes are often attributed to micro-vessel occlusion and infarcts of mesentery and abdominal viscera. Abdominal pain due to sickle cell vaso-occlusive crisis is often indistinguishable from an acute intra-abdominal disease process such as acute cholecystitis, acute pancreatitis, hepatic infarction, ischemic colitis and acute appendicitis. In the majority of cases, however, no specific cause is identified and spontaneous resolution occurs. This chapter will focus on etiologies, pathophysiology and management of abdominal pain in patients with sickle cell disease.

Stem cells in retinal regeneration: past, present and future.

PubMed

Ramsden, Conor M; Powner, Michael B; Carr, Amanda-Jayne F; Smart, Matthew J K; da Cruz, Lyndon; Coffey, Peter J

2013-06-01

Stem cell therapy for retinal disease is under way, and several clinical trials are currently recruiting. These trials use human embryonic, foetal and umbilical cord tissue-derived stem cells and bone marrow-derived stem cells to treat visual disorders such as age-related macular degeneration, Stargardt's disease and retinitis pigmentosa. Over a decade of analysing the developmental cues involved in retinal generation and stem cell biology, coupled with extensive surgical research, have yielded differing cellular approaches to tackle these retinopathies. Here, we review these various stem cell-based approaches for treating retinal diseases and discuss future directions and challenges for the field.

New Perspective on Dextran Sodium Sulfate Colitis: Antigen-Specific T Cell Development during Intestinal Inflammation

PubMed Central

Morgan, Mary E.; Zheng, Bin; Koelink, Pim J.; van de Kant, Hendrick J. G.; Haazen, Lizette C. J. M.; van Roest, Manon; Garssen, Johan; Folkerts, Gert; Kraneveld, Aletta D.

2013-01-01

CD4+ T cell responses against oral antigens can develop in inflammatory bowel disease (IBD) patients, which may modulate disease. Dextran sodium sulfate (DSS) colitis is commonly used to study IBD, however, it is not considered the best model in which to study T cell involvement in intestinal disease. Our aim was to determine if antigen-specific T cells could be induced during DSS colitis and if they could be detected after disease resolution. To induce antigen-specific T cells, the tracking antigen, ovalbumin (OVA), was administered orally during colitis initiation. Disease severity was monitored, and the antigen-reactivity of CD4+ T cells examined using CD69 expression. While OVA-directed, CD4+ Foxp3+ regulatory T cells could be detected in the spleens of both OVA-treated control and DSS mice, OVA-reactive, CD4+ Foxp3-T cells were only found in the OVA and DSS-treated mice. These results indicate that during DSS colitis T cells develop that are specific against oral antigens, and they are found systemically after colitis resolution. This gives added depth and utility to the DSS model as well as a way to track T cells that are primed against luminal antigens. PMID:23936123

Autologous mesenchymal stem cell treatment increased T regulatory cells with no effect on disease activity in two systemic lupus erythematosus patients.

PubMed

Carrion, F; Nova, E; Ruiz, C; Diaz, F; Inostroza, C; Rojo, D; Mönckeberg, G; Figueroa, F E

2010-03-01

Mesenchymal stem cells (MSCs) exert suppressive effects in several disease models including lupus prone mice. However, autologous MSC therapy has not been tested in human systemic lupus erythematosus (SLE). We evaluate the safety and efficacy of bone marrow (BM)-derived MSCs in two SLE patients; the suppressor effect of these cells in-vitro and the change in CD4+CD25+FoxP3+ T regulatory (Treg) cells in response to treatment. Two females (JQ and SA) of 19 and 25 years of age, fulfilling the 1997 American College of Rheumatology (ACR) criteria for SLE were infused with autologous BM-derived MSCs. Disease activity indexes and immunological parameters were assessed at baseline, 1, 2, 7 and 14 weeks. Peripheral blood lymphocyte (PBL) subsets and Treg cells were quantitated by flow cytometry, and MSCs tested for in-vitro suppression of activation and proliferation of normal PBLs. No adverse effects or change in disease activity indexes were noted during 14 weeks of follow-up, although circulating Treg cells increased markedly. Patient MSCs effectively suppressed in-vitro PBL function. However, JQ developed overt renal disease 4 months after infusion. MSC infusion was without adverse effects, but did not modify initial disease activity in spite of increasing CD4+CD25+FoxP3+ cell counts. One patient subsequently had a renal flare. We speculate that the suppressive effects of MSC-induced Treg cells might be dependent on a more inflammatory milieu, becoming clinically evident in patients with higher degrees of disease activity.

Reprint of "iPSCs, aging and age-related diseases".

PubMed

Isobe, Ken-ichi; Cheng, Zhao; Nishio, Naomi; Suganya, Thanasegan; Tanaka, Yuriko; Ito, Sachiko

2015-01-25

Human histocompatibility antigens are quite heterogeneous and promote the rejection of transplanted tissue. Recent advances in stem cell research that enable the use of a patient's own stem cells for transplantation are very important because rejection could be avoided. In particular, Yamanaka’s group in Japan gave new hope to patients with incurable diseases when they developed induced murine pluripotent stem cells (iPSCs) in 2006 and human iPSCs in 2007. Whereas embryonic stem cells (ESCs) are derived from the inner cell mass and are supported in culture by LIF, iPSCs are derived from fetal or adult somatic cells. Through the application of iPSC technology, adult somatic cells can develop a pluripotent state. One advantage of using iPSCs instead of ESCs in regenerative medicine is that (theoretically) immune rejection could be avoided, although there is some debate about immune rejection of a patient's own iPSCs. Many diseases occur in elderly patients. In order to use regenerative medicine with the elderly, it is important to demonstrate that iPSCs can indeed be generated from older patients. Recent findings have shown that iPSCs can be established from aged mice and aged humans. These iPSCs can differentiate to cells from all three germ layers. However, it is not known whether iPSCs from aged mice or humans show early senescence. Before clinical use of iPSCs, issues related to copy number variation, tumorigenicity and immunogenicity must be resolved. It is particularly important that researchers have succeeded in generating iPSCs that have differentiated to somatic cells related to specific diseases of the elderly, including atherosclerosis, diabetes, Alzheimer's disease and Parkinson's disease. These efforts will facilitate the use of personalized stem cell transplantation therapy for currently incurable diseases.

iPSCs, aging and age-related diseases.

PubMed

Isobe, Ken-Ichi; Cheng, Zhao; Nishio, Naomi; Suganya, Thanasegan; Tanaka, Yuriko; Ito, Sachiko

2014-09-25

Human histocompatibility antigens are quite heterogeneous and promote the rejection of transplanted tissue. Recent advances in stem cell research that enable the use of a patient's own stem cells for transplantation are very important because rejection could be avoided. In particular, Yamanaka's group in Japan gave new hope to patients with incurable diseases when they developed induced murine pluripotent stem cells (iPSCs) in 2006 and human iPSCs in 2007. Whereas embryonic stem cells (ESCs) are derived from the inner cell mass and are supported in culture by LIF, iPSCs are derived from fetal or adult somatic cells. Through the application of iPSC technology, adult somatic cells can develop a pluripotent state. One advantage of using iPSCs instead of ESCs in regenerative medicine is that (theoretically) immune rejection could be avoided, although there is some debate about immune rejection of a patient's own iPSCs. Many diseases occur in elderly patients. In order to use regenerative medicine with the elderly, it is important to demonstrate that iPSCs can indeed be generated from older patients. Recent findings have shown that iPSCs can be established from aged mice and aged humans. These iPSCs can differentiate to cells from all three germ layers. However, it is not known whether iPSCs from aged mice or humans show early senescence. Before clinical use of iPSCs, issues related to copy number variation, tumorigenicity and immunogenicity must be resolved. It is particularly important that researchers have succeeded in generating iPSCs that have differentiated to somatic cells related to specific diseases of the elderly, including atherosclerosis, diabetes, Alzheimer's disease and Parkinson's disease. These efforts will facilitate the use of personalized stem cell transplantation therapy for currently incurable diseases. Copyright © 2014 Elsevier B.V. All rights reserved.

Switched Memory B Cells Are Increased in Oligoarticular and Polyarticular Juvenile Idiopathic Arthritis and Their Change Over Time Is Related to Response to Tumor Necrosis Factor Inhibitors.

PubMed

Marasco, Emiliano; Aquilani, Angela; Cascioli, Simona; Moneta, Gian Marco; Caiello, Ivan; Farroni, Chiara; Giorda, Ezio; D'Oria, Valentina; Marafon, Denise Pires; Magni-Manzoni, Silvia; Carsetti, Rita; De Benedetti, Fabrizio

2018-04-01

To investigate whether abnormalities in B cell subsets in patients with juvenile idiopathic arthritis (JIA) correlate with clinical features and response to treatment. A total of 109 patients diagnosed as having oligoarticular JIA or polyarticular JIA were enrolled in the study. B cell subsets in peripheral blood and synovial fluid were analyzed by flow cytometry. Switched memory B cells were significantly increased in patients compared to age-matched healthy controls (P < 0.0001). When patients were divided according to age at onset of JIA, in patients with early-onset disease (presenting before age 6 years) the expansion in switched memory B cells was more pronounced than that in patients with late-onset disease and persisted throughout the disease course. In longitudinal studies, during methotrexate (MTX) treatment, regardless of the presence or absence of active disease, the number of switched memory B cells increased significantly (median change from baseline 36% [interquartile range {IQR} 15, 66]). During treatment with MTX plus tumor necrosis factor inhibitors (TNFi), in patients maintaining disease remission, the increase in switched memory B cells was significantly lower than that in patients who experienced active disease (median change from baseline 4% [IQR -6, 32] versus 41% [IQR 11, 73]; P = 0.004). The yearly rate of increases in switched memory B cells was 1.5% in healthy controls, 1.2% in patients who maintained remission during treatment with MTX plus TNFi, 4.7% in patients who experienced active disease during treatment with MTX plus TNFi, and ~4% in patients treated with MTX alone. Switched memory B cells expand during the disease course at a faster rate in JIA patients than in healthy children. This increase is more evident in patients with early-onset JIA. TNFi treatment inhibits this increase in patients who achieve and maintain remission, but not in those with active disease. © 2018, American College of Rheumatology.

Immunopathology of childhood celiac disease-Key role of intestinal epithelial cells.

PubMed

Pietz, Grzegorz; De, Rituparna; Hedberg, Maria; Sjöberg, Veronika; Sandström, Olof; Hernell, Olle; Hammarström, Sten; Hammarström, Marie-Louise

2017-01-01

Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria. Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells. More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells. A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease.

Validity of simple clinical and biological parameters as screening tool for sickle cell anemia for referral to tertiary center in highly resource constraints.

PubMed

Kadima, Bertin Tshimanga; Gini-Ehungu, Jean Lambert; Mbutiwi, Fiston Ikwa Ndol; Bahati, John Tunda; Aloni, Michel Ntetani

2017-11-01

In the Democratic Republic of Congo, the incidence of sickle cell anemia (SCA) is estimated around 40 000 neonates per year. However, it is notoriously difficult to perform conventional electrophoresis in all hospitals and laboratories, especially at peripheral levels and rural area. A panel of multiple clinical and laboratory features that would enhance sickle cell disease were assessed for the detection of the disease in highly resource-scarce settings. A prospective study was conducted in Kinshasa. Venous blood samples were drawn from each study participant in order to determine the hematologic parameters, the peripheral smears, and the hemoglobin electrophoresis. We used Cohen's κ statistic to examine the agreement of each variable and diagnosis of sickle cell disease. A total of 807 patients were screened for sickle cell disease. Among these 807 children, 36 (4.5%) were homozygous for Hb S disease. The presence of at least 8% erythroblasts (PPV: 91%, NPV: 99%, sensitivity: 83.3%, specificity: 99.6%, κ value: .86) and sickle cells (PPV:100%, NPV: 98%, sensitivity: 50%, specificity: 100%, κ value: .66) in the peripheral blood smear had an acceptable agreement for sickle cell disease. These two biological markers may guide the clinician in the decision-making to initiate the management of the children as a sickle cell patient, pending confirmation of the disease by electrophoresis techniques. © 2017 Wiley Periodicals, Inc.

Graft-versus-host disease

MedlinePlus

GVHD; Bone marrow transplant - graft-versus-host disease; Stem cell transplant - graft-versus-host disease; Allogeneic transplant - ... GVHD may occur after a bone marrow, or stem cell, transplant in which someone receives bone marrow ...

Pathophysiological consequences of VEGF-induced vascular permeability

NASA Astrophysics Data System (ADS)

Weis, Sara M.; Cheresh, David A.

2005-09-01

Although vascular endothelial growth factor (VEGF) induces angiogenesis, it also disrupts vascular barrier function in diseased tissues. Accordingly, VEGF expression in cancer and ischaemic disease has unexpected pathophysiological consequences. By uncoupling endothelial cell-cell junctions VEGF causes vascular permeability and oedema, resulting in extensive injury to ischaemic tissues after stroke or myocardial infarction. In cancer, VEGF-mediated disruption of the vascular barrier may potentiate tumour cell extravasation, leading to widespread metastatic disease. Therefore, by blocking the vascular permeability promoting effects of VEGF it may be feasible to reduce tissue injury after ischaemic disease and minimize the invasive properties of circulating tumour cells.

Identification of mast cells in buffy coat preparations from dogs with inflammatory skin diseases.

PubMed

Cayatte, S M; McManus, P M; Miller, W H; Scott, D W

1995-02-01

In 100 dogs with 4 inflammatory dermatologic diseases, buffy coat preparations from EDTA-treated blood samples were examined cytologically. Fifty-four dogs had atopy, 26 had flea-bite hypersensitivity, 17 had sarcoptic mange, and 3 had food allergy. Twenty-eight dogs had 2 or more concurrent skin diseases; most of these had secondary pyoderma. Dogs did not have mast cell tumors. Thirteen samples contained 1 or more mast cells/4 slides reviewed. This study revealed that dogs with inflammatory skin diseases can have a few to many mast cells evident on cytologic examination of buffy coat preparations.

The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy

PubMed Central

Honigberg, Lee A.; Smith, Ashley M.; Sirisawad, Mint; Verner, Erik; Loury, David; Chang, Betty; Li, Shyr; Pan, Zhengying; Thamm, Douglas H.; Miller, Richard A.; Buggy, Joseph J.

2010-01-01

Activation of the B-cell antigen receptor (BCR) signaling pathway contributes to the initiation and maintenance of B-cell malignancies and autoimmune diseases. The Bruton tyrosine kinase (Btk) is specifically required for BCR signaling as demonstrated by human and mouse mutations that disrupt Btk function and prevent B-cell maturation at steps that require a functional BCR pathway. Herein we describe a selective and irreversible Btk inhibitor, PCI-32765, that is currently under clinical development in patients with B-cell non-Hodgkin lymphoma. We have used this inhibitor to investigate the biologic effects of Btk inhibition on mature B-cell function and the progression of B cell-associated diseases in vivo. PCI-32765 blocked BCR signaling in human peripheral B cells at concentrations that did not affect T cell receptor signaling. In mice with collagen-induced arthritis, orally administered PCI-32765 reduced the level of circulating autoantibodies and completely suppressed disease. PCI-32765 also inhibited autoantibody production and the development of kidney disease in the MRL-Fas(lpr) lupus model. Occupancy of the Btk active site by PCI-32765 was monitored in vitro and in vivo using a fluorescent affinity probe for Btk. Active site occupancy of Btk was tightly correlated with the blockade of BCR signaling and in vivo efficacy. Finally, PCI-32765 induced objective clinical responses in dogs with spontaneous B-cell non-Hodgkin lymphoma. These findings support Btk inhibition as a therapeutic approach for the treatment of human diseases associated with activation of the BCR pathway. PMID:20615965

T follicular helper cell differentiation, function, and roles in disease

PubMed Central

Crotty, Shane

2014-01-01

Summary Follicular helper T (Tfh) cells are specialized providers of T cell help to B cells, and are essential for germinal center formation, affinity maturation, and the development of most high affinity antibodies and memory B cells. Tfh cell differentiation is a multi-stage, multi-factorial process involving B cell lymphoma 6 (Bcl6) and other transcription factors. This article reviews understanding of Tfh cell biology, including their differentiation, migration, transcriptional regulation, and B cell help functions. Tfh cells are critical components of many protective immune responses against pathogens. As such, there is strong interest in harnessing Tfh cells to improve vaccination strategies. Tfh cells also have roles in a range of other diseases, particularly autoimmune diseases. Overall, there have been dramatic advances in this young field, but there is much to be learned about Tfh cell biology in the interest of applying that knowledge to biomedical needs. PMID:25367570

CD30-Positive T-Cell Lymphoproliferative Disease of the Oral Mucosa in Children: A Manifestation of Epstein-Barr Virus-Associated T-Lymphoproliferative Disorder.

PubMed

Hong, Mineui; Ko, Young Hyeh

2015-11-01

Eosinophilic ulcer of the oral mucosa (EUOM) is a very rare, benign, self-limiting ulcerative lesion of the oral cavity of unknown pathogenesis, and belongs to the same spectrum of CD30(+) T-cell lymphoproliferative disease (LPD) of the oral mucosa. The etiology and pathogenesis of the disease are unknown. We report two cases in children who were initially diagnosed with EUOM and CD30(+) T-cell LPD, respectively. However, retrospective analysis revealed that a majority of infiltrated atypical T cells were positive for Epstein-Barr virus (EBV). The present cases suggest that the pathogenesis and etiology of EUOM or CD30(+) T-cell LPD occurring in children are different from those in adults. EUOM or CD30(+) T-cell LPD in children is a manifestation of EBV-positive T-cell LPD, and should therefore be distinguished from the disease in adults.

NK cells are biologic and biochemical targets of 6-mercaptopurine in Crohn's disease patients.

PubMed

Yusung, Susy; McGovern, Dermot; Lin, Lin; Hommes, Daniel; Lagishetty, Venu; Braun, Jonathan

2017-02-01

NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn's disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD. Copyright © 2016 Elsevier Inc. All rights reserved.

Exosomes as nanocarriers for immunotherapy of cancer and inflammatory diseases.

PubMed

Tran, Thanh-Huyen; Mattheolabakis, George; Aldawsari, Hibah; Amiji, Mansoor

2015-09-01

Cell secreted exosomes (30-100nm vesicles) play a major role in intercellular communication due to their ability to transfer proteins and nucleic acids from one cell to another. Depending on the originating cell type and the cargo, exosomes can have immunosuppressive or immunostimulatory effects, which have potential application as immunotherapies for cancer and autoimmune diseases. Cellular components shed from tumor cells or antigen presenting cells (APCs), such as dendritic cells, macrophages and B cells, have been shown to be efficiently packaged in exosomes. In this review, we focus on the application of exosomes as nanocarriers and immunological agents for cancer and autoimmune immunotherapy. APC-derived exosomes demonstrate effective therapeutic efficacy for the treatment of cancer and experimental autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. In addition to their intrinsic immunomodulating activity, exosomes have many advantages over conventional nanocarriers for drug and gene delivery. Copyright © 2015 Elsevier Inc. All rights reserved.

Cell reprogramming and neuronal differentiation applied to neurodegenerative diseases: Focus on Parkinson's disease.

PubMed

Wenker, Shirley D; Casalía, Mariana; Candedo, Verónica Cavaliere; Casabona, Juan Cruz; Pitossi, Fernando J

2015-11-14

Adult cells from patients can be reprogrammed to induced pluripotent stem cells (iPSCs) which successively can be used to obtain specific cells such as neurons. This remarkable breakthrough represents a new way of studying diseases and brought new therapeutic perspectives in the field of regenerative medicine. This is particular true in the neurology field, where few techniques are amenable to study the affected tissue of the patient during illness progression, in addition to the lack of neuroprotective therapies for many diseases. In this review we discuss the advantages and unresolved issues of cell reprogramming and neuronal differentiation. We reviewed evidence using iPSCs-derived neurons from neurological patients. Focusing on data obtained from Parkinson's disease (PD) patients, we show that iPSC-derived neurons possess morphological and functional characteristics of this disease and build a case for the use of this technology to study PD and other neuropathologies while disease is in progress. These data show the enormous impact that this new technology starts to have on different purposes such as the study and design of future therapies of neurological disease, especially PD. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Formin like 1 expression is increased on CD4+ T lymphocytes in spontaneous autoimmune uveitis.

PubMed

Degroote, Roxane L; Uhl, Patrizia B; Amann, Barbara; Krackhardt, Angela M; Ueffing, Marius; Hauck, Stefanie M; Deeg, Cornelia A

2017-02-10

The membrane protein expression repertoire of cells changes in course of activation. In equine recurrent uveitis (ERU), a spontaneous autoimmune disease in horses with relapsing and ultimately blinding inner eye inflammation, CD4+ T lymphocytes are the crucial pathogenic cells activated in the periphery directly prior to an inflammatory episode. In order to find relevant changes in the membrane proteome associated to disease, we sorted CD4+ lymphocytes and compared protein abundance from the generated proteome datasets of both healthy horses and ERU cases. We detected formin like 1, a key player in actin dependent cellular processes such as phagocytosis, cell adhesion and cell migration, with significantly higher abundance in the CD4+ cell membrane proteome of horses with ERU. In transmigration experiments, we demonstrated higher migration rate of cells originating from diseased animals connecting formin like 1 to the migratory ability of cells. These findings are the first description of formin like 1 in association to processes involved in migration of inflammatory CD4+ T cells across the blood-retinal barrier in a spontaneous ocular autoimmune disease and suggest formin like 1 to play a role in the molecular mechanisms of ERU disease pathogenesis. Data are available via ProteomeXchange with identifier PXD005384. This comparative proteomic study of membrane proteins of CD4+ T cells identified a novel protein, formin like 1, with expression on the plasma cell membrane of equine CD4+ T cells and a significant change of abundance on CD4+ T cells of horses with a spontaneous autoimmune disease. Functional studies in a cell culture model for transmigration at the blood-retinal barrier (BRB) unraveled a strong impact of formin like 1 on migratory processes of CD4+ T cells across the BRB, a key event in uveitis pathogenesis. These findings provide novel knowledge about changes in the CD4+ immune cell membrane proteome in a spontaneously and naturally occurring autoimmune disease in horses with high relevance for veterinary medicine. Additionally, this model has proven translational quality for human medicine and provides novel proteomic information on autoimmune uveitis in man. Copyright © 2017 Elsevier B.V. All rights reserved.

Cross-Species Transcriptome Profiling Identifies New Alveolar Epithelial Type I Cell–Specific Genes

PubMed Central

Sunohara, Mitsuhiro; Pouldar, Tiffany M.; Wang, Hongjun; Liu, Yixin; Rieger, Megan E.; Tran, Evelyn; Flodby, Per; Siegmund, Kimberly D.; Crandall, Edward D.; Laird-Offringa, Ite A.

2017-01-01

Diseases involving the distal lung alveolar epithelium include chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung adenocarcinoma. Accurate labeling of specific cell types is critical for determining the contribution of each to the pathogenesis of these diseases. The distal lung alveolar epithelium is composed of two cell types, alveolar epithelial type 1 (AT1) and type 2 (AT2) cells. Although cell type–specific markers, most prominently surfactant protein C, have allowed detailed lineage tracing studies of AT2 cell differentiation and the cells’ roles in disease, studies of AT1 cells have been hampered by a lack of genes with expression unique to AT1 cells. In this study, we performed genome-wide expression profiling of multiple rat organs together with purified rat AT2, AT1, and in vitro differentiated AT1-like cells, resulting in the identification of 54 candidate AT1 cell markers. Cross-referencing with genes up-regulated in human in vitro differentiated AT1-like cells narrowed the potential list to 18 candidate genes. Testing the top four candidate genes at RNA and protein levels revealed GRAM domain 2 (GRAMD2), a protein of unknown function, as highly specific to AT1 cells. RNA sequencing (RNAseq) confirmed that GRAMD2 is transcriptionally silent in human AT2 cells. Immunofluorescence verified that GRAMD2 expression is restricted to the plasma membrane of AT1 cells and is not expressed in bronchial epithelial cells, whereas reverse transcription–polymerase chain reaction confirmed that it is not expressed in endothelial cells. Using GRAMD2 as a new AT1 cell–specific gene will enhance AT1 cell isolation, the investigation of alveolar epithelial cell differentiation potential, and the contribution of AT1 cells to distal lung diseases. PMID:27749084

Human cord blood applications in cell therapy: looking back and look ahead.

PubMed

Zhou, Hongyan; Chang, Stephen; Rao, Mahendra

2012-08-01

Human umbilical cord blood (UCB) has been used as a reliable source of stem cells for blood-borne diseases and disorders. Recent advances in cell reprogramming technology to produce induced pluripotent stem (iPS) cells, which can be differentiated to multiple adult cell types, has further expanded the potential of cord blood cell therapy for treatment of non-blood-borne diseases. However, in order to harness this breakthrough technology and to provide clinical-grade cells for the patient, standardization of iPS production and differentiation, and good manufacturing practice (GMP) need to be employed. UCB is an ethical source of stem cells and has been used to treat diseases including leukemia, cancer and blood disorders. The development of iPS cell technology could potentially greatly increase the application of cord blood cells as a treatment for a broader range of diseases, UCB-iPS banks could, therefore, be a valuable complementary source of clinical-grade cells for cell therapy. The current applicability of GMP to UCB and UCB-iPS cell-based cell therapy will be discussed. Although cord blood stem cell therapies have been practiced for decades, UCB-iPS cell therapies are a new innovation currently in development. Successful clinical applications of such novel cell therapies will depend on the production of GMP-compliant cells and the establishment of cell banks.

Different subsets of natural killer T cells may vary in their roles in health and disease.

PubMed

Kumar, Vipin; Delovitch, Terry L

2014-07-01

Natural killer T cells (NKT) can regulate innate and adaptive immune responses. Type I and type II NKT cell subsets recognize different lipid antigens presented by CD1d, an MHC class-I-like molecule. Most type I NKT cells express a semi-invariant T-cell receptor (TCR), but a major subset of type II NKT cells reactive to a self antigen sulphatide use an oligoclonal TCR. Whereas TCR-α dominates CD1d-lipid recognition by type I NKT cells, TCR-α and TCR-β contribute equally to CD1d-lipid recognition by type II NKT cells. These variable modes of NKT cell recognition of lipid-CD1d complexes activate a host of cytokine-dependent responses that can either exacerbate or protect from disease. Recent studies of chronic inflammatory and autoimmune diseases have led to a hypothesis that: (i) although type I NKT cells can promote pathogenic and regulatory responses, they are more frequently pathogenic, and (ii) type II NKT cells are predominantly inhibitory and protective from such responses and diseases. This review focuses on a further test of this hypothesis by the use of recently developed techniques, intravital imaging and mass cytometry, to analyse the molecular and cellular dynamics of type I and type II NKT cell antigen-presenting cell motility, interaction, activation and immunoregulation that promote immune responses leading to health versus disease outcomes. © 2014 John Wiley & Sons Ltd.

Mucosal-Associated Invariant T Cell Deficiency in Chronic Obstructive Pulmonary Disease.

PubMed

Kwon, Yong Soo; Jin, Hye-Mi; Cho, Young-Nan; Kim, Moon-Ju; Kang, Jeong-Hwa; Jung, Hyun-Ju; Park, Ki-Jeong; Kee, Hae Jin; Kee, Seung-Jung; Park, Yong-Wook

2016-01-01

Mucosal-associated invariant T (MAIT) cells have been reported to play an important role in mucosal immunity. However, little is known about the roles of MAIT cells in chronic obstructive pulmonary disease (COPD). The aims of this study were to examine the levels of circulating MAIT cells and their subsets in COPD patients and to investigate the potential relationship between clinical parameters and MAIT cell levels. Forty-five COPD patients and 57 healthy control subjects were enrolled in the study. Circulating MAIT cells and their subset levels in the peripheral blood were measured by flow cytometry. Disease grades were classified according to the GOLD criteria for the assessment of severity of COPD. Circulating MAIT cell levels were found to be significantly reduced in COPD patients. In particular, this MAIT cell deficiency was more prominent in CD8+ and double-negative T cell subsets. Interestingly, elevated serum C-reactive protein level and reduced FEV1/FVC ratio were associated with MAIT cell deficiency in COPD patients. Furthermore, the circulating MAIT levels were found to be significantly lower in patients with moderate to severe COPD than in patients with mild COPD. Our data shows that MAIT cells are numerically deficient in the peripheral blood of patients with COPD. In addition, this MAIT cell deficiency was found to reflect inflammatory activity and disease severity. These findings provide important information for monitoring the changes in MAIT cell levels and for predicting the prognosis during the disease course.

A Study of Varlilumab and Atezolizumab in Patients With Advanced Cancer

ClinicalTrials.gov

2018-04-26

Carcinoma, Renal Cell; Kidney Diseases; Kidney Neoplasms; Urogenital Neoplasms; Urologic Diseases; Urologic Neoplasms; Neoplasms by Histologic Type; Neoplasms; Clear-cell Metastatic Renal Cell Carcinoma; Melanoma; Triple Negative Breast Cancer; Bladder Cancer; Head and Neck Cancer; Non-small Cell Lung Cancer

Venous thromboembolism in adults with sickle cell disease: A serious and under-recognized complication

PubMed Central

Naik, Rakhi P.; Streiff, Michael B.; Haywood, Carlton; Nelson, Julie A.; Lanzkron, Sophie

2013-01-01

BACKGROUND Sickle cell disease is recognized as a hypercoagulable state; however the frequency and characteristics of venous thromboembolism in sickle cell patients have not been well-defined. PURPOSE To establish the prevalence and risk factors for venous thromboembolism in a large cohort of patients with sickle cell disease and determine the relationship between venous thromboembolism and mortality. METHODS We performed a cross-sectional study of 404 sickle cell disease patients cared for at the Sickle Cell Center for Adults at Johns Hopkins. Demographic, sickle cell disease-specific comorbidity, and venous thromboembolism data were collected on all patients. RESULTS 101 patients (25%) had a history of venous thromboembolism with a median age at diagnosis of 29.9 years. A history of non-catheter-related venous thromboembolism was found in 18.8% of patients. Sickle variant genotypes conferred a higher risk of non-catheter-related venous thromboembolism compared to sickle cell anemia genotypes (SS/Sβ0) (relative risk (RR) 1.77, 95% confidence interval (CI) 1.18–2.66). Tricuspid regurgitant jet velocity ≥ 2.5 m/s was also associated with non-catheter-related venous thromboembolism (RR 1.65, CI 1.12–2.45). Thirty patients (7.4%) died during the study period. Adjusting for all variables, non-catheter-related venous thromboembolism was independently correlated with death (RR 3.63, CI 1.66–7.92). CONCLUSION Venous thromboembolism is common in adults with sickle cell disease. Sickle variant genotypes and tricuspid regurgitant jet velocity ≥ 2.5m/s are associated with non-catheter-related venous thromboembolism. In addition, non-catheter-related venous thromboembolism appears to be an independent risk factor for death in our cohort. These results suggest that disease-specific prophylaxis and treatment strategies for venous thromboembolism should be investigated in sickle cell disease patients. PMID:23582935

Low expression of CD39+/CD45RA+ on regulatory T cells (Treg) cells in type 1 diabetic children in contrast to high expression of CD101+/CD129+ on Treg cells in children with coeliac disease

PubMed Central

Åkesson, K; Tompa, A; Rydén, A; Faresjö, M

2015-01-01

Type 1 diabetes (T1D) and coeliac disease are both characterized by an autoimmune feature. As T1D and coeliac disease share the same risk genes, patients risk subsequently developing the other disease. This study aimed to investigate the expression of T helper (Th), T cytotoxic (Tc) and regulatory T cells (Treg) in T1D and/or coeliac disease children in comparison to healthy children. Subgroups of T cells (Th : CD4+ or Tc : CD8+); naive (CD27+CD28+CD45RA+CCR7+), central memory (CD27+CD28+CD45RA−CCR7+), effector memory (early differentiated; CD27+CD28+CD45RA−CCR7− and late differentiated; CD27−CD28−CD45RA−CCR7−), terminally differentiated effector cells (TEMRA; CD27−CD28−CD45RA+CCR7−) and Treg (CD4+CD25+FOXP3+CD127−) cells, and their expression of CD39, CD45RA, CD101 and CD129, were studied by flow cytometry in T1D and/or coeliac disease children or without any of these diseases (reference group). Children diagnosed with both T1D and coeliac disease showed a higher percentage of TEMRA CD4+ cells (P < 0·05), but lower percentages of both early and late effector memory CD8+ cells (P < 0·05) compared to references. Children with exclusively T1D had lower median fluorescence intensity (MFI) of forkhead box protein 3 (FoxP3) (P < 0·05) and also a lower percentage of CD39+ and CD45RA+ within the Treg population (CD4+CD25+FOXP3+CD127−) (P < 0·05). Children with exclusively coeliac disease had a higher MFI of CD101 (P < 0·01), as well as a higher percentage of CD129+ (P < 0·05), in the CD4+CD25hi lymphocyte population, compared to references. In conclusion, children with combined T1D and coeliac disease have a higher percentage of differentiated CD4+ cells compared to CD8+ cells. T1D children show signs of low CD39+/CD45RA+ Treg cells that may indicate loss of suppressive function. Conversely, children with coeliac disease show signs of CD101+/CD129+ Treg cells that may indicate suppressor activity. PMID:25421756

Circulating Organ-Specific MicroRNAs Serve as Biomarkers in Organ-Specific Diseases: Implications for Organ Allo- and Xeno-Transplantation

PubMed Central

Zhou, Ming; Hara, Hidetaka; Dai, Yifan; Mou, Lisha; Cooper, David K. C.; Wu, Changyou; Cai, Zhiming

2016-01-01

Different cell types possess different miRNA expression profiles, and cell/tissue/organ-specific miRNAs (or profiles) indicate different diseases. Circulating miRNA is either actively secreted by living cells or passively released during cell death. Circulating cell/tissue/organ-specific miRNA may serve as a non-invasive biomarker for allo- or xeno-transplantation to monitor organ survival and immune rejection. In this review, we summarize the proof of concept that circulating organ-specific miRNAs serve as non-invasive biomarkers for a wide spectrum of clinical organ-specific manifestations such as liver-related disease, heart-related disease, kidney-related disease, and lung-related disease. Furthermore, we summarize how circulating organ-specific miRNAs may have advantages over conventional methods for monitoring immune rejection in organ transplantation. Finally, we discuss the implications and challenges of applying miRNA to monitor organ survival and immune rejection in allo- or xeno-transplantation. PMID:27490531

Brain Aggregates: An Effective In Vitro Cell Culture System Modeling Neurodegenerative Diseases.

PubMed

Ahn, Misol; Kalume, Franck; Pitstick, Rose; Oehler, Abby; Carlson, George; DeArmond, Stephen J

2016-03-01

Drug discovery for neurodegenerative diseases is particularly challenging because of the discrepancies in drug effects between in vitro and in vivo studies. These discrepancies occur in part because current cell culture systems used for drug screening have many limitations. First, few cell culture systems accurately model human aging or neurodegenerative diseases. Second, drug efficacy may differ between dividing and stationary cells, the latter resembling nondividing neurons in the CNS. Brain aggregates (BrnAggs) derived from embryonic day 15 gestation mouse embryos may represent neuropathogenic processes in prion disease and reflect in vivo drug efficacy. Here, we report a new method for the production of BrnAggs suitable for drug screening and suggest that BrnAggs can model additional neurological diseases such as tauopathies. We also report a functional assay with BrnAggs by measuring electrophysiological activities. Our data suggest that BrnAggs could serve as an effective in vitro cell culture system for drug discovery for neurodegenerative diseases. © 2016 American Association of Neuropathologists, Inc. All rights reserved.

Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib.

PubMed

Okamoto, Koh; Proia, Laurie A; Demarais, Patricia L

2016-01-01

Cryptococcus is a unique environmental fungus that can cause disease most often in immunocompromised individuals with defective cell-mediated immunity. Chronic lymphocytic leukemia (CLL) is not known to be a risk factor for cryptococcal disease although cases have been described mainly in patients treated with agents that suppress cell-mediated immunity. Ibrutinib is a new biologic agent used for treatment of CLL, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. It acts by inhibiting Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor critical for B-cell survival and proliferation. Ibrutinib use has not been associated previously with cryptococcal disease. However, recent evidence suggested that treatments aimed at blocking the function of Bruton's tyrosine kinase could pose a higher risk for cryptococcal infection in a mice model. Here, we report the first case of disseminated cryptococcal disease in a patient with CLL treated with ibrutinib. When evaluating possible infection in CLL patients receiving ibrutinib, cryptococcal disease, which could be life threatening if overlooked, could be considered.

Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements

PubMed Central

Mumbach, Maxwell R; Satpathy, Ansuman T; Boyle, Evan A; Dai, Chao; Gowen, Benjamin G; Cho, Seung Woo; Nguyen, Michelle L; Rubin, Adam J; Granja, Jeffrey M; Kazane, Katelynn R; Wei, Yuning; Nguyen, Trieu; Greenside, Peyton G; Corces, M Ryan; Tycko, Josh; Simeonov, Dimitre R; Suliman, Nabeela; Li, Rui; Xu, Jin; Flynn, Ryan A; Kundaje, Anshul; Khavari, Paul A; Marson, Alexander; Corn, Jacob E; Quertermous, Thomas; Greenleaf, William J; Chang, Howard Y

2018-01-01

The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer–promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases. PMID:28945252

Cholecystectomy in patients with sickle cell disease: experience at a regional hospital in southeast Georgia.

PubMed Central

Rudolph, R.; Williams, J. S.

1992-01-01

The treatment of patients with sickle cell disease and cholelithiasis is controversial. This retrospective study assesses the outcome of preoperative transfusion and timely cholecystectomy in symptomatic sickle cell disease patients. Fourteen patients who had undergone cholecystectomy were determined to have sickle cell disease. The patients' mean age was 17.9 years. Eleven patients were female. Thirteen patients had complained of abdominal pain. Ultrasound confirmed the diagnosis of cholelithiasis in 12 of 13 patients tested. Hemoglobin before treatment averaged 7.7 g/dL. Transfusion or exchange transfusion was given to 12 patients, raising the average hemoglobin to 10.3 g/dL. Postoperative morbidity was 14%: one patient had a urinary tract infection and another a left-lower-lobe pneumonia. No sickle cell crises or deaths occurred. Postoperative hospital stay averaged 4.4 days. With judicious use of preoperative transfusion, early cholecystectomy for symptomatic gallstones was well tolerated by sickle cell disease patients and is advisable to avoid the morbid sequelae of acute cholecystitis and peroperative sickle cell crisis. PMID:1507260

New therapeutic possibilities for vein graft disease in the post-edifoligide era.

PubMed

Cai, Xinjiang; Freedman, Neil J

2006-07-01

Vein graft neointimal hyperplasia involves proliferation and migration of vascular smooth muscle cells into the vessel intima, and ultimately engenders accelerated atherosclerosis and vein graft failure. Since a myriad of stimuli provoke smooth muscle cell proliferation, molecular therapies for vein graft disease have targeted mechanisms fundamental to all cell proliferation - the 'cell-cycle' machinery. Preclinically, the most successful of these therapies has been edifoligide (E2F decoy), a double-stranded oligodeoxynucleotide that binds to the transcription factor known as E2F. Recently, PRoject of Ex vivo vein GRaft Engineering via Transfection (PREVENT) III and IV demonstrated that edifoligide failed to benefit human vein grafts employed to treat lower-extremity ischemia and coronary heart disease, respectively. The clinical failure of edifoligide calls into question previous models of vein graft disease and lends credence to recent animal studies demonstrating that vein graft arterialization substantially involves the immigration into the vein graft of a variety of vascular progenitor cells. Future vein graft disease therapies will likely target not only proliferation of graft-intrinsic cells, but also immigration of graft-extrinsic cells.

Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases. Comprehensive Review of the Recent Literature 2010–2012

PubMed Central

2013-01-01

A conference, “Stem Cells and Cell Therapies in Lung Biology and Lung Diseases,” was held July 25 to 28, 2011 at the University of Vermont to review the current understanding of the role of stem and progenitor cells in lung repair after injury and to review the current status of cell therapy and ex vivo bioengineering approaches for lung diseases. These are rapidly expanding areas of study that provide further insight into and challenge traditional views of mechanisms of lung repair after injury and pathogenesis of several lung diseases. The goals of the conference were to summarize the current state of the field, to discuss and debate current controversies, and to identify future research directions and opportunities for basic and translational research in cell-based therapies for lung diseases. The goal of this article, which accompanies the formal conference report, is to provide a comprehensive review of the published literature in lung regenerative medicine from the last conference report through December 2012. PMID:23869446

IL-17 in psoriasis: Implications for therapy and cardiovascular co-morbidities

PubMed Central

Golden, Jackelyn B.; McCormick, Thomas S.; Ward, Nicole L.

2013-01-01

Psoriasis is a prevalent, chronic inflammatory disease of the skin mediated by cross-talk occurring between epidermal keratinocytes, dermal vascular cells and immunocytes, including activated antigen presenting cells (APCs), monocytes/macrophages, and Th1 and Th17 cells. Increased proliferation of keratinocytes and endothelial cells in conjunction with immune cell infiltration leads to the distinct epidermal and vascular hyperplasia that is characteristic of lesional psoriatic skin. Interaction of activated T cells with monocytes/macrophages occurs via the Th17/IL-23 axis and is crucial for maintaining the chronic inflammation. Recent epidemiological evidence has demonstrated that psoriasis patients have an increased risk of developing and dying of cardiovascular disease. Similar pathology between psoriasis and cardiovascular disease, including involvement of key immunologic cell populations together with release of common inflammatory mediators such as IL-17A suggest a mechanistic link between the two diseases. This review will focus on concepts critical to psoriasis pathogenesis, systemic manifestations of psoriasis, the role of IL-17 in psoriasis and cardiovascular disease and the potential role for IL-17 in mediating cardiovascular co-morbidities in psoriasis patients. PMID:23562549

Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.

PubMed

Cao, Lei; Tan, Lan; Jiang, Teng; Zhu, Xi-Chen; Yu, Jin-Tai

2015-08-01

Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques.

Microbiota-specific Th17 cells: Yin and Yang in regulation of inflammatory bowel disease

PubMed Central

Wei, Wu; Feidi, Chen; Zhanju, Liu; Yingzi, Cong

2016-01-01

Multiple mechanisms are involved in regulation of host response to microbiota to maintain the intestinal homeostasis. Th17 cells are enriched in the intestinal lamina propria (LP) under steady conditions. Many studies have demonstrated that microbiota reactive Th17 cells in the intestines mediate the pathogenesis of inflammatory bowel diseases. However, clinical trials of anti-IL-17A or anti-IL-17RA antibodies in patients with Crohn’s Disease show no improvement or even exacerbation of disease. Accumulating data has also indicated that Th17 cells may provide a protective effect as well to the intestines from inflammatory insults under homeostasis regulation, even under inflammatory conditions. Thus both pro-inflammatory and anti-inflammatory functions of intestinal Th17 cells have emerged under various conditions. In this review article, we will summarize recent progresses of Th17 cells in regulation of intestinal homeostasis as well as in the pathogenesis of inflammatory bowel diseases. PMID:27057688

Molecular Diagnosis in Autoimmune Skin Blistering Conditions

PubMed Central

Otten, J.V.; Hashimoto, T.; Hertl, M.; Payne, A.S.; Sitaru, C.

2014-01-01

Blister formation in skin and mucous membranes results from a loss of cell-cell or cell-matrix adhesion and is a common outcome of pathological events in a variety of conditions, including autoimmune and genetic diseases, viral and bacterial infections, or injury by physical and chemical factors. Autoantibodies against structural components maintaining cell-cell and cell-matrix adhesion induce tissue damage in autoimmune blistering diseases. Detection of these autoantibodies either tissue-bound or circulating in serum is essential to diagnose the autoimmune nature of disease. Various immunofluorescence methods as well as molecular immunoassays, including enzyme-linked immunosorbent assay and immunoblotting, belong to the modern diagnostic algorithms for these disorders. There is still a considerable need to increase awareness of the rare autoimmune blistering diseases, which often show a severe, chronic-relapsing course, among physicians and the public. This review article describes the immunopathological features of autoimmune bullous diseases and the molecular immunoassays currently available for their diagnosis and monitoring. PMID:24160488

Comparing ESC and iPSC-Based Models for Human Genetic Disorders.

PubMed

Halevy, Tomer; Urbach, Achia

2014-10-24

Traditionally, human disorders were studied using animal models or somatic cells taken from patients. Such studies enabled the analysis of the molecular mechanisms of numerous disorders, and led to the discovery of new treatments. Yet, these systems are limited or even irrelevant in modeling multiple genetic diseases. The isolation of human embryonic stem cells (ESCs) from diseased blastocysts, the derivation of induced pluripotent stem cells (iPSCs) from patients' somatic cells, and the new technologies for genome editing of pluripotent stem cells have opened a new window of opportunities in the field of disease modeling, and enabled studying diseases that couldn't be modeled in the past. Importantly, despite the high similarity between ESCs and iPSCs, there are several fundamental differences between these cells, which have important implications regarding disease modeling. In this review we compare ESC-based models to iPSC-based models, and highlight the advantages and disadvantages of each system. We further suggest a roadmap for how to choose the optimal strategy to model each specific disorder.

A Review of the Literature: Use of the Health Belief Model in Sickle Cell Research

ERIC Educational Resources Information Center

Mayo-Gamble, Tilicia L.

2014-01-01

Individuals with sickle cell disease experience a life-time of morbidity as well as a decreased lifespan. Since African Americans are disproportionately affected by the disease, sickle cell contributes to growing health disparities within this population. Thus, addressing issues related to the disease presents an increased need for health…

Mast cell hyperactivity underpins the development of oxygen-induced retinopathy

PubMed Central

Matsuda, Kenshiro; Okamoto, Noriko; Kondo, Masatoshi; Arkwright, Peter D.; Karasawa, Kaoru; Ishizaka, Saori; Yokota, Shinichi; Matsuda, Akira; Jung, Kyungsook; Oida, Kumiko; Jang, Hyosun; Noda, Eiichiro; Kakinuma, Ryota; Yasui, Koujirou; Kaku, Uiko; Mori, Yasuo; Onai, Nobuyuki; Ohteki, Toshiaki; Tanaka, Akane

2017-01-01

Mast cells are classically thought to play an important role in protection against helminth infections and in the induction of allergic diseases; however, recent studies indicate that these cells also contribute to neovascularization, which is critical for tissue remodeling, chronic inflammation, and carcinogenesis. Here, we demonstrate that mast cells are essential for sprouting angiogenesis in a murine model of oxygen-induced retinopathy (OIR). Although mouse strains lacking mast cells did not exhibit retinal neovascularization following hypoxia, these mice developed OIR following infusion of mast cells or after injection of mast cell tryptase (MCT). Relative hypoxia stimulated mast cell degranulation via transient receptor potential ankyrin 1. Subsequent surges in MCT stimulated retinal endothelial cells to produce monocyte chemotactic protein-1 (MCP1) and angiogenic factors, leading to sprouting angiogenesis. Mast cell stabilizers as well as specific tryptase and MCP1 inhibitors prevented the development of OIR in WT mice. Preterm infants with early retinopathy of prematurity had markedly higher plasma MCT levels than age-matched infants without disease, suggesting mast cells contribute to human disease. Together, these results suggest therapies that suppress mast cell activity should be further explored as a potential option for preventing eye diseases and subsequent blindness induced by neovascularization. PMID:28990934

Sickle Cell Disease as a Neurodevelopmental Disorder

ERIC Educational Resources Information Center

Schatz, Jeffrey; McClellan, Catherine B.

2006-01-01

Sickle cell disease (SCD) is a blood disorder; however, the central nervous system (CNS) is one of the organs frequently affected by the disease. Brain disease can begin early in life and often leads to neurocognitive dysfunction. Approximately one-fourth to one-third of children with SCD have some form of CNS effects from the disease, which…

Expression profiling of cardiovascular disease

PubMed Central

2004-01-01

Cardiovascular disease is the most important cause of morbidity and mortality in developed countries, causing twice as many deaths as cancer in the USA. The major cardiovascular diseases, including coronary artery disease (CAD), myocardial infarction (MI), congestive heart failure (CHF) and common congenital heart disease (CHD), are caused by multiple genetic and environmental factors, as well as the interactions between them. The underlying molecular pathogenic mechanisms for these disorders are still largely unknown, but gene expression may play a central role in the development and progression of cardiovascular disease. Microarrays are high-throughput genomic tools that allow the comparison of global expression changes in thousands of genes between normal and diseased cells/tissues. Microarrays have recently been applied to CAD/MI, CHF and CHD to profile changes in gene expression patterns in diseased and non-diseased patients. This same technology has also been used to characterise endothelial cells, vascular smooth muscle cells and inflammatory cells, with or without various treatments that mimic disease processes involved in CAD/MI. These studies have led to the identification of unique subsets of genes associated with specific diseases and disease processes. Ongoing microarray studies in the field will provide insights into the molecular mechanism of cardiovascular disease and may generate new diagnostic and therapeutic markers. PMID:15588496

Superantigens and their association with dermatological inflammatory diseases: facts and hypotheses.

PubMed

Jappe, U

2000-01-01

Superantigens have been suggested to play an important role in the pathogenesis of several inflammatory skin diseases as well as systemic diseases such as atopic dermatitis, psoriasis, vasculitis, T-cell lymphoma and autoimmune diseases. Infections often precede the onset and relapse of these diseases, and antibiotic treatment with or without additional glucocorticosteroids and immunoglobulins is occasionally successful. Superantigens are microbial proteins that are able to stimulate up to 20% of the naive T-cell population in a non-specific way. They are produced by gram-positive and -negative bacteria as well as by viruses, parasites and yeasts. The importance of the pathogenic role of superantigens is determined by the potency to induce inflammation by extensive cytokine release after T-cell stimulation and/or T-cell-mediated cytotoxicity and, thereby, tissue damage. Furthermore, superantigens may be able to induce autoimmune processes by stimulation of autoreactive T-cells as well as autoantibody production by stimulation of B-cells. Among the diseases associated with superantigens, atopic dermatitis, guttate and chronic plaque psoriasis, as well as Kawasaki disease, are by far the best-characterized. Nevertheless, conflicting results have been obtained and formal proof of a pathogenic role of superantigens in these diseases is still lacking. The aim of this review is to summarize the data on superantigens in terms of their distribution in microorganisms, their interactions with the adaptive immune system and their contribution to skin pathology.

Regulatory roles of mast cells in immune responses.

PubMed

Morita, Hideaki; Saito, Hirohisa; Matsumoto, Kenji; Nakae, Susumu

2016-09-01

Mast cells are important immune cells for host defense through activation of innate immunity (via toll-like receptors or complement receptors) and acquired immunity (via FcεRI). Conversely, mast cells also act as effector cells that exacerbate development of allergic or autoimmune disorders. Yet, several lines of evidence show that mast cells act as regulatory cells to suppress certain inflammatory diseases. Here, we review the mechanisms by which mast cells suppress diseases.

Let There Be Light: Gene and Cell Therapy for Blindness.

PubMed

Dalkara, Deniz; Goureau, Olivier; Marazova, Katia; Sahel, José-Alain

2016-02-01

Retinal degenerative diseases are a leading cause of irreversible blindness. Retinal cell death is the main cause of vision loss in genetic disorders such as retinitis pigmentosa, Stargardt disease, and Leber congenital amaurosis, as well as in complex age-related diseases such as age-related macular degeneration. For these blinding conditions, gene and cell therapy approaches offer therapeutic intervention at various disease stages. The present review outlines advances in therapies for retinal degenerative disease, focusing on the progress and challenges in the development and clinical translation of gene and cell therapies. A significant body of preclinical evidence and initial clinical results pave the way for further development of these cutting edge treatments for patients with retinal degenerative disorders.

Let There Be Light: Gene and Cell Therapy for Blindness

PubMed Central

Dalkara, Deniz; Goureau, Olivier; Marazova, Katia; Sahel, José-Alain

2016-01-01

Retinal degenerative diseases are a leading cause of irreversible blindness. Retinal cell death is the main cause of vision loss in genetic disorders such as retinitis pigmentosa, Stargardt disease, and Leber congenital amaurosis, as well as in complex age-related diseases such as age-related macular degeneration. For these blinding conditions, gene and cell therapy approaches offer therapeutic intervention at various disease stages. The present review outlines advances in therapies for retinal degenerative disease, focusing on the progress and challenges in the development and clinical translation of gene and cell therapies. A significant body of preclinical evidence and initial clinical results pave the way for further development of these cutting edge treatments for patients with retinal degenerative disorders. PMID:26751519

Gut-liver axis: gut microbiota in shaping hepatic innate immunity.

PubMed

Wu, Xunyao; Tian, Zhigang

2017-11-01

Gut microbiota play an essential role in shaping immune cell responses. The liver was continuously exposed to metabolic products of intestinal commensal bacterial through portal vein and alteration of gut commensal bateria was always associated with increased risk of liver inflammation and autoimmune disease. Considered as a unique immunological organ, the liver is enriched with a large number of innate immune cells. Herein, we summarize the available literature of gut microbiota in shaping the response of hepatic innate immune cells including NKT cells, NK cells, γδ T cells and Kupffer cells during health and disease. Such knowledge might help to develop novel and innovative strategies for the prevention and therapy of innate immune cell-related liver disease.

Prospects of apoptotic cell-based therapies for transplantation and inflammatory diseases.

PubMed

Saas, Philippe; Kaminski, Sandra; Perruche, Sylvain

2013-10-01

Apoptotic cell removal or interactions of early-stage apoptotic cells with immune cells are associated with an immunomodulatory microenvironment that can be harnessed to exert therapeutic effects. While the involved immune mechanisms are still being deciphered, apoptotic cell infusion has been tested in different experimental models where inflammation is deregulated. This includes chronic and acute inflammatory disorders such as arthritis, contact hypersensitivity and acute myocardial infarction. Apoptotic cell infusion has also been used in transplantation settings to prevent or treat acute and chronic rejection, as well as to limit acute graft-versus-host disease associated with allogeneic hematopoietic cell transplantation. Here, we review the mechanisms involved in apoptotic cell-induced immunomodulation and data obtained in preclinical models of transplantation and inflammatory diseases.

Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey

PubMed Central

Kuçi, Zyrafete; Bönig, Halvard; Kreyenberg, Hermann; Bunos, Milica; Jauch, Anna; Janssen, Johannes W.G.; Škifić, Marijana; Michel, Kristina; Eising, Ben; Lucchini, Giovanna; Bakhtiar, Shahrzad; Greil, Johann; Lang, Peter; Basu, Oliver; von Luettichau, Irene; Schulz, Ansgar; Sykora, Karl-Walter; Jarisch, Andrea; Soerensen, Jan; Salzmann-Manrique, Emilia; Seifried, Erhard; Klingebiel, Thomas; Bader, Peter; Kuçi, Selim

2016-01-01

To circumvent donor-to-donor heterogeneity which may lead to inconsistent results after treatment of acute graft-versus-host disease with mesenchymal stromal cells generated from single donors we developed a novel approach by generating these cells from pooled bone marrow mononuclear cells of 8 healthy “3rd-party” donors. Generated cells were frozen in 209 vials and designated as mesenchymal stromal cell bank. These vials served as a source for generation of clinical grade mesenchymal stromal cell end-products, which exhibited typical mesenchymal stromal cell phenotype, trilineage differentiation potential and at later passages expressed replicative senescence-related markers (p21 and p16). Genetic analysis demonstrated their genomic stability (normal karyotype and a diploid pattern). Importantly, clinical end-products exerted a significantly higher allosuppressive potential than the mean allosuppressive potential of mesenchymal stromal cells generated from the same donors individually. Administration of 81 mesenchymal stromal cell end-products to 26 patients with severe steroid-resistant acute graft-versus-host disease in 7 stem cell transplant centers who were refractory to many lines of treatment, induced a 77% overall response at the primary end point (day 28). Remarkably, although the cohort of patients was highly challenging (96% grade III/IV and only 4% grade II graft-versus-host disease), after treatment with mesenchymal stromal cell end-products the overall survival rate at two years follow up was 71±11% for the entire patient cohort, compared to 51.4±9.0% in graft-versus-host disease clinical studies, in which mesenchymal stromal cells were derived from single donors. Mesenchymal stromal cell end-products may, therefore, provide a novel therapeutic tool for the effective treatment of severe acute graft-versus-host disease. PMID:27175026

Fetal progenitor cell transplantation treats methylmalonic aciduria in a mouse model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buck, Nicole E., E-mail: nicole.buck@mcri.edu.au; Pennell, Samuel D.; Wood, Leonie R.

Highlights: Black-Right-Pointing-Pointer Fetal cells were transplanted into a methylmalonic acid mouse model. Black-Right-Pointing-Pointer Cell engraftment was detected in liver, spleen and bone marrow. Black-Right-Pointing-Pointer Biochemical disease correction was measured in blood samples. Black-Right-Pointing-Pointer A double dose of 5 million cells (1 week apart) proved more effective. Black-Right-Pointing-Pointer Higher levels of engraftment may be required for greater disease correction. -- Abstract: Methylmalonic aciduria is a rare disorder caused by an inborn error of organic acid metabolism. Current treatment options are limited and generally focus on disease management. We aimed to investigate the use of fetal progenitor cells to treat this disordermore » using a mouse model with an intermediate form of methylmalonic aciduria. Fetal liver cells were isolated from healthy fetuses at embryonic day 15-17 and intravenously transplanted into sub-lethally irradiated mice. Liver donor cell engraftment was determined by PCR. Disease correction was monitored by urine and blood methylmalonic acid concentration and weight change. Initial studies indicated that pre-transplantation sub-lethal irradiation followed by transplantation with 5 million cells were suitable. We found that a double dose of 5 million cells (1 week apart) provided a more effective treatment. Donor cell liver engraftment of up to 5% was measured. Disease correction, as defined by a decrease in blood methylmalonic acid concentration, was effected in methylmalonic acid mice transplanted with a double dose of cells and who showed donor cell liver engraftment. Mean plasma methylmalonic acid concentration decreased from 810 {+-} 156 (sham transplanted) to 338 {+-} 157 {mu}mol/L (double dose of 5 million cells) while mean blood C3 carnitine concentration decreased from 20.5 {+-} 4 (sham transplanted) to 5.3 {+-} 1.9 {mu}mol/L (double dose of 5 million cells). In conclusion, higher levels of engraftment may be required for greater disease correction; however these studies show promising results for cell transplantation biochemical correction of a metabolic disorder.« less

From the basics to application of cell therapy, a steppingstone to the conquest of neurodegeneration: a meeting report.

PubMed

Park, Dong-Hyuk; Eve, David J; Borlongan, Cesario V; Klasko, Stephen K; Cruz, L Eduardo; Sanberg, Paul R

2009-02-01

The annual meeting of the American Society for Neural Therapy and Repair (ASNTR) showcases the latest research trends in neurodegenerative disease and the related medical regenerative science. The 2008 ASNTR meeting covered a variety of different topics ranging from basic research to exploration of currently unknown pathogenesis and mechanisms for specific neurodegenerative disease such as Parkinson's disease, Alzheimer's disease, or stroke. This included studies to characterize stem cells, such as neural stem cells, embryonic stem cells, bone marrow mesenchymal stem cells, and human umbilical cord blood cells, for transplantation and the conditions necessary to maximize the efficacy of endogenous and exogenous stem cells, such as isolation, purification, differentiation, and migration. Moreover, a number of studies looked at methods for more advanced application of transplantation of cells or specific factors, through tissue engineering or manipulation beyond simple injection. Finally, well-known or previously un-known dietary supplementation or pharmacological materials that can affect the nervous system positively or negatively, were also important topics.

Platelets, lymphocytes and erythrocytes from Alzheimer's disease patients: the quest for blood cell-based biomarkers.

PubMed

Pluta, Ryszard; Ułamek-Kozioł, Marzena; Januszewski, Sławomir; Czuczwar, Stanisław J

2018-01-01

In elderly population, Alzheimer's disease is a common neurodegenerative disorder and accounts for about 70% of all cases of dementia. The neurodegenerative processes of this disease start presumably 20 years ahead of the clinical beginning of the disorder. The postmortem histopathological examination, brains from Alzheimer's disease patients with characteristic features like amyloid plaques and neurofibrillary tangles, neuronal and synaptic disintegration confirm the final diagnosis of Alzheimer's disease. Senile plaques are composed of -amyloid peptide, deriving from the amyloid protein precursor, which is present not only in the brain tissue, but also in other non-neuronal tissues. Some investigations reported that platelets possess amyloid protein precursor and all the enzymatic activities required for the metabolism of this protein throughout the same pathways present in the brain. Thus, platelets may be a good peripheral blood cell-based biomarker to study the onset of Alzheimer's disease. Another line of research indicated molecular and cellular aberrations in blood lymphocytes and erythrocytes from Alzheimer's disease patients and emphasizes the systemic nature of the disease. In this review, we will summarize the recent knowledge on the involvement and/or response of platelets, lymphocytes and red blood cells in the circulation during Alzheimer's disease development. The facts will be reviewed with the special possibility for applying the above blood cells as Alzheimer's disease preclinical and antemortem blood cell-based biomarkers.

2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling.

PubMed

Centeno, Eduarda G Z; Cimarosti, Helena; Bithell, Angela

2018-05-22

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field.

Stem cell biology and drug discovery

PubMed Central

2011-01-01

There are many reasons to be interested in stem cells, one of the most prominent being their potential use in finding better drugs to treat human disease. This article focuses on how this may be implemented. Recent advances in the production of reprogrammed adult cells and their regulated differentiation to disease-relevant cells are presented, and diseases that have been modeled using these methods are discussed. Remaining difficulties are highlighted, as are new therapeutic insights that have emerged. PMID:21649940

Cholelithiasis in a toddler with sickle cell disease.

PubMed

Schinasi, Dana Aronson; Mistry, Rakesh D; Mistry, Rakesh

2011-06-01

Cholelithiasis is rarely seen in toddlers and school-aged children, even in the setting of sickle cell anemia. In addition to more common etiologies, such as gastroenteritis, constipation, and urinary tract infection, the differential diagnoses of acute abdominal pain in young children with sickle cell disease include vaso-occlusive pain crisis and splenic sequestration. We describe a case of a toddler with sickle cell disease initially presenting with abdominal pain who was found to have symptomatic cholelithiasis.

Disease-specific induced pluripotent stem cells: a platform for human disease modeling and drug discovery.

PubMed

Jang, Jiho; Yoo, Jeong-Eun; Lee, Jeong-Ah; Lee, Dongjin R; Kim, Ji Young; Huh, Yong Jun; Kim, Dae-Sung; Park, Chul-Yong; Hwang, Dong-Youn; Kim, Han-Soo; Kang, Hoon-Chul; Kim, Dong-Wook

2012-03-31

The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens.

The lived experiences of adolescents with sickle cell disease in Kingston, Jamaica.

PubMed

Forrester, Andrea Brown; Barton-Gooden, Antoinette; Pitter, Cynthia; Lindo, Jascinth L M

2015-01-01

To explore the lived experiences of adolescents with sickle cell disease, in Kingston, Jamaica. A descriptive qualitative design was used for this research. In-depth interviews were conducted with six adolescents with sickle cell disease at a Sickle Cell Unit operated by the University of the West Indies. Interviews were audiotaped, transcribed, and thematically analyzed. The majority of the adolescents demonstrated a positive self-concept. They reported strong family, school, and peer support which made them feel accepted. All were actively engaged in social activities such as parties, but had challenges participating in sporting activities. Various coping strategies were utilized to address challenges of the disease including praying, watching television, and surfing the Internet. Sickle cell disease can be very challenging for the adolescent, but with positive self-concept and increased social support, especially from family and peers, these adolescents were able to effectively cope with their condition and live productive lives.

[Pathophysiology of sickle cell disease].

PubMed

Elion, J; Laurance, S; Lapouméroulie, C

2010-12-01

It has been 100 years since Herrick published the first medical case report of sickle cell disease. In 1949, Pauling discovered hemoglobin S (HbS). As early as the 1960-70s, emerged a coherent detailed molecular-level description of pathophysiology of sickle disease. It involved polymerization of deoxyhemoglobin S with formation of long fibers inside red blood cells (RBC) causing a distorted sickle shape and shortened lifespan. These changes constitute the basic disease process and account for hemolytic anemia and for obstructive events underlying vasoocclusive crises (VOC). However, they do not explain the mechanisms that trigger VOC. The purpose of this review is to present recent data on dehydration of sickle cell RBC, abnormalities in RBC adhesion to the vascular endothelium, the role of inflammatory events and of activation of all cells in the vessel, and abnormalities of vascular tone and carbon monoxide metabolism. These data provide new insight into the pathophysiology of the first molecular disease.

Cell type-selective disease-association of genes under high regulatory load

PubMed Central

Galhardo, Mafalda; Berninger, Philipp; Nguyen, Thanh-Phuong; Sauter, Thomas; Sinkkonen, Lasse

2015-01-01

We previously showed that disease-linked metabolic genes are often under combinatorial regulation. Using the genome-wide ChIP-Seq binding profiles for 93 transcription factors in nine different cell lines, we show that genes under high regulatory load are significantly enriched for disease-association across cell types. We find that transcription factor load correlates with the enhancer load of the genes and thereby allows the identification of genes under high regulatory load by epigenomic mapping of active enhancers. Identification of the high enhancer load genes across 139 samples from 96 different cell and tissue types reveals a consistent enrichment for disease-associated genes in a cell type-selective manner. The underlying genes are not limited to super-enhancer genes and show several types of disease-association evidence beyond genetic variation (such as biomarkers). Interestingly, the high regulatory load genes are involved in more KEGG pathways than expected by chance, exhibit increased betweenness centrality in the interaction network of liver disease genes, and carry longer 3′ UTRs with more microRNA (miRNA) binding sites than genes on average, suggesting a role as hubs integrating signals within regulatory networks. In summary, epigenetic mapping of active enhancers presents a promising and unbiased approach for identification of novel disease genes in a cell type-selective manner. PMID:26338775

Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses.

PubMed

Sima, Ni; Li, Rong; Huang, Wei; Xu, Miao; Beers, Jeanette; Zou, Jizhong; Titus, Steven; Ottinger, Elizabeth A; Marugan, Juan J; Xie, Xing; Zheng, Wei

2018-04-10

Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency in PPT1 or TPP1 enzyme function results in lysosomal accumulation of pathological lipofuscin-like material in the patient cells. There is currently no small-molecular drug treatment for NCLs. We have generated induced pluripotent stem cells (iPSC) from three patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). Using these new disease models, we evaluated the effect of δ-tocopherol (DT) and hydroxypropyl-β-cyclodextrin (HPBCD) with the enzyme replacement therapy as the control. Treatment with the relevant recombinant enzyme or DT significantly ameliorated the lipid accumulation and lysosomal enlargement in the disease cells. A combination therapy of δ-tocopherol and HPBCD further improved the effect compared to that of either drug used as a single therapy. The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development.

A successful education program for parents of infants with newly diagnosed sickle cell disease.

PubMed

Day, S; Brunson, G; Wang, W

1992-02-01

The most dramatic recent advance in the care of young children with sickle cell disease was the demonstration by a cooperative study that the use of oral penicillin prophylaxis is highly effective in decreasing the risk of pneumococcal sepsis. Subsequently, the need for more comprehensive education of the parents of these children to ensure compliance with penicillin administration has become apparent. Over the past 4 years, the Mid-South Sickle Cell Disease Program has used a seven-phase educational process for the parents of more than 200 infants with newly diagnosed sickle cell disease. This has resulted in excellent compliance and a marked decrease in the incidence of pneumococcal sepsis among sickle cell patients at our center.

Selective T-Cell Depletion to Reduce GVHD (Patients) Receiving Stem Cell Tx to Treat Leukemia, Lymphoma or MDS

ClinicalTrials.gov

2016-09-21

Graft vs Host Disease; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myelomonocytic, Chronic; Leukemia, Lymphocytic; Lymphoma; Lymphoma, Mantle-cell; Lymphoma, Non-Hodgkin; Hodgkin Disease

Immunopathology of childhood celiac disease—Key role of intestinal epithelial cells

PubMed Central

Hedberg, Maria; Sjöberg, Veronika; Sandström, Olof; Hernell, Olle; Hammarström, Sten

2017-01-01

Background & Aims Celiac disease is a chronic inflammatory disease of the small intestine mucosa due to permanent intolerance to dietary gluten. The aim was to elucidate the role of small intestinal epithelial cells in the immunopathology of celiac disease in particular the influence of celiac disease-associated bacteria. Methods Duodenal biopsies were collected from children with active celiac disease, treated celiac disease, and clinical controls. Intestinal epithelial cells were purified and analyzed for gene expression changes at the mRNA and protein levels. Two in vitro models for human intestinal epithelium, small intestinal enteroids and polarized tight monolayers, were utilized to assess how interferon-γ, interleukin-17A, celiac disease-associated bacteria and gluten influence intestinal epithelial cells. Results More than 25 defense-related genes, including IRF1, SPINK4, ITLN1, OAS2, CIITA, HLA-DMB, HLA-DOB, PSMB9, TAP1, BTN3A1, and CX3CL1, were significantly upregulated in intestinal epithelial cells at active celiac disease. Of these genes, 70% were upregulated by interferon-γ via the IRF1 pathway. Most interestingly, IRF1 was also upregulated by celiac disease-associated bacteria. The NLRP6/8 inflammasome yielding CASP1 and biologically active interleukin-18, which induces interferon-γ in intraepithelial lymphocytes, was expressed in intestinal epithelial cells. Conclusion A key factor in the epithelial reaction in celiac disease appears to be over-expression of IRF1 that could be inherent and/or due to presence of undesirable microbes that act directly on IRF1. Dual activation of IRF1 and IRF1-regulated genes, both directly and via the interleukin-18 dependent inflammasome would drastically enhance the inflammatory response and lead to the pathological situation seen in active celiac disease. PMID:28934294

Autoantigen-specific B-cell depletion overcomes failed immune tolerance in type 1 diabetes.

PubMed

Henry, Rachel A; Kendall, Peggy L; Thomas, James W

2012-08-01

Eliminating autoantigen-specific B cells is an attractive alternative to global B-cell depletion for autoimmune disease treatment. To identify the potential for targeting a key autoimmune B-cell specificity in type 1 diabetes, insulin-binding B cells were tracked within a polyclonal repertoire using heavy chain B-cell receptor (BCR) transgenic (VH125Tg) mice. Insulin-specific B cells are rare in the periphery of nonautoimmune VH125Tg/C57BL/6 mice and WT/NOD autoimmune mice, whereas they clearly populate 1% of mature B-cell subsets in VH125Tg/NOD mice. Autoantigen upregulates CD86 in anti-insulin B cells, suggesting they are competent to interact with T cells. Endogenous insulin occupies anti-insulin BCR beginning with antigen commitment in bone marrow parenchyma, as identified by a second anti-insulin monoclonal antibody. Administration of this monoclonal antibody selectively eliminates insulin-reactive B cells in vivo and prevents disease in WT/NOD mice. Unexpectedly, developing B cells are less amenable to depletion, despite increased BCR sensitivity. These findings exemplify how a critical type 1 diabetes B-cell specificity escapes immune tolerance checkpoints. Disease liability is corrected by eliminating this B-cell specificity, providing proof of concept for a novel therapeutic approach for autoimmune disease.

Deficiency of interstitial cells of Cajal in the small intestine of patients with Crohn's disease.

PubMed

Porcher, Christophe; Baldo, Marjolaine; Henry, Monique; Orsoni, Pierre; Julé, Yvon; Ward, Sean M

2002-01-01

Interstitial cells of Cajal are critical for the generation of electrical slow waves that regulate the phasic contractile activity of the tunica muscularis of the GI tract. Under certain pathophysiological conditions loss of interstitial cells of Cajal may play a role in the generation of certain motility disorders. The aim of the present study was to determine if there is an abnormality in the density or distribution of interstitial cells of Cajal from patients with Crohn's disease. Small intestines from control subjects and patients with Crohn's disease were examined using immunohistochemistry and antibodies against the Kit receptor, which is expressed in interstitial cells of Cajal within the tunica muscularis of the GI tract. The density and distribution of interstitial cells of Cajal were assessed in the longitudinal and circular muscle layers and in the myenteric and deep muscular plexus regions of Crohn's and control tissues. Tissues from Crohn's disease patients showed an almost complete abolition of interstitial cells of Cajal within the longitudinal and circular muscle layers and a significant reduction in numbers at the level of the myenteric and deep muscular plexuses. In tissues from Crohn's disease patients, the density of interstitial cells of Cajal was reduced throughout the tunica muscularis in comparison to control small intestines. The disturbance of intestinal motility that occurs in patients with Crohn's disease may be a consequence of the loss of or defects in specific populations of interstitial cells of Cajal within the tunica muscularis.

Killer (FASL regulatory) B cells are present during latent TB and are induced by BCG stimulation in participants with and without latent tuberculosis.

PubMed

van Rensburg, Ilana C; Loxton, Andre G

2018-01-01

Regulatory B cells (Bregs) have been shown to be present during several disease states. The phenotype of the cells is not completely defined and the function of these cells differ between disease. The presence of FASL expressing (killer) B cells during latent and successfully treated TB disease have been shown but whether these cells are similar to regulatory B cells remain unclear. We assessed the receptor expression of FASL/IL5 (killer B cells), CD24/CD38 (regulatory B cells) on whole peripheral blood of participants with untreated active TB and healthy controls. We then isolated B cells from a second cohort of M.tb exposed (Quantiferon (QFN) positive) and unexposed (Quantiferon negative) HIV negative participants, and evaluated the frequency of killer B cells induced following stimulation with BCG and/or CD40 and IL5. Our data reveal no difference in the expression on CD24 and CD38 between participants with active TB and the controls. There was also no difference in the frequency of regulatory B cells measured in the peripheral blood mononuclear cells (PBMC) fraction between latent TB and uninfected controls. We did however notice that regulatory B cells (CD24hiCD38hi) population express the FASL receptor. The expression of killer B cell phenotype (CD178+IL5RA+) was significantly higher in controls compared to those with active TB disease (1,06% vs 0,455%). Furthermore, we found that BCG restimulation significantly induced the FASL/IL5RA B cells but this was only evident in the QFN positive group. Our data suggest that both regulatory and killer B cells are present during latent and active TB disease but that the frequency of these populations are increased during latent disease. We also show that the FASL+IL5RA+ B killer B cells are induced in latent TB infection following BCG restimulation but whether these cells are indicative of protection remains unclear. Copyright © 2017 Elsevier Ltd. All rights reserved.

Lck is a relevant target in chronic lymphocytic leukaemia cells whose expression variance is unrelated to disease outcome.

PubMed

Till, Kathleen J; Allen, John C; Talab, Fatima; Lin, Ke; Allsup, David; Cawkwell, Lynn; Bentley, Alison; Ringshausen, Ingo; Duckworth, Andrew D; Pettitt, Andrew R; Kalakonda, Nagesh; Slupsky, Joseph R

2017-12-01

Pathogenesis of chronic lymphocytic leukaemia (CLL) is contingent upon antigen receptor (BCR) expressed by malignant cells of this disease. Studies on somatic hypermutation of the antigen binding region, receptor expression levels and signal capacity have all linked BCR on CLL cells to disease prognosis. Our previous work showed that the src-family kinase Lck is a targetable mediator of BCR signalling in CLL cells, and that variance in Lck expression associated with ability of BCR to induce signal upon engagement. This latter finding makes Lck similar to ZAP70, another T-cell kinase whose aberrant expression in CLL cells also associates with BCR signalling capacity, but also different because ZAP70 is not easily pharmacologically targetable. Here we describe a robust method of measuring Lck expression in CLL cells using flow cytometry. However, unlike ZAP70 whose expression in CLL cells predicts prognosis, we find Lck expression and disease outcome in CLL are unrelated despite observations that its inhibition produces effects that biologically resemble the egress phenotype taken on by CLL cells treated with idelalisib. Taken together, our findings provide insight into the pathobiology of CLL to suggest a more complex relationship between expression of molecules within the BCR signalling pathway and disease outcome.

The gamma delta T cell repertoire in Graves' disease and multinodular goitre.

PubMed Central

McIntosh, R S; Tandon, N; Pickerill, A P; Davies, R; Barnett, D; Weetman, A P

1993-01-01

gamma delta T cells are a subset of T cells with unknown function, and restriction of the gamma delta T cell receptor (TCR) repertoire has been described in rheumatoid arthritis and multiple sclerosis. Elevated numbers of gamma delta T cells have been reported in the peripheral blood and thyroids of patients with Graves' disease. We have carried out flow cytometric analysis on peripheral blood mononuclear cells (PBMC) and intrathyroidal lymphocytes (ITL) from 12 patients with Graves' disease and nine patients with multinodular goitre (MNG), a thyroid disease of unknown etiology. There was no significant difference between the proportion of gamma delta T cells in the PBMC of Graves' and MNG patients, nor between the PBMC and ITL populations in either patient group. We have also carried out polymerase chain reaction amplification on RNA prepared from matched PBMC, ITL and the activated (CD25+) subset of ITL using six TCR V delta-family specific primers. Although there were differences in the amounts of each V delta transcript amplified from PBMC and ITL, there was no difference between the two patient groups. No consistent differences were therefore found between the gamma delta T cell populations in Graves' and MNG patients, arguing against the direct involvement of this T cell subset in the pathogenesis of Graves' disease. Images Fig. 1 PMID:8252809

Human intestinal mucosal mast cells: expanded population in untreated coeliac disease.

PubMed Central

Strobel, S; Busuttil, A; Ferguson, A

1983-01-01

Previous retrospective studies of intestinal mucosal mast cells in coeliac disease have given divergent results, and we have recently reported that inappropriate methodology could account for these discrepancies. In this prospective study, mucosal mast cell counts were performed in Carnoy fixed, peroral jejunal biopsy specimens from patients with coeliac disease, both untreated and treated with a gluten-free diet; and from controls (mainly irritable bowel syndrome). Mean mucosal mast cell count in 27 control subjects was 146/mm2, SD 29. Significantly higher values were obtained in untreated coeliac disease (mean 243, SD 41, p less than 0.001) returning to the normal range in coeliacs treated with a gluten-free diet with normal jejunal biopsy morphology. In seven patients mucosal mast cell counts were performed in multiple jejunal biopsies, and these showed that mucosal mast cell distribution was not patchy. There was no evidence of degranulation of intestinal mucosal mast cells under the conditions of routine biopsy (overnight fast). An increase in mucosal mast cells in untreated coeliac disease may be one explanation for the high number of IgE positive stained cells in the intestinal mucosa that has been reported by some authors. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 PMID:6826106

Necroptosis: an emerging type of cell death in liver diseases.

PubMed

Saeed, Waqar Khalid; Jun, Dae Won

2014-09-21

Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ's physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ's physiological function can be prevented.

The role of necroptosis in the treatment of diseases.

PubMed

Cho, Young Sik

2018-04-11

Necroptosis is an emerging form of programmed cell death occurring via active and well-regulated necrosis, distinct from apoptosis morphologically, and biochemically. Necroptosis is mainly unmasked when apoptosis is compromised in response to cell stress. Unlike apoptotic cells, which are cleared by macrophages or neighboring cells, necrotic cells release danger signals, triggering inflammation, and exacerbating tissue damage. Evidence increasingly suggests that programmed necrosis is not only associated with pathophysiology of disease, but also induces innate immune response to viral infection. Therefore, necroptotic cell death plays both physiological and pathological roles. Physiologically, necroptosis induce an innate immune response as well as premature assembly of viral particles in cells infected with virus that abrogates host apoptotic machinery. On the other hand, necroptosis per se is detrimental, causing various diseases such as sepsis, neurodegenerative diseases and ischemic reperfusion injury. This review discusses the signaling pathways leading to necroptosis, associated necroptotic proteins with target-specific inhibitors and diseases involved. Several studies currently focus on protective approaches to inhibit necroptotic cell death. In cancer biology, however, anticancer drug resistance severely hampers the efficacy of chemotherapy based on apoptosis. Pharmacological switch of cell death finds therapeutic application in drug-resistant cancers. Therefore, the possible clinical role of necroptosis in cancer control will be discussed in brief.

Pathogenic or Therapeutic Extracellular Vesicles in Rheumatic Diseases: Role of Mesenchymal Stem Cell-Derived Vesicles

PubMed Central

Cosenza, Stella; Ruiz, Maxime; Maumus, Marie; Jorgensen, Christian; Noël, Danièle

2017-01-01

Extracellular vesicles (EVs) are important mediators of cell-to-cell communication pathways via the transport of proteins, mRNA, miRNA and lipids. There are three main types of EVs, exosomes, microparticles and apoptotic bodies, which are classified according to their size and biogenesis. EVs are secreted by all cell types and their function reproduces that of the parental cell. They are involved in many biological processes that regulate tissue homeostasis and physiopathology of diseases. In rheumatic diseases, namely osteoarthritis (OA) and rheumatoid arthritis (RA), EVs have been isolated from synovial fluid and shown to play pathogenic roles contributing to progression of both diseases. By contrast, EVs may have therapeutic effect via the delivery of molecules that may stop disease evolution. In particular, EVs derived from mesenchymal stem cells (MSCs) reproduce the main functions of the parental cells and therefore represent the ideal type of EVs for modulating the course of either disease. The aim of this review is to discuss the role of EVs in OA and RA focusing on their potential pathogenic effect and possible therapeutic options. Special attention is given to MSCs and MSC-derived EVs for modulating OA and RA progression with the perspective of developing innovative therapeutic strategies. PMID:28441721

Proceedings: Regenerative Medicine for Lung Diseases: A CIRM Workshop Report.

PubMed

Kadyk, Lisa C; DeWitt, Natalie D; Gomperts, Brigitte

2017-10-01

The mission of the California Institute of Regenerative Medicine (CIRM) is to accelerate treatments to patients with unmet medical needs. In September 2016, CIRM sponsored a workshop held at the University of California, Los Angeles, to discuss regenerative medicine approaches for treatment of lung diseases and to identify the challenges remaining for advancing such treatments to the clinic and market approval. Workshop participants discussed current preclinical and clinical approaches to regenerative medicine in the lung, as well as the biology of lung stem cells and the role of stem cells in the etiology of various lung diseases. The outcome of this effort was the recognition that whereas transient cell delivery approaches are leading the way in the clinic, recent advances in the understanding of lung stem cell biology, in vitro and in vivo disease modeling, gene editing and replacement methods, and cell engraftment approaches raise the prospect of developing cures for some lung diseases in the foreseeable future. In addition, advances in in vitro modeling using lung organoids and "lung on a chip" technology are setting the stage for high quality small molecule drug screening to develop treatments for lung diseases with complex biology. Stem Cells Translational Medicine 2017;6:1823-1828. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

Events of hospitalization among children with sickle cell disease.

PubMed

Fosdal, Marian B; Wojner-Alexandrov, Anne W

2007-08-01

Previous research has identified vaso-occlusive pain crisis as the most common reason for hospitalization among pediatric patients with sickle cell disease. We sought to identify contributors to hospitalization and length of stay (LOS) for this patient population. A descriptive design was used to determine factors associated with hospitalization and LOS for patients with sickle cell disease at an urban tertiary care pediatric hospital in the Midwest. Sickle cell disease as a principal or secondary diagnosis during calendar year 2003 was used to identify patients for study inclusion. Data were collected from subjects' medical records and the hospital accounting system. 72 African American subjects, ranging in age from infant to 24 years (mean = 10.3) met study inclusion criteria, and accounted for 186 hospitalizations. Sickle cell pain crisis was the most common diagnosis associated with hospitalization (n = 122). Adolescent age was significantly associated with longer LOS (r = .451; p<.001), and females stayed on average 2.1 days longer than male subjects (p = .001). Age and gender appear to be associated with LOS in pediatric patients with sickle cell disease, although specific factors underlying these findings remain unclear. Further research is necessary to determine how the complex interplay of social, cultural, developmental, and physiologic factors may contribute to the hospitalization experience of children and adolescents with sickle cell disease.

The use of stem cells in regenerative medicine for Parkinson's and Huntington's Diseases.

PubMed

Lescaudron, L; Naveilhan, P; Neveu, I

2012-01-01

Cell transplantation has been proposed as a means of replacing specific cell populations lost through neurodegenerative processes such as that seen in Parkinson's or Huntington's diseases. Improvement of the clinical symptoms has been observed in a number of Parkinson and Huntington's patients transplanted with freshly isolated fetal brain tissue but such restorative approach is greatly hampered by logistic and ethical concerns relative to the use of fetal tissue, in addition to potential side effects that remain to be controlled. In this context, stem cells that are capable of self-renewal and can differentiate into neurons, have received a great deal of interest, as demonstrated by the numerous studies based on the transplantation of neural stem/progenitor cells, embryonic stem cells or mesenchymal stem cells into animal models of Parkinson's or Huntington's diseases. More recently, the induction of pluripotent stem cells from somatic adult cells has raised a new hope for the treatment of neurodegenerative diseases. In the present article, we review the main experimental approaches to assess the efficiency of cell-based therapy for Parkinson's or Huntington's diseases, and discuss the recent advances in using stem cells to replace lost dopaminergic mesencephalic or striatal neurons. Characteristics of the different stem cells are extensively examined with a special attention to their ability of producing neurotrophic or immunosuppressive factors, as these may provide a favourable environment for brain tissue repair and long-term survival of transplanted cells in the central nervous system. Thus, stem cell therapy can be a valuable tool in regenerative medicine.

Modeling neurological diseases with induced pluripotent cells reprogrammed from immortalized lymphoblastoid cell lines.

PubMed

Fujimori, Koki; Tezuka, Toshiki; Ishiura, Hiroyuki; Mitsui, Jun; Doi, Koichiro; Yoshimura, Jun; Tada, Hirobumi; Matsumoto, Takuya; Isoda, Miho; Hashimoto, Ryota; Hattori, Nubutaka; Takahashi, Takuya; Morishita, Shinichi; Tsuji, Shoji; Akamatsu, Wado; Okano, Hideyuki

2016-10-03

Patient-specific induced pluripotent stem cells (iPSCs) facilitate understanding of the etiology of diseases, discovery of new drugs and development of novel therapeutic interventions. A frequently used starting source of cells for generating iPSCs has been dermal fibroblasts (DFs) isolated from skin biopsies. However, there are also numerous repositories containing lymphoblastoid B-cell lines (LCLs) generated from a variety of patients. To date, this rich bioresource of LCLs has been underused for generating iPSCs, and its use would greatly expand the range of targeted diseases that could be studied by using patient-specific iPSCs. However, it remains unclear whether patient's LCL-derived iPSCs (LiPSCs) can function as a disease model. Therefore, we generated Parkinson's disease patient-specific LiPSCs and evaluated their utility as tools for modeling neurological diseases. We established iPSCs from two LCL clones, which were derived from a healthy donor and a patient carrying PARK2 mutations, by using existing non-integrating episomal protocols. Whole genome sequencing (WGS) and comparative genomic hybridization (CGH) analyses showed that the appearance of somatic variations in the genomes of the iPSCs did not vary substantially according to the original cell types (LCLs, T-cells and fibroblasts). Furthermore, LiPSCs could be differentiated into functional neurons by using the direct neurosphere conversion method (dNS method), and they showed several Parkinson's disease phenotypes that were similar to those of DF-iPSCs. These data indicate that the global LCL repositories can be used as a resource for generating iPSCs and disease models. Thus, LCLs are the powerful tools for generating iPSCs and modeling neurological diseases.

Bone Marrow-Derived Mesenchymal Stem Cell Therapy as a Candidate Disease-Modifying Strategy in Parkinson's Disease and Multiple System Atrophy

PubMed Central

Park, Hyun Jung

2009-01-01

Parkinson's disease (PD) and multiple system atrophy (MSA) are neurodegenerative diseases representative of α-synucleinopathies characterized pathologically by α-synuclein-abundant Lewy bodies and glial cytoplasmic inclusions, respectively. Embryonic stem cells, fetal mesencephalic neurons, and neural stem cells have been introduced as restorative strategies in PD animals and patients, but ethical and immunological problems as well as the serious side effects of tumorigenesis and disabling dyskinesia have limited clinical application of these stem cells. Meanwhile, cell therapy using mesenchymal stem cells (MSCs) is attractive clinically because these cells are free from ethical and immunological problems. MSCs are present in adult bone marrow and represent <0.01% of all nucleated bone marrow cells. MSCs are themselves capable of multipotency, differentiating under appropriate conditions into chondrocytes, skeletal myocytes, and neurons. According to recent studies, the neuroprotective effect of MSCs is mediated by their ability to produce various trophic factors that contribute to functional recovery, neuronal cell survival, and stimulation of endogenous regeneration and by immunoregulatory properties that not only inhibit nearly all cells participating in the immune response cell-cell-contact-dependent mechanism, but also release various soluble factors associated with immunosuppressive activity. However, the use of MSCs as neuroprotectives in PD and MSA has seldom been studied. Here we comprehensively review recent advances in the therapeutic roles of MSCs in PD and MSA, especially focusing on their neuroprotective properties and use in disease-modifying therapeutic strategies. PMID:19513327

Genetics Home Reference: Camurati-Engelmann disease

MedlinePlus

... the growth and division (proliferation) of cells, the maturation of cells to carry out specific functions (differentiation), ... Educational Resources (6 links) Children's Hospital of Philadelphia: Skeletal Dysplasias Disease InfoSearch: Camurati Engelmann Disease KidsHealth from ...

75 FR 33897 - Agency Request for Emergency Approval of an Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-15

... Leukemias Disability Benefits Questionnaire, VA Form 21-0960B. c. Parkinson's Disease Disability Benefits...: Hairy cell leukemia and other chronic B-cell leukemias, Parkinson's disease, and ischemic heart disease... Form 21-0960B--500. c. Parkinson's Disease Disability Benefits Questionnaire, VA Form 21-0960C--1,250...

Marek’s disease virus-induced transient cecal tonsil atrophy

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of domestic chickens that is caused by a highly cell-associated oncogenic '-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latent infection within CD4+ T cells. MD is characterized by bursal/th...

Marek's Disease Virus-Induced Immunosuppression: Array Analysis of Chicken Immune Response Gene Expression Profiling

USDA-ARS?s Scientific Manuscript database

Marek’s disease (MD) is a lymphoproliferative disease of chickens induced by a highly cell-associated oncogenic alpha-herpesvirus, Marek’s disease virus (MDV). MDV replicates in chicken lymphocytes and establishes a latency infection within CD4+ T cells. Host-virus interaction, immune responses to...

Anti-bacterial antibody and T cell responses in bronchiectasis are differentially associated with lung colonization and disease.

PubMed

Jaat, Fathia G; Hasan, Sajidah F; Perry, Audrey; Cookson, Sharon; Murali, Santosh; Perry, John D; Lanyon, Clare V; De Soyza, Anthony; Todryk, Stephen M

2018-05-30

As a way to determine markers of infection or disease informing disease management, and to reveal disease-associated immune mechanisms, this study sought to measure antibody and T cell responses against key lung pathogens and to relate these to patients' microbial colonization status, exacerbation history and lung function, in Bronchiectasis (BR) and Chronic Obstructive Pulmonary Disease (COPD). One hundred nineteen patients with stable BR, 58 with COPD and 28 healthy volunteers were recruited and spirometry was performed. Bacterial lysates were used to measure specific antibody responses by ELISA and T cells by ELIspot. Cytokine secretion by lysate-stimulated T cells was measured by multiplex cytokine assay whilst activation phenotype was measured by flow cytometry. Typical colonization profiles were observed in BR and COPD, dominated by P.aeruginosa, H.influenzae, S.pneumoniae and M.catarrhalis. Colonization frequency was greater in BR, showing association with increased antibody responses against P.aeruginosa compared to COPD and HV, and with sensitivity of 73% and specificity of 95%. Interferon-gamma T cell responses against P.aeruginosa and S.pneumoniae were reduced in BR and COPD, whilst reactive T cells in BR had similar markers of homing and senescence compared to healthy volunteers. Exacerbation frequency in BR was associated with increased antibodies against P. aeruginosa, M.catarrhalis and S.maltophilia. T cell responses against H.influenzae showed positive correlation with FEV 1 % (r = 0.201, p = 0.033) and negative correlation with Bronchiectasis Severity Index (r = - 0.287, p = 0.0035). Our findings suggest a difference in antibody and T cell immunity in BR, with antibody being a marker of exposure and disease in BR for P.aeruginosa, M.catarrhalis and H.influenzae, and T cells a marker of reduced disease for H.influenzae.

Vaccination strategies for Parkinson disease

PubMed Central

Romero-Ramos, Marina; von Euler Chelpin, Marianne; Sanchez-Guajardo, Vanesa

2014-01-01

Parkinson disease is the second most common neurodegenerative disease in the world, but there is currently no available cure for it. Current treatments only alleviate some of the symptoms for a few years, but they become ineffective in the long run and do not stop the disease. Therefore it is of outmost importance to develop therapeutic strategies that can prevent, stop, or cure Parkinson disease. A very promising target for these therapies is the peripheral immune system due to its probable involvement in the disease and its potential as a tool to modulate neuroinflammation. But for such strategies to be successful, we need to understand the particular state of the peripheral immune system during Parkinson disease in order to avoid its weaknesses. In this review we examine the available data regarding how dopamine regulates the peripheral immune system and how this regulation is affected in Parkinson disease; the specific cytokine profiles observed during disease progression and the alterations documented to date in patients’ peripheral blood mononuclear cells. We also review the different strategies used in Parkinson disease animal models to modulate the adaptive immune response to salvage dopaminergic neurons from cell death. After analyzing the evidence, we hypothesize the need to prime the immune system to restore natural tolerance against α-synuclein in Parkinson disease, including at the same time B and T cells, so that T cells can reprogram microglia activation to a beneficial pattern and B cell/IgG can help neurons cope with the pathological forms of α-synuclein. PMID:24670306

The Use of Induced Pluripotent Stem Cells for the Study and Treatment of Liver Diseases.

PubMed

Hansel, Marc C; Davila, Julio C; Vosough, Massoud; Gramignoli, Roberto; Skvorak, Kristen J; Dorko, Kenneth; Marongiu, Fabio; Blake, William; Strom, Stephen C

2016-02-01

Liver disease is a major global health concern. Liver cirrhosis is one of the leading causes of death in the world and currently the only therapeutic option for end-stage liver disease (e.g., acute liver failure, cirrhosis, chronic hepatitis, cholestatic diseases, metabolic diseases, and malignant neoplasms) is orthotropic liver transplantation. Transplantation of hepatocytes has been proposed and used as an alternative to whole organ transplant to stabilize and prolong the lives of patients in some clinical cases. Although these experimental therapies have demonstrated promising and beneficial results, their routine use remains a challenge due to the shortage of donor livers available for cell isolation, variable quality of those tissues, the potential need for lifelong immunosuppression in the transplant recipient, and high costs. Therefore, new therapeutic strategies and more reliable clinical treatments are urgently needed. Recent and continuous technological advances in the development of stem cells suggest they may be beneficial in this respect. In this review, we summarize the history of stem cell and induced pluripotent stem cell (iPSC) technology in the context of hepatic differentiation and discuss the potential applications the technology may offer for human liver disease modeling and treatment. This includes developing safer drugs and cell-based therapies to improve the outcomes of patients with currently incurable health illnesses. We also review promising advances in other disease areas to highlight how the stem cell technology could be applied to liver diseases in the future. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

PubMed Central

Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

2013-01-01

Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA. PMID:23208423

B lymphocyte lineage cells and the respiratory system

PubMed Central

Kato, Atsushi; Hulse, Kathryn E.; Tan, Bruce K.; Schleimer, Robert P.

2013-01-01

Adaptive humoral immune responses in the airways are mediated by B cells and plasma cells that express highly evolved and specific receptors and produce immunoglobulins of most isotypes. In some cases, such as autoimmune diseases or inflammatory diseases caused by excessive exposure to foreign antigens, these same immune cells can cause disease by virtue of overly vigorous responses. This review discusses the generation, differentiation, signaling, activation and recruitment pathways of B cells and plasma cells, with special emphasis on unique characteristics of subsets of these cells functioning within the respiratory system. The primary sensitization events that generate B cells responsible for effector responses throughout the airways usually occur in the upper airways, in tonsils and adenoid structures that make up Waldeyer’s Ring. Upon secondary exposure to antigen in the airways, antigen-processing dendritic cells migrate into secondary lymphoid organs such as lymph nodes that drain the upper and lower airways and further B cell expansion takes place at those sites. Antigen exposure in the upper or lower airways can also drive expansion of B lineage cells in the airway mucosal tissue and lead to the formation of inducible lymphoid follicles or aggregates that can mediate local immunity or disease. PMID:23540615

The promises of stem cells: stem cell therapy for movement disorders.

PubMed

Mochizuki, Hideki; Choong, Chi-Jing; Yasuda, Toru

2014-01-01

Despite the multitude of intensive research, the exact pathophysiological mechanisms underlying movement disorders including Parkinson's disease, multiple system atrophy and Huntington's disease remain more or less elusive. Treatments to halt these disease progressions are currently unavailable. With the recent induced pluripotent stem cells breakthrough and accomplishment, stem cell research, as the vast majority of scientists agree, holds great promise for relieving and treating debilitating movement disorders. As stem cells are the precursors of all cells in the human body, an understanding of the molecular mechanisms that govern how they develop and work would provide us many fundamental insights into human biology of health and disease. Moreover, stem-cell-derived neurons may be a renewable source of replacement cells for damaged neurons in movement disorders. While stem cells show potential for regenerative medicine, their use as tools for research and drug testing is thought to have more immediate impact. The use of stem-cell-based drug screening technology could be a big boost in drug discovery for these movement disorders. Particular attention should also be given to the involvement of neural stem cells in adult neurogenesis so as to encourage its development as a therapeutic option. Copyright © 2013 Elsevier Ltd. All rights reserved.

Chimeric antigen receptor T-cell therapy in AML: How close are we?

PubMed Central

Gill, Saar

2016-01-01

The majority of patients presenting with acute myeloid leukemia (AML) initially respond to chemotherapy but post-remission therapy is required to consolidate this response and achieve long-term disease-free survival. The most effective form of post-remission therapy relies on T-cell immunotherapy in the form of allogeneic hematopoietic cell transplantation (HCT). However, patients with active disease cannot usually expect to be cured with HCT. This inherent dichotomy implies that traditional T cell-based immunotherapy in the form of allogeneic HCT stops being efficacious somewhere between the measurable residual disease (MRD) and the morphologically obvious range. This is in part because the full power of T cells must be restrained in order to avoid lethal graft-versus-host disease (GVHD) and partly because only a sub-population of donor T cells are expected to be able to recognize AML cells via their T cell receptor. Chimeric antigen receptor (CAR) T cell therapy, most advanced in the treatment of patients with B-cell malignancies, may circumvent some of these limitations. However, major challenges remain to be overcome before CAR T cell therapy can be safely applied to AML. PMID:27890255

[MAIT cells in autoimmunity].

PubMed

Miyake, Sachiko

2014-01-01

Mucosal associated invariant T (MAIT) cells express a semi-invariant TCRα chain: Vα7.2-Jα33 in humans and Vα19-Jα33 in mice. They are restricted by a nonpolymorphic MHC-related molecule-1 (MR1), and cells are selected in the thymus. Interestingly, MAIT cells require B cells as well as commensal flora for their peripheral expansion. MAIT cells display antimicrobial capacity. Recently, vitamin metabolites were demonstrated as antigens created by intestinal flora for MAIT cells. MAIT cells play a protective role against autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS), wheras they play a pathogenic role in murine models of arthritis. In patients with autoimmune diseases, the frequency of MAIT cells in peripheral blood was significantly reduced. The frequency of MAIT cells reflected the disease activity in MS patients, suggesting the involvement of MAIT cells in the regulation of autoimmune diseases.

Human Tonsil-Derived Follicular Dendritic-Like Cells are Refractory to Human Prion Infection in Vitro and Traffic Disease-Associated Prion Protein to Lysosomes

PubMed Central

Krejciova, Zuzana; De Sousa, Paul; Manson, Jean; Ironside, James W.; Head, Mark W.

2014-01-01

The molecular mechanisms involved in human cellular susceptibility to prion infection remain poorly defined. This is due, in part, to the absence of any well characterized and relevant cultured human cells susceptible to infection with human prions, such as those involved in Creutzfeldt-Jakob disease. In variant Creutzfeldt-Jakob disease, prion replication is thought to occur first in the lymphoreticular system and then spread into the brain. We have, therefore, examined the susceptibility of a human tonsil-derived follicular dendritic cell-like cell line (HK) to prion infection. HK cells were found to display a readily detectable, time-dependent increase in cell-associated abnormal prion protein (PrPTSE) when exposed to medium spiked with Creutzfeldt-Jakob disease brain homogenate, resulting in a coarse granular perinuclear PrPTSE staining pattern. Despite their high level of cellular prion protein expression, HK cells failed to support infection, as judged by longer term maintenance of PrPTSE accumulation. Colocalization studies revealed that exposure of HK cells to brain homogenate resulted in increased numbers of detectable lysosomes and that these structures immunostained intensely for PrPTSE after exposure to Creutzfeldt-Jakob disease brain homogenate. Our data suggest that human follicular dendritic-like cells and perhaps other human cell types are able to avoid prion infection by efficient lysosomal degradation of PrPTSE. PMID:24183781

Control of Cytomegalovirus Viremia after Allogeneic Stem Cell Transplantation: A Review on CMV-Specific T Cell Reconstitution.

PubMed

van der Heiden, Pim; Marijt, Erik; Falkenburg, Fred; Jedema, Inge

2018-04-04

Recipients of allogeneic stem cell transplantation (alloSCT) are at risk for reactivation of endogenous herpesviruses due to profound and prolonged T cell deficiency following conditions such as graft-versus-host disease, immunosuppression, and/or T cell depletion. Reactivation of endogenous cytomegalovirus (CMV) is the most frequently occurring herpesvirus reactivation following alloSCT. Antiviral medication is often used in pre-emptive treatment strategies initiated when increases in CMV viral loads are detected as a result of active reactivation of the virus. Despite pre-emptive antiviral treatment, the incidence of CMV disease in CMV-seropositive alloSCT patients is still 10% at 1 year following alloSCT. This illustrates the necessity for adequate CMV-specific T cell immunity for long-term control of CMV and prevention of CMV disease. In this review, we analyzed the available studies on the influence of donor CMV status on CMV-specific T cell reconstitution and CMV disease. Furthermore, we reviewed the available studies on the safety and efficacy of adoptive transfer of donor CMV-specific T cells for the prevention and treatment of CMV disease following alloSCT, including studies on adoptive transfer of third-party CMV-specific T cells as a possible alternative when donor T cells are not available. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Let's Talk about the Needs of African American Children with Sickle Cell Disease: A Recognized "Other Health Impairment."

ERIC Educational Resources Information Center

Dooley, Elizabeth A.; Perkins, Nechelle

Children who inherit sickle cell disease, primarily African Americans and Hispanics, are at risk for serious medical conditions and require special care both at home and in school. Sickle cell disease is recognized as an "Other Health Impairment" and identified students may be eligible for special education services under the Individuals…

The cell biology of polycystic kidney disease

PubMed Central

Chapin, Hannah C.

2010-01-01

Polycystic kidney disease is a common genetic disorder in which fluid-filled cysts displace normal renal tubules. Here we focus on autosomal dominant polycystic kidney disease, which is attributable to mutations in the PKD1 and PKD2 genes and which is characterized by perturbations of renal epithelial cell growth control, fluid transport, and morphogenesis. The mechanisms that connect the underlying genetic defects to disease pathogenesis are poorly understood, but their exploration is shedding new light on interesting cell biological processes and suggesting novel therapeutic targets. PMID:21079243

Vitamin D Actions on CD4+ T Cells in Autoimmune Disease

PubMed Central

Hayes, Colleen Elizabeth; Hubler, Shane L.; Moore, Jerott R.; Barta, Lauren E.; Praska, Corinne E.; Nashold, Faye E.

2015-01-01

This review summarizes and integrates research on vitamin D and CD4+ T-lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene–environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4+ T-cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4+ T lymphocytes is summarized to support the thesis that calcitriol is sunlight’s main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data are summarized to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3+CD4+ T-regulatory cell and CD4+ T-regulatory cell type 1 (Tr1) cell functions, and a Th1–Tr1 switch. The proposed Th1–Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell–cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, unanswered questions and potentially informative future research directions are highlighted to speed delivery of etiology-based strategies to reduce autoimmune disease. PMID:25852682

Squamous cell carcinoma arising in Hailey-Hailey disease of the vulva.

PubMed

Cockayne, S E; Rassl, D M; Thomas, S E

2000-03-01

A 61-year-old woman, who was known to have Hailey-Hailey disease, presented with increasing vulval soreness. Biopsy showed vulval intraepithelial neoplasia (VIN) 3 and subsequent histology from a vulvectomy specimen showed extensive VIN with early invasive squamous cell carcinoma. This may be another example of chronic inflammation of the vulval area leading to the development of squamous cell carcinoma. However, in this case, chronic human papillomavirus may also have played a part, leading to VIN and reactivation of the Hailey-Hailey disease. We can find no previous reports of squamous cell carcinoma developing in the setting of Hailey-Hailey disease.

Induced pluripotent stem cells in Alzheimer's disease: applications for disease modeling and cell-replacement therapy.

PubMed

Yang, Juan; Li, Song; He, Xi-Biao; Cheng, Cheng; Le, Weidong

2016-05-17

Alzheimer's disease (AD) is the most common cause of dementia in those over the age of 65. While a numerous of disease-causing genes and risk factors have been identified, the exact etiological mechanisms of AD are not yet completely understood, due to the inability to test theoretical hypotheses on non-postmortem and patient-specific research systems. The use of recently developed and optimized induced pluripotent stem cells (iPSCs) technology may provide a promising platform to create reliable models, not only for better understanding the etiopathological process of AD, but also for efficient anti-AD drugs screening. More importantly, human-sourced iPSCs may also provide a beneficial tool for cell-replacement therapy against AD. Although considerable progress has been achieved, a number of key challenges still require to be addressed in iPSCs research, including the identification of robust disease phenotypes in AD modeling and the clinical availabilities of iPSCs-based cell-replacement therapy in human. In this review, we highlight recent progresses of iPSCs research and discuss the translational challenges of AD patients-derived iPSCs in disease modeling and cell-replacement therapy.

Treatment of inflammatory diseases with mesenchymal stem cells.

PubMed

Newman, Robert E; Yoo, Dana; LeRoux, Michelle A; Danilkovitch-Miagkova, Alla

2009-06-01

Human mesenchymal stem cells (hMSCs) are rare progenitor cells present in adult bone marrow that have the capacity to differentiate into a variety of tissue types, including bone, cartilage, tendon, fat, and muscle. In addition to multilineage differentiation capacity, MSCs regulate immune and inflammatory responses, providing therapeutic potential for treating diseases characterized by the presence of an inflammatory component. The availability of bone marrow and the ability to isolate and expand hMSCs ex vivo make these cells an attractive candidate for drug development. The low immunogenicity of these cells suggests that hMSCs can be transplanted universally without matching between donors and recipients. MSCs universality, along with the ability to manufacture and store these cells long-term, present a unique opportunity to produce an "off-the-shelf" cellular drug ready for treatment of diseases in acute settings. Accumulated animal and human data support MSC therapeutic potential for inflammatory diseases. Several phase III clinical trials for treatment of acute Graft Versus Host Disease (GVHD) and Crohn's disease are currently in progress. The current understanding of cellular and molecular targets underlying the mechanisms of MSCs action in inflammatory settings as well as clinical experience with hMSCs is summarized in this review.

Alternate pathogenesis of systemic neoplasia in the bivalve mollusc Mytilus.

PubMed

Moore, J D; Elston, R A; Drum, A S; Wilkinson, M T

1991-09-01

The proliferative disease systemic neoplasia, also termed hemic neoplasia or disseminated sarcoma, was studied in four Puget Sound, Washington populations of the bay mussel (Mytilus sp.). Using flow cytometric measurement of DAPI-stained cells withdrawn from the hemolymph, DNA content frequency histograms were generated for 73 individuals affected by the disease. The cells manifesting systemic neoplasia were found to exist as either of two separate types, characterized by G0G1 phase nuclear DNA contents of either approximately 4.9 x haploid (pentaploid form) or approximately 3.8 x haploid (tetraploid form). The two disease forms were found to coexist in all four mussel populations sampled, with overall relative prevalences of 66% pentaploid form, 29% tetraploid form, and 5% exhibiting both disease forms simultaneously. These findings represent the first unequivocal demonstration of multiple cell types in a bivalve neoplasia. The two forms appear to represent separate pathogenetic processes rather than sequential stages of a single pathogenesis. Two cell cycling parameters associated with proliferative activity were employed to compare the alternate forms: (i) the percentage of cells assigned to the DNA Synthesis (S) phase of the neoplastic cell cycle, and (ii) the proportion of neoplastic cell mitotic figures in hemocytological preparations. Mean values for both parameters were significantly higher for mussels with the tetraploid form of the disease, suggesting a higher rate of proliferation relative to the pentaploid form. Qualitatively, cells of the tetraploid form contained slightly lower nuclear and cytoplasmic volumes compared to those of the pentaploid form. An observed wide variation in neoplastic cell nuclear size within either disease form may reflect the distribution of cells in the G0G1, S, and G2M phases of the cell cycle. Potential etiologic relationships between the two forms are discussed.

Presence of Antigen-Experienced T Cells with Low Grade of Differentiation and Proliferative Potential in Chronic Chagas Disease Myocarditis

PubMed Central

Cabeza-Meckert, Patricia; Viotti, Rodolfo; Garelli, Fernando; Favaloro, Liliana E.; Favaloro, Roberto R.; Laguens, Rubén; Laucella, Susana A.

2014-01-01

Background The main consequence of chronic Trypanosoma cruzi infection is the development of myocarditis in approximately 20–30% of infected individuals but not until 10–20 years after the initial infection. We have previously shown that circulating interferon-γ-secreting T cells responsive to Trypanosoma cruzi antigens in chronic Chagas disease patients display a low grade of differentiation and the frequency of these T lymphocytes decreases along with the severity of heart disease. This study thought to explore the expression of inhibitory receptors, transcription factors of type 1 or regulatory T cells, and markers of T cell differentiation, immunosenescence or active cell cycle in cardiac explants from patients with advanced Chagas disease myocarditis. Methodology/Principal Findings The expression of different markers for T and B cells as well as for macrophages was evaluated by immunohistochemistry and immunofluorescence techniques in cardiac explants from patients with advanced chronic Chagas disease submitted to heart transplantation. Most infiltrating cells displayed markers of antigen-experienced T cells (CD3+, CD4+, CD8+, CD45RO+) with a low grade of differentiation (CD27+, CD57−, CD45RA−, PD-1−). A skewed T helper1/T cytotoxic 1 profile was supported by the expression of T-bet; whereas FOXP3+ cells were scarce and located only in areas of severe myocarditis. In addition, a significant proliferative capacity of CD3+ T cells, assessed by Ki67 staining, was found. Conclusions/Significance The quality of T cell responses and immunoregulatory mechanisms might determine the pattern of the cellular response and the severity of disease in chronic Trypanosoma cruzi infection. PMID:25144227

Modeling Dynamic Fluctuations in Type 1 Diabetes Progression: Quantifying β-cell variation after the appearance of islet-specific autoimmune responses

PubMed Central

Nelson, Patrick; Smith, Noah; Ciupe, Stanca; Zou, Weiping; Omenn, Gilbert S.; Pietropaolo, Massimo

2015-01-01

Type 1 diabetes (T1DM) is a chronic autoimmune disease with a long prodrome, which is characterized by dysfunction and ultimately destruction of pancreatic β-cells. Because of the limited access to pancreatic tissue and pancreatic lymph nodes during the normoglycemic phase of the disease, little is known about the dynamics involved in the chain of events leading to the clinical onset of the disease in humans. In particular, during T1DM progression there is limited information about temporal fluctuations of immunologic abnormalities and their effect on pancreatic β-cell function and mass. Therefore, our understanding of the pathoetiology of T1DM relies almost entirely on studies in animal models of this disease. In an effort to elucidate important mechanisms that may play a critical role in the progression to overt disease, we propose a mathematical model that takes into account the dynamics of functional and dysfunctional β-cells, regulatory T cells, and pathogenic T cells. The model assumes that all individuals carrying susceptible HLA haplotypes will develop variable degrees of T1DM-related immunologic abnormalities. The results provide information about the concentrations and ratios of pathogenic T cells and regulatory T cells, the timing in which β-cells become dysfunctional, and how certain kinetic parameters affect the progression to T1DM. Our model is able to describe changes in the ratio of pathogenic T cells and regulatory T cells after the appearance islet antibodies in the pancreas. Finally, we discuss the robustness of the model and its ability to assist experimentalists in designing studies to test complicated theories about the disease. PMID:19835428

Beta Thalassemia (For Parents)

MedlinePlus

... July 2015 More on this topic for: Parents Kids Teens Blood Transfusions Iron Iron-Deficiency Anemia Blood Test: Hemoglobin Electrophoresis Sickle Cell Disease Alpha Thalassemia Anemia Word! Anemia About Anemia Stem Cell Transplants Blood Transfusions Anemia Sickle Cell Disease ...

Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease.

PubMed

Racke, M K; Bonomo, A; Scott, D E; Cannella, B; Levine, A; Raine, C S; Shevach, E M; Röcken, M

1994-11-01

The properties and outcome of an immune response are best predicted by the lymphokine phenotype of the responding T cells. Cytokines produced by CD4+ T helper type 1 (Th1) T cells mediate delayed type hypersensitivity (DTH) and inflammatory responses, whereas cytokines produced by Th2 T cells mediate helper T cell functions for antibody production. To determine whether induction of Th2-like cells would modulate an inflammatory response, interleukin 4 (IL-4) was administered to animals with experimental allergic encephalomyelitis (EAE), a prototypic autoimmune disease produced by Th1-like T cells specific for myelin basic protein (MBP). IL-4 treatment resulted in amelioration of clinical disease, the induction of MBP-specific Th2 cells, diminished demyelination, and inhibition of the synthesis of inflammatory cytokines in the central nervous system (CNS). Modulation of an immune response from one dominated by excessive activity of Th1-like T cells to one dominated by the protective cytokines produced by Th2-like T cells may have applicability to the therapy of certain human autoimmune diseases.

Therapeutic application of stem cells in gastroenterology: an up-date.

PubMed

Burra, Patrizia; Bizzaro, Debora; Ciccocioppo, Rachele; Marra, Fabio; Piscaglia, Anna Chiara; Porretti, Laura; Gasbarrini, Antonio; Russo, Francesco Paolo

2011-09-14

Adult stem cells represent the self-renewing progenitors of numerous body tissues, and they are currently classified according to their origin and differentiation ability. In recent years, the research on stem cells has expanded enormously and holds therapeutic promises for many patients suffering from currently disabling diseases. This paper focuses on the possible use of stem cells in the two main clinical settings in gastroenterology, i.e., hepatic and intestinal diseases, which have a strong impact on public health worldwide. Despite encouraging results obtained in both regenerative medicine and immune-mediated conditions, further studies are needed to fully understand the biology of stem cells and carefully assess their putative oncogenic properties. Moreover, the research on stem cells arouses fervent ethical, social and political debate. The Italian Society of Gastroenterology sponsored a workshop on stem cells held in Verona during the XVI Congress of the Federation of Italian Societies of Digestive Diseases (March 6-9, 2010). Here, we report on the issues discussed, including liver and intestinal diseases that may benefit from stem cell therapy, the biology of hepatic and intestinal tissue repair, and stem cell usage in clinical trials.

Role of T cell receptor delta gene in susceptibility to celiac disease.

PubMed

Roschmann, E; Wienker, T F; Volk, B A

1996-02-01

There is a strong genetic influence on the susceptibility to celiac disease. Although in the vast majority of patients with celiac disease, the HLA-DQ(alpha1*0501, beta1*0201) heterodimer encoded by the alleles HLA-DQA1*0501 and HLA-DQB1*0201 seems to confer the primary disease susceptibility, it cannot be excluded that other genes contribute to disease susceptibility, as indicated by the difference in concordance rates between monozygotic twins and HLA identical siblings (70% vs. 30%). Obviously other genes involved in the genetic control of T cell mediated immune response could potentially influence susceptibility to celiac disease. The density of T cells using the gammadelta T cell receptor (TCR) is considerably increased in the jejunal epithelium of patients with celiac disease, an abnormality considered to be specific for celiac disease. This suggests an involvement of gammadelta T cells in the pathogenesis of the disease. To ascertain whether the TCR delta (TCRD) gene contributes to celiac disease susceptibility we carried out an association study and genetic linkage analysis using a highly polymorphic microsatellite marker at the TCRD locus on chromosome 14q11.2. The association study demonstrated no significant difference in allele frequencies of the TCRD gene marker between celiac disease patients and controls; accordingly, the relative risk estimates did not reach the level of statistical significance. In the linkage analysis, performed in 23 families, the logarithm of the odds (LOD) scores calculated for celiac disease versus the TCRD gene marker excluded linkage, suggesting that there is no determinant contributing to celiac disease status at or 5 cM distant to the analyzed TCRD gene marker. In conclusion, the results of the present study provide no evidence that the analyzed TCRD gene contributes substantially to celiac disease susceptibility.

B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex.

PubMed

Wallace, Caroline H; Wu, Bill X; Salem, Mohammad; Ansa-Addo, Ephraim A; Metelli, Alessandra; Sun, Shaoli; Gilkeson, Gary; Shlomchik, Mark J; Liu, Bei; Li, Zihai

2018-04-05

GARP, a cell surface docking receptor for binding and activating latent TGF-β, is highly expressed by platelets and activated Tregs. While GARP is implicated in immune invasion in cancer, the roles of the GARP-TGF-β axis in systemic autoimmune diseases are unknown. Although B cells do not express GARP at baseline, we found that the GARP-TGF-β complex is induced on activated human and mouse B cells by ligands for multiple TLRs, including TLR4, TLR7, and TLR9. GARP overexpression on B cells inhibited their proliferation, induced IgA class-switching, and dampened T cell-independent antibody production. In contrast, B cell-specific deletion of GARP-encoding gene Lrrc32 in mice led to development of systemic autoimmune diseases spontaneously as well as worsening of pristane-induced lupus-like disease. Canonical TGF-β signaling more readily upregulates GARP in Peyer patch B cells than in splenic B cells. Furthermore, we demonstrated that B cells are required for the induction of oral tolerance of T cell-dependent antigens via GARP. Our studies reveal for the first time to our knowledge that cell surface GARP-TGF-β is an important checkpoint for regulating B cell peripheral tolerance, highlighting a mechanism of autoimmune disease pathogenesis.

Regulation of Memory T Cells by Interleukin-23.

PubMed

Li, Yanchun; Wang, Hongbo; Lu, Honghua; Hua, Shucheng

2016-01-01

Interleukin-23 (IL-23), a member of the IL-12 family of cytokines, is a heterodimeric cytokine. It is composed of subunits p40 (shared with IL-12) and p19 (an IL-12 p35-related subunit) and is secreted by several types of immune cells, such as natural killer cells and dendritic cells. The IL-23 receptor is composed of the subunit IL-12Rβ1 and the IL-23-specific subunit IL-23R. The binding of IL-23 to its specific cell surface receptor regulates a number of functions, including proliferation and differentiation of cells and secretion of cell factors. Memory T cells are a subset of T cells that secrete numerous important cell factors, and they function in the immune response to infection and diseases like cancer, autoimmune disease and bronchial asthma. IL-23R is expressed on the surface of memory T cells, which suggests that it can specifically regulate memory T cell function. IL-23 has been widely used as a clinical indicator in immune-related diseases and shows potential for use in disease treatment. Here we review the current progress in the study of the role of IL-23 in the regulation of memory T cells. © 2016 S. Karger AG, Basel.

Paracrine effects and heterogeneity of marrow-derived stem/progenitor cells: relevance for the treatment of respiratory diseases.

PubMed

Conese, Massimo; Carbone, Annalucia; Castellani, Stefano; Di Gioia, Sante

2013-01-01

Stem cell-based treatment may represent a hope for the treatment of acute lung injury and pulmonary fibrosis, and other chronic lung diseases, such as cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). It is well established in preclinical models that bone marrow-derived stem and progenitor cells exert beneficial effects on inflammation, immune responses and repairing of damage in virtually all lung-borne diseases. While it was initially thought that the positive outcome was due to a direct engraftment of these cells into the lung as endothelial and epithelial cells, paracrine factors are now considered the main mechanism through which stem and progenitor cells exert their therapeutic effect. This knowledge has led to the clinical use of marrow cells in pulmonary hypertension with endothelial progenitor cells (EPCs) and in COPD with mesenchymal stromal (stem) cells (MSCs). Bone marrow-derived stem cells, including hematopoietic stem/progenitor cells, MSCs, EPCs and fibrocytes, encompass a wide array of cell subsets with different capacities of engraftment and injured tissue-regenerating potential. The characterization/isolation of the stem cell subpopulations represents a major challenge to improve the efficacy of transplantation protocols used in regenerative medicine and applied to lung disorders. Copyright © 2013 S. Karger AG, Basel.

TOPICAL REVIEW: Stem cells engineering for cell-based therapy

NASA Astrophysics Data System (ADS)

Taupin, Philippe

2007-09-01

Stem cells carry the promise to cure a broad range of diseases and injuries, from diabetes, heart and muscular diseases, to neurological diseases, disorders and injuries. Significant progresses have been made in stem cell research over the past decade; the derivation of embryonic stem cells (ESCs) from human tissues, the development of cloning technology by somatic cell nuclear transfer (SCNT) and the confirmation that neurogenesis occurs in the adult mammalian brain and that neural stem cells (NSCs) reside in the adult central nervous system (CNS), including that of humans. Despite these advances, there may be decades before stem cell research will translate into therapy. Stem cell research is also subject to ethical and political debates, controversies and legislation, which slow its progress. Cell engineering has proven successful in bringing genetic research to therapy. In this review, I will review, in two examples, how investigators are applying cell engineering to stem cell biology to circumvent stem cells' ethical and political constraints and bolster stem cell research and therapy.

Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

PubMed

Liu, Ying; Deng, Wenbin

2016-05-01

With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control and to complement the iPSC-based approach for ALS disease modeling studies. Much knowledge has been generated from the study of both ALS iPSCs and ESCs. As these methods have advantages and disadvantages that should be balanced on experimental design in order for them to complement one another, combining the diverse methods would help build an expanded knowledge of ALS pathophysiology. The goals are to reverse engineer the human disease using ESCs and iPSCs, generate lineage reporter lines and in vitro disease models, target disease related genes, in order to better understand the molecular and cellular mechanisms of differentiation regulation along neural (neuronal versus glial) lineages, to unravel the pathogenesis of the neurodegenerative disease, and to provide appropriate cell sources for replacement therapy. This article is part of a Special Issue entitled SI: PSC and the brain. Copyright © 2015 Elsevier B.V. All rights reserved.

Highly conserved CDR3 region in circulating CD4+Vβ5+ T cells may be associated with cytotoxic activity in Chagas disease

PubMed Central

Menezes, C A S; Sullivan, A K; Falta, M T; Mack, D G; Freed, B M; Rocha, M O C; Gollob, K J; Fontenot, A P; Dutra, W O

2012-01-01

Human infection with Trypanosoma cruzi leads to Chagas disease, which presents as several different clinical conditions ranging from an asymptomatic form to a severe dilated cardiomyopathy. Several studies have demonstrated that T cells play a critical role in the development of cardiac pathology, as well as in immunoregulation during chronic disease. However, the mechanisms that drive protective or pathogenic T cell response are not known. We have shown that CD4+ T cells from chagasic patients preferentially express T cell receptor (TCR) β-chain variable region (Vβ) 5. The aim of this work was to determine whether T cells expressing this particular Vβ region displayed variable or restricted CDR3 sequences, as an indicator of the nature of the stimulus leading to the activation of these T cells in vivo. Additionally, we aimed to evaluate phenotypic characteristics of these cells that might be associated with pathology. CDR3 junctional region sequencing of Vβ5·1 expressing CD4+ T cells revealed the occurrence of a highly homologous CDR3 region with conserved TCR Jβ region usage among patients with cardiac, but not indeterminate, Chagas disease. Moreover, correlation analysis indicated that the frequency of CD4+Vβ5·1+ cells is associated with granzyme A expression, suggesting that these cells might display cytotoxic function. Together these results provide new insight into T cell recognition of antigens involved in Chagas disease and suggest that these cells may be implicated in the pathogenesis of chagasic cardiomyopathy. PMID:22774985

Anti-thymocyte globulin as graft-versus-host disease prevention in the setting of allogeneic peripheral blood stem cell transplantation: a review from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

PubMed Central

Baron, Frédéric; Mohty, Mohamad; Blaise, Didier; Socié, Gérard; Labopin, Myriam; Esteve, Jordi; Ciceri, Fabio; Giebel, Sebastian; Gorin, Norbert Claude; Savani, Bipin N; Schmid, Christoph; Nagler, Arnon

2017-01-01

Allogeneic hematopoietic stem cell transplantation is increasingly used as treatment for patients with life-threatening blood diseases. Its curative potential is largely based on immune-mediated graft-versus-leukemia effects caused by donor T cells contained in the graft. Unfortunately, donor T cells are also the cause of graft-versus-host disease. The vast majority of human leukocyte antigen-matched allogeneic hematopoietic stem cell transplants are nowadays carried out with peripheral blood stem cells as the stem cell source. In comparison with bone marrows, peripheral blood stem cells contain more hematopoietic stem/progenitor cells but also one log more T cells. Consequently, the use of peripheral blood stem cells instead of bone marrow has been associated with faster hematologic recovery and a lower risk of relapse in patients with advanced disease, but also with a higher incidence of chronic graft-versus-host disease. These observations have been the basis for several studies aimed at assessing the impact of immunoregulation with anti-thymocyte globulin on transplantation outcomes in patients given human leukocyte antigen-matched peripheral blood stem cells from related or unrelated donors. After a brief introduction on anti-thymocyte globulin, this article reviews recent studies assessing the impact of anti-thymocyte globulin on transplantation outcomes in patients given peripheral blood stem cells from human leukocyte antigen-matched related or unrelated donors as well as in recipients of grafts from human leukocyte antigen haploidentical donors. PMID:27927772

Nitric oxide functions as a signal in plant disease resistance.

PubMed

Delledonne, M; Xia, Y; Dixon, R A; Lamb, C

1998-08-06

Recognition of an avirulent pathogen triggers the rapid production of the reactive oxygen intermediates superoxide (O2-) and hydrogen peroxide (H2O2). This oxidative burst drives crosslinking of the cell wall, induces several plant genes involved in cellular protection and defence, and is necessary for the initiation of host cell death in the hypersensitive disease-resistance response. However, this burst is not enough to support a strong disease-resistance response. Here we show that nitric oxide, which acts as a signal in the immune, nervous and vascular systems, potentiates the induction of hypersensitive cell death in soybean cells by reactive oxygen intermediates and functions independently of such intermediates to induce genes for the synthesis of protective natural products. Moreover, inhibitors of nitric oxide synthesis compromise the hypersensitive disease-resistance response of Arabidopsis leaves to Pseudomonas syringae, promoting disease and bacterial growth. We conclude that nitric oxide plays a key role in disease resistance in plants.

Understanding cell cycle and cell death regulation provides novel weapons against human diseases.

PubMed

Wiman, K G; Zhivotovsky, B

2017-05-01

Cell division, cell differentiation and cell death are the three principal physiological processes that regulate tissue homoeostasis in multicellular organisms. The growth and survival of cells as well as the integrity of the genome are regulated by a complex network of pathways, in which cell cycle checkpoints, DNA repair and programmed cell death have critical roles. Disruption of genomic integrity and impaired regulation of cell death may both lead to uncontrolled cell growth. Compromised cell death can also favour genomic instability. It is becoming increasingly clear that dysregulation of cell cycle and cell death processes plays an important role in the development of major disorders such as cancer, cardiovascular disease, infection, inflammation and neurodegenerative diseases. Research achievements in these fields have led to the development of novel approaches for treatment of various conditions associated with abnormalities in the regulation of cell cycle progression or cell death. A better understanding of how cellular life-and-death processes are regulated is essential for this development. To highlight these important advances, the Third Nobel Conference entitled 'The Cell Cycle and Cell Death in Disease' was organized at Karolinska Institutet in 2016. In this review we will summarize current understanding of cell cycle progression and cell death and discuss some of the recent advances in therapeutic applications in pathological conditions such as cancer, neurological disorders and inflammation. © 2017 The Association for the Publication of the Journal of Internal Medicine.

Intrinsic hyporesponsiveness of invariant natural killer T cells precedes the onset of lupus

PubMed Central

Yang, J-Q; Kim, P J; Halder, R C; Singh, R R

2013-01-01

Patients with systemic lupus erythematosus (SLE) display reduced numbers and functions of invariant natural killer T (iNK T) cells, which are restored upon treatment with corticosteroids and rituximab. It is unclear whether the iNK T cell insufficiency is a consequence of disease or is a primary abnormality that precedes the onset of disease. To address this, we analysed iNK T cell function at different stages of disease development using the genetically lupus-susceptible NZB × NZW F1 (BWF1) model. We found that iNK T cell in-vivo cytokine responses to an iNK T cell ligand α-galactosylceramide (α-GalCer) were lower in BWF1 mice than in non-autoimmune BALB/c and major histocompatibility complex (MHC)-matched NZB × N/B10.PL F1 mice, although iNK T cell numbers in the periphery were unchanged in BWF1 mice compared to control mice. Such iNK T cell hyporesponsiveness in BWF1 mice was detected at a young age long before the animals exhibited any sign of autoimmunity. In-vivo activation of iNK T cells is known to transactivate other immune cells. Such transactivated T and B cell activation markers and/or cytokine responses were also lower in BWF1 mice than in BALB/c controls. Finally, we show that iNK T cell responses were markedly deficient in the NZB parent but not in NZW parent of BWF1 mice, suggesting that BWF1 might inherit the iNK T cell defect from NZB mice. Thus, iNK T cells are functionally insufficient in lupus-prone BWF1 mice. Such iNK T cell insufficiency precedes the onset of disease and may play a pathogenic role during early stages of disease development in SLE. PMID:23607366

Interferon-γ production by tubulointerstitial human CD56bright natural killer cells contributes to renal fibrosis and chronic kidney disease progression.

PubMed

Law, Becker M P; Wilkinson, Ray; Wang, Xiangju; Kildey, Katrina; Lindner, Mae; Rist, Melissa J; Beagley, Kenneth; Healy, Helen; Kassianos, Andrew J

2017-07-01

Natural killer (NK) cells are a population of lymphoid cells that play a significant role in mediating innate immune responses. Studies in mice suggest a pathological role for NK cells in models of kidney disease. In this study, we characterized the NK cell subsets present in native kidneys of patients with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Significantly higher numbers of total NK cells (CD3 - CD56 + ) were detected in renal biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue using multi-color flow cytometry. At a subset level, both the CD56 dim NK cell subset and particularly the CD56 bright NK cell subset were elevated in fibrotic kidney tissue. However, only CD56 bright NK cells significantly correlated with the loss of kidney function. Expression of the tissue-retention and -activation molecule CD69 on CD56 bright NK cells was significantly increased in fibrotic biopsy specimens compared with non-fibrotic kidney tissue, indicative of a pathogenic phenotype. Further flow cytometric phenotyping revealed selective co-expression of activating receptor CD335 (NKp46) and differentiation marker CD117 (c-kit) on CD56 bright NK cells. Multi-color immunofluorescent staining of fibrotic kidney tissue localized the accumulation of NK cells within the tubulointerstitium, with CD56 bright NK cells (NKp46 + CD117 + ) identified as the source of pro-inflammatory cytokine interferon-γ within the NK cell compartment. Thus, activated interferon-γ-producing CD56 bright NK cells are positioned to play a key role in the fibrotic process and progression to chronic kidney disease. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

Biomarker Discovery by Modeling Behçet's Disease with Patient-Specific Human Induced Pluripotent Stem Cells.

PubMed

Son, Mi-Young; Kim, Young-Dae; Seol, Binna; Lee, Mi-Ok; Na, Hee-Jun; Yoo, Bin; Chang, Jae-Suk; Cho, Yee Sook

2017-01-15

Behçet's disease (BD) is a chronic inflammatory and multisystemic autoimmune disease of unknown etiology. Due to the lack of a specific test for BD, its diagnosis is very difficult and therapeutic options are limited. Induced pluripotent stem cell (iPSC) technology, which provides inaccessible disease-relevant cell types, opens a new era for disease treatment. In this study, we generated BD iPSCs from patient somatic cells and differentiated them into hematopoietic precursor cells (BD iPSC-HPCs) as BD model cells. Based on comparative transcriptome analysis using our BD model cells, we identified eight novel BD-specific genes, AGTR2, CA9, CD44, CXCL1, HTN3, IL-2, PTGER4, and TSLP, which were differentially expressed in BD patients compared with healthy controls or patients with other immune diseases. The use of CXCL1 as a BD biomarker was further validated at the protein level using both a BD iPSC-HPC-based assay system and BD patient serum samples. Furthermore, we show that our BD iPSC-HPC-based drug screening system is highly effective for testing CXCL1 BD biomarkers, as determined by monitoring the efficacy of existing anti-inflammatory drugs. Our results shed new light on the usefulness of patient-specific iPSC technology in the development of a benchmarking platform for disease-specific biomarkers, phenotype- or target-driven drug discovery, and patient-tailored therapies.

Potential of Gene Editing and Induced Pluripotent Stem Cells (iPSCs) in Treatment of Retinal Diseases.

PubMed

Chuang, Katherine; Fields, Mark A; Del Priore, Lucian V

2017-12-01

The advent of gene editing has introduced the ability to make changes to the genome of cells, thus allowing for correction of genetic mutations in patients with monogenic diseases. Retinal diseases are particularly suitable for the application of this new technology because many retinal diseases, such as Stargardt disease, retinitis pigmentosa (RP), and Leber congenital amaurosis (LCA), are monogenic. Moreover, gene delivery techniques such as the use of adeno-associated virus (AAV) vectors have been optimized for intraocular use, and phase III trials are well underway to treat LCA, a severe form of inherited retinal degeneration, with gene therapy. This review focuses on the use of gene editing techniques and another relatively recent advent, induced pluripotent stem cells (iPSCs), and their potential for the study and treatment of retinal disease. Investment in these technologies, including overcoming challenges such as off-target mutations and low transplanted cell integration, may allow for future treatment of many debilitating inherited retinal diseases.

Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management.

PubMed

Yazdanbakhsh, Karina; Ware, Russell E; Noizat-Pirenne, France

2012-07-19

Red blood cell transfusions have reduced morbidity and mortality for patients with sickle cell disease. Transfusions can lead to erythrocyte alloimmunization, however, with serious complications for the patient including life-threatening delayed hemolytic transfusion reactions and difficulty in finding compatible units, which can cause transfusion delays. In this review, we discuss the risk factors associated with alloimmunization with emphasis on possible mechanisms that can trigger delayed hemolytic transfusion reactions in sickle cell disease, and we describe the challenges in transfusion management of these patients, including opportunities and emerging approaches for minimizing this life-threatening complication.

Systemic Epstein-Barr Virus-positive T-Cell Lymphoproliferative Disease of Childhood With Good Response to Steroid Therapy.

PubMed

Kim, Do-Hoon; Kim, Myungshin; Kim, Yonggoo; Han, Kyungja; Han, Eunhee; Lee, Jae Wook; Chung, Nack-Gyun; Cho, Bin

2017-11-01

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood is a rare disease and has a very fulminant clinical course with high mortality. A 21-month-old female patient was referred to our hospital with a 1 week history of fever and was subsequently diagnosed with systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood. After starting treatment with dexamethasone, she showed early defervescence and improvement of laboratory parameters, and has remained disease-free after stopping steroid treatment, although longer follow-up is necessary. Our report underscores the possibility that this disease entity may be heterogenous in terms of prognosis.

Stem Cell Pathology.

PubMed

Fu, Dah-Jiun; Miller, Andrew D; Southard, Teresa L; Flesken-Nikitin, Andrea; Ellenson, Lora H; Nikitin, Alexander Yu

2018-01-24

Rapid advances in stem cell biology and regenerative medicine have opened new opportunities for better understanding disease pathogenesis and the development of new diagnostic, prognostic, and treatment approaches. Many stem cell niches are well defined anatomically, thereby allowing their routine pathological evaluation during disease initiation and progression. Evaluation of the consequences of genetic manipulations in stem cells and investigation of the roles of stem cells in regenerative medicine and pathogenesis of various diseases such as cancer require significant expertise in pathology for accurate interpretation of novel findings. Therefore, there is an urgent need for developing stem cell pathology as a discipline to facilitate stem cell research and regenerative medicine. This review provides examples of anatomically defined niches suitable for evaluation by diagnostic pathologists, describes neoplastic lesions associated with them, and discusses further directions of stem cell pathology.

HSC extrinsic sex-related and intrinsic autoimmune disease-related human B-cell variation is recapitulated in humanized mice.

PubMed

Borsotti, Chiara; Danzl, Nichole M; Nauman, Grace; Hölzl, Markus A; French, Clare; Chavez, Estefania; Khosravi-Maharlooei, Mohsen; Glauzy, Salome; Delmotte, Fabien R; Meffre, Eric; Savage, David G; Campbell, Sean R; Goland, Robin; Greenberg, Ellen; Bi, Jing; Satwani, Prakash; Yang, Suxiao; Bathon, Joan; Winchester, Robert; Sykes, Megan

2017-10-24

B cells play a major role in antigen presentation and antibody production in the development of autoimmune diseases, and some of these diseases disproportionally occur in females. Moreover, immune responses tend to be stronger in female vs male humans and mice. Because it is challenging to distinguish intrinsic from extrinsic influences on human immune responses, we used a personalized immune (PI) humanized mouse model, in which immune systems were generated de novo from adult human hematopoietic stem cells (HSCs) in immunodeficient mice. We assessed the effect of recipient sex and of donor autoimmune diseases (type 1 diabetes [T1D] and rheumatoid arthritis [RA]) on human B-cell development in PI mice. We observed that human B-cell levels were increased in female recipients regardless of the source of human HSCs or the strain of immunodeficient recipient mice. Moreover, mice injected with T1D- or RA-derived HSCs displayed B-cell abnormalities compared with healthy control HSC-derived mice, including altered B-cell levels, increased proportions of mature B cells and reduced CD19 expression. Our study revealed an HSC-extrinsic effect of recipient sex on human B-cell reconstitution. Moreover, the PI humanized mouse model revealed HSC-intrinsic defects in central B-cell tolerance that recapitulated those in patients with autoimmune diseases. These results demonstrate the utility of humanized mouse models as a tool to better understand human immune cell development and regulation.

The number and growth pattern of plasmacytoid dendritic cells vary in different types of reactive lymph nodes: an immunohistochemical study.

PubMed

Rollins-Raval, Marian A; Marafioti, Teresa; Swerdlow, Steven H; Roth, Christine G

2013-06-01

Plasmacytoid dendritic cells, which play a fundamental role in the innate immune response, are best known for their presence in hyaline-vascular Castleman disease and histiocytic necrotizing lymphadenitis. The relative number and distribution in many reactive entities as detected using more sensitive methods are uncertain, and their diagnostic implications are unknown. Immunohistochemical studies for plasmacytoid dendritic cell-associated markers CD123 and CD2AP were performed on 42 lymph nodes with hyaline-vascular Castleman disease, histiocytic necrotizing lymphadenitis, sarcoidosis, necrotizing granulomatous inflammation, viral infection, dermatopathic lymphadenopathy, autoimmune disease, and a histologic pattern compatible with toxoplasmosis. The overall plasmacytoid dendritic cell numbers and growth patterns (tight aggregates, loose aggregates/clusters, scattered single cells) were assessed. Plasmacytoid dendritic cells were present in all cases and were predominantly distributed in loose aggregates/clusters or singly. They were most numerous in granulomatous inflammation and histiocytic necrotizing lymphadenitis, whereas viral infections showed the fewest overall numbers and a predominant pattern of scattered single cells. Tight aggregates of plasmacytoid dendritic cells were most numerous in hyaline-vascular Castleman disease (100% sensitive, 68% specific). Plasmacytoid dendritic cells are not limited to a small number of reactive lymphadenopathies but are found in many reactive processes, often with a predominant pattern of loose aggregates/clusters and scattered single cells. However, tight aggregates were a characteristic feature of hyaline-vascular Castleman disease, and viral infections typically showed only few scattered cells distributed singly. Copyright © 2013 Elsevier Inc. All rights reserved.

The intersection between asthma and acute chest syndrome in children with sickle-cell anaemia

PubMed Central

DeBaun, Michael R; Strunk, Robert C

2016-01-01

Acute chest syndrome is a frequent cause of acute lung disease in children with sickle-cell disease. Asthma is common in children with sickle-cell disease and is associated with increased incidence of vaso-occlusive pain events, acute chest syndrome episodes, and earlier death. Risk factors for asthma exacerbation and an acute chest syndrome episode are similar, and both can present with shortness of breath, chest pain, cough, and wheezing. Despite overlapping risk factors and symptoms, an acute exacerbation of asthma or an episode of acute chest syndrome are two distinct entities that need disease-specific management strategies. Although understanding has increased about asthma as a comorbidity in sickle-cell disease and its effects on morbidity, substantial gaps remain in knowledge about best management. PMID:27353685

The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells.

PubMed

Machado-Santos, Joana; Saji, Etsuji; Tröscher, Anna R; Paunovic, Manuela; Liblau, Roland; Gabriely, Galina; Bien, Christian G; Bauer, Jan; Lassmann, Hans

2018-06-04

Multiple sclerosis is an inflammatory demyelinating disease in which active demyelination and neurodegeneration are associated with lymphocyte infiltrates in the brain. However, so far little is known regarding the phenotype and function of these infiltrating lymphocyte populations. In this study, we performed an in-depth phenotypic characterization of T and B cell infiltrates in a large set of multiple sclerosis cases with different disease and lesion stages and compared the findings with those seen in inflammatory, non-inflammatory and normal human controls. In multiple sclerosis lesions, we found a dominance of CD8+ T cells and a prominent contribution of CD20+ B cells in all disease courses and lesion stages, including acute multiple sclerosis cases with very short disease duration, while CD4+ T cells were sparse. A dominance of CD8+ T cells was also seen in other inflammatory controls, such as Rasmussen's encephalitis and viral encephalitis, but the contribution of B cells in these diseases was modest. Phenotypic analysis of the CD8+ T cells suggested that part of the infiltrating cells in active lesions proliferate, show an activated cytotoxic phenotype and are in part destroyed by apoptosis. Further characterization of the remaining cells suggest that CD8+ T cells acquire features of tissue-resident memory cells, which may be focally reactivated in active lesions of acute, relapsing and progressive multiple sclerosis, while B cells, at least in part, gradually transform into plasma cells. The loss of surface molecules involved in the egress of leucocytes from inflamed tissue, such as S1P1 or CCR7, and the upregulation of CD103 expression may be responsible for the compartmentalization of the inflammatory response in established lesions. Similar phenotypic changes of tissue-infiltrating CD8+ T cells were also seen in Rasmussen's encephalitis. Our data underline the potential importance of CD8+ T lymphocytes and B cells in the inflammatory response in established multiple sclerosis lesions. Tissue-resident T and B cells may represent guardians of previous inflammatory brain disease, which can be reactivated and sustain the inflammatory response, when they are re-exposed to their specific antigen.

Vitamin D and rheumatic diseases.

PubMed

Rossini, M; Gatti, D; Viapiana, O; Caimmi, C; Idolazzi, L; Fracassi, E; Adami, S

2014-07-28

Vitamin D has some well-known effects on calcium, phosphate and bone metabolism, but it has recently shown to have many other effects, which may potentially be relevant to patients with extra-skeletal rheumatic diseases. Such effects may be justified by: 1) the presence of the vitamin D receptors also on extra-osseous cells, such as cartilage cells, sinoviocytes, muscle cells; 2) the proven role of vitamin D in the control of the transcription of genes involved in rheumatic diseases; 3) the evidence that vitamin D has multiple endocrine effects not only on calcium homeostasis; 4) the activation of vitamin D not only in the kidneys, but also in monocyte-macrophage and lymphocytic cell lines and in some epithelial cells with additional intracrine and paracrine effects. Vitamin D deficiency has been reported in numerous metabolic, degenerative, inflammatory and autoimmune rheumatic diseases. In some cases this association was also related to the risk of developing a rheumatic disease or the degree of disease activity. However there is no conclusive evidence of the efficacy of a preventive or therapeutic strategy based on vitamin D supplementation in extra-skeletal rheumatic diseases. This review aims to provide an overview of the latest evidence concerning the relationship between vitamin D and the most relevant rheumatic diseases.

Engineered in vitro disease models.

PubMed

Benam, Kambez H; Dauth, Stephanie; Hassell, Bryan; Herland, Anna; Jain, Abhishek; Jang, Kyung-Jin; Karalis, Katia; Kim, Hyun Jung; MacQueen, Luke; Mahmoodian, Roza; Musah, Samira; Torisawa, Yu-suke; van der Meer, Andries D; Villenave, Remi; Yadid, Moran; Parker, Kevin K; Ingber, Donald E

2015-01-01

The ultimate goal of most biomedical research is to gain greater insight into mechanisms of human disease or to develop new and improved therapies or diagnostics. Although great advances have been made in terms of developing disease models in animals, such as transgenic mice, many of these models fail to faithfully recapitulate the human condition. In addition, it is difficult to identify critical cellular and molecular contributors to disease or to vary them independently in whole-animal models. This challenge has attracted the interest of engineers, who have begun to collaborate with biologists to leverage recent advances in tissue engineering and microfabrication to develop novel in vitro models of disease. As these models are synthetic systems, specific molecular factors and individual cell types, including parenchymal cells, vascular cells, and immune cells, can be varied independently while simultaneously measuring system-level responses in real time. In this article, we provide some examples of these efforts, including engineered models of diseases of the heart, lung, intestine, liver, kidney, cartilage, skin and vascular, endocrine, musculoskeletal, and nervous systems, as well as models of infectious diseases and cancer. We also describe how engineered in vitro models can be combined with human inducible pluripotent stem cells to enable new insights into a broad variety of disease mechanisms, as well as provide a test bed for screening new therapies.

Th17 Pathway As a Target for Multipotent Stromal Cell Therapy in Dogs: Implications for Translational Research

PubMed Central

Kol, A.; Walker, N. J.; Nordstrom, M.; Borjesson, D. L.

2016-01-01

Detrimental Th17 driven inflammatory and autoimmune disease such as Crohn’s disease, graft versus host disease and multiple sclerosis remain a significant cause of morbidity and mortality worldwide. Multipotent stromal/stem cell (MSC) inhibit Th17 polarization and activation in vitro and in rodent models. As such, MSC based therapeutic approaches are being investigated as novel therapeutic approaches to treat Th17 driven diseases in humans. The significance of naturally occurring diseases in dogs is increasingly recognized as a realistic platform to conduct pre-clinical testing of novel therapeutics. Full characterization of Th17 cells in dogs has not been completed. We have developed and validated a flow-cytometric method to detect Th17 cells in canine blood. We further demonstrate that Th17 and other IL17 producing cells are present in tissues of dogs with naturally occurring chronic inflammatory diseases. Finally, we have determined the kinetics of a canine specific Th17 polarization in vitro and demonstrate that canine MSC inhibit Th17 polarization in vitro, in a PGE2 independent mechanism. Our findings provide fundamental research tools and suggest that naturally occurring diseases in dogs, such as inflammatory bowel disease, may be harnessed to translate novel MSC based therapeutic strategies that target the Th17 pathway. PMID:26872054

Interleukin-35 induces regulatory B cells that suppress autoimmune disease.

PubMed

Wang, Ren-Xi; Yu, Cheng-Rong; Dambuza, Ivy M; Mahdi, Rashid M; Dolinska, Monika B; Sergeev, Yuri V; Wingfield, Paul T; Kim, Sung-Hye; Egwuagu, Charles E

2014-06-01

Interleukin-10 (IL-10)-producing regulatory B (Breg) cells suppress autoimmune disease, and increased numbers of Breg cells prevent host defense to infection and promote tumor growth and metastasis by converting resting CD4(+) T cells to regulatory T (Treg) cells. The mechanisms mediating the induction and development of Breg cells remain unclear. Here we show that IL-35 induces Breg cells and promotes their conversion to a Breg subset that produces IL-35 as well as IL-10. Treatment of mice with IL-35 conferred protection from experimental autoimmune uveitis (EAU), and mice lacking IL-35 (p35 knockout (KO) mice) or defective in IL-35 signaling (IL-12Rβ2 KO mice) produced less Breg cells endogenously or after treatment with IL-35 and developed severe uveitis. Adoptive transfer of Breg cells induced by recombinant IL-35 suppressed EAU when transferred to mice with established disease, inhibiting pathogenic T helper type 17 (TH17) and TH1 cells while promoting Treg cell expansion. In B cells, IL-35 activates STAT1 and STAT3 through the IL-35 receptor comprising the IL-12Rβ2 and IL-27Rα subunits. As IL-35 also induced the conversion of human B cells into Breg cells, these findings suggest that IL-35 may be used to induce autologous Breg and IL-35(+) Breg cells and treat autoimmune and inflammatory disease.

New pharmacological strategies in rheumatic diseases.

PubMed

Schiotis, R E; Buzoianu, A D; Mureșanu, D F; Suciu, S

2016-01-01

Targeting the pathogenic pathway of chronic inflammation represents an unmet challenge for controlling disease activity, preventing functional disability, and maintaining an adequate quality of life in patients with rheumatic diseases. Abatacept, a novel molecule that inhibits co-stimulation signal, induces an inhibitory effect on the T-cells. This will further interfere with the activity of several cell lines, leading to the normalization of the immune response. In the latest years, abatacept has been extensively investigated in studies of rheumatoid arthritis for which it was recently approved as a second line biologic treatment in Romania. This review presents the clinical efficacy of abatacept in several rheumatic diseases and highlights the safety profile of this biological agent. Abbreviations : ACR = American College of Rheumatology, ADR = Adverse drug reaction, APC = antigen presenting cell, ApS = psoriatic arthritis, CRP = C reactive protein, CTLA-4 = Cytotoxic T-Cell Lymphocyte Antigen-4, DAS = Disease activity score, DMARDs = Disease modifying antirheumatic drugs, EMA = European Medicine Agency, EULAR = European League Against Rheumatism, FDA = Food and Drugs Administration, HBV = Hepatitis B virus, JIA = Juvenile Idiopathic Arthritis, LDA = low disease activity (LDA), MRI = magnetic resonance imaging (MRI), MTX = methotrexate, RA = rheumatoid arthritis, RCT = randomized controlled trial, SS = Sjogren's syndrome, TCR = T cell receptor.

Transplantation of embryonic stem cell-derived dopaminergic neurons in MPTP-treated monkeys.

PubMed

Takahashi, Jun; Takagi, Yasushi; Saiki, Hidemoto

2009-01-01

One of the target diseases of cell-replacement therapy is Parkinson's disease. Clinical experiences with fetal dopaminergic cell graft have shown that the therapy is effective, but limited and accompanied by side effects, such as dyskinesia. So, the therapy needs to be further improved and sophisticated. Embryonic stem (ES) cells are expected to be another donor cell for the treatment, because of its proliferative and differentiation capacities. For clinical application, experiments using non-human primates are important, because size, anatomy, and biological characteristics of the brain are different between rodents and primates. Here, we would like to discuss induction of dopaminergic neurons from monkey ES cells and cell transplantation into the brain of monkey Parkinson's disease model.

Enterocolitis induced by autoimmune targeting of enteric glial cells: A possible mechanism in Crohn's disease?

NASA Astrophysics Data System (ADS)

Cornet, Anne; Savidge, Tor C.; Cabarrocas, Julie; Deng, Wen-Lin; Colombel, Jean-Frederic; Lassmann, Hans; Desreumaux, Pierre; Liblau, Roland S.

2001-11-01

Early pathological manifestations of Crohn's disease (CD) include vascular disruption, T cell infiltration of nerve plexi, neuronal degeneration, and induction of T helper 1 cytokine responses. This study demonstrates that disruption of the enteric glial cell network in CD patients represents another early pathological feature that may be modeled after CD8+ T cell-mediated autoimmune targeting of enteric glia in double transgenic mice. Mice expressing a viral neoself antigen in astrocytes and enteric glia were crossed with specific T cell receptor transgenic mice, resulting in apoptotic depletion of enteric glia to levels comparable in CD patients. Intestinal and mesenteric T cell infiltration, vasculitis, T helper 1 cytokine production, and fulminant bowel inflammation were characteristic hallmarks of disease progression. Immune-mediated damage to enteric glia therefore may participate in the initiation and/or the progression of human inflammatory bowel disease.

Pathophysiologically based drug treatment of sickle cell disease.

PubMed

Steinberg, Martin H

2006-04-01

Sickle cell disease is a systemic disorder that is caused by a mutation (Glu6Val) in the gene that encodes beta globin. The sickle hemoglobin molecule (HbS) is a tetramer of two alpha-globin chains and two sickle beta-globin chains, and has the tendency to polymerize when deoxygenated. HbS facilitates abnormal interactions between the sickle erythrocyte and leukocytes and endothelial cells, which trigger a complex pathobiology. This multifaceted pathophysiology provides the opportunity to interrupt the disease at multiple sites, including polymerization of HbS, erythrocyte density and cell-cell interactions. For example, it is possible to induce higher concentrations of fetal hemoglobin, which disrupts the pathology-initiating step of HbS polymerization. Furthermore, it is possible to improve the hydration of sickle erythrocytes and it might be feasible to counteract the endothelial, inflammatory and oxidative abnormalities of sickle cell disease. A therapeutic approach that targets several sites of pathobiology might be most promising.

Update on Mastocytosis (Part 2): Categories, Prognosis, and Treatment.

PubMed

Azaña, J M; Torrelo, A; Matito, A

2016-01-01

Mastocytosis is a term used to describe a heterogeneous group of disorders characterized by clonal proliferation of mast cells in different organs. The organ most often affected is the skin. The World Health Organization classifies cutaneous mastocytosis into mastocytoma, maculopapular cutaneous mastocytosis, and diffuse mastocytosis. The systemic variants in this classification are as follows: indolent systemic mastocytosis (SM), aggressive SM, SM with an associated clonal hematological non-mast cell lineage disease, mast cell leukemia, mast cell sarcoma, and extracutaneous mastocytoma. The two latest systemic variants are rare. Although the course of disease is unpredictable in children, lesions generally resolve by early adulthood. In adults, however, the disease tends to persist. The goal of treatment should be to control clinical manifestations caused by the release of mast cell mediators and, in more aggressive forms of the disease, to reduce mast cell burden. Copyright © 2015 Elsevier España, S.L.U. and AEDV. All rights reserved.

In vitro generation of three-dimensional substrate-adherent embryonic stem cell-derived neural aggregates for application in animal models of neurological disorders.

PubMed

Hargus, Gunnar; Cui, Yi-Fang; Dihné, Marcel; Bernreuther, Christian; Schachner, Melitta

2012-05-01

In vitro-differentiated embryonic stem (ES) cells comprise a useful source for cell replacement therapy, but the efficiency and safety of a translational approach are highly dependent on optimized protocols for directed differentiation of ES cells into the desired cell types in vitro. Furthermore, the transplantation of three-dimensional ES cell-derived structures instead of a single-cell suspension may improve graft survival and function by providing a beneficial microenvironment for implanted cells. To this end, we have developed a new method to efficiently differentiate mouse ES cells into neural aggregates that consist predominantly (>90%) of postmitotic neurons, neural progenitor cells, and radial glia-like cells. When transplanted into the excitotoxically lesioned striatum of adult mice, these substrate-adherent embryonic stem cell-derived neural aggregates (SENAs) showed significant advantages over transplanted single-cell suspensions of ES cell-derived neural cells, including improved survival of GABAergic neurons, increased cell migration, and significantly decreased risk of teratoma formation. Furthermore, SENAs mediated functional improvement after transplantation into animal models of Parkinson's disease and spinal cord injury. This unit describes in detail how SENAs are efficiently derived from mouse ES cells in vitro and how SENAs are isolated for transplantation. Furthermore, methods are presented for successful implantation of SENAs into animal models of Huntington's disease, Parkinson's disease, and spinal cord injury to study the effects of stem cell-derived neural aggregates in a disease context in vivo.

Generation, characterization and potential therapeutic applications of mature and functional hepatocytes from stem cells.

PubMed

Zhang, Zhenzhen; Liu, Jianfang; Liu, Yang; Li, Zheng; Gao, Wei-Qiang; He, Zuping

2013-02-01

Liver cancer is the sixth most common tumor in the world and the majority of patients with this disease usually die within 1 year. The effective treatment for end-stage liver disease (also known as liver failure), including liver cancer or cirrhosis, is liver transplantation. However, there is a severe shortage of liver donors worldwide, which is the major handicap for the treatment of patients with liver failure. Scarcity of liver donors underscores the urgent need of using stem cell therapy to the end-stage liver disease. Notably, hepatocytes have recently been generated from hepatic and extra-hepatic stem cells. We have obtained mature and functional hepatocytes from rat hepatic stem cells. Here, we review the advancements on hepatic differentiation from various stem cells, including hepatic stem cells, embryonic stem cells, the induced pluripotent stem cells, hematopoietic stem cells, mesenchymal stem cells, and probably spermatogonial stem cells. The advantages, disadvantages, and concerns on differentiation of these stem cells into hepatic cells are highlighted. We further address the methodologies, phenotypes, and functional characterization on the differentiation of numerous stem cells into hepatic cells. Differentiation of stem cells into mature and functional hepatocytes, especially from an extra-hepatic stem cell source, would circumvent the scarcity of liver donors and human hepatocytes, and most importantly it would offer an ideal and promising source of hepatocytes for cell therapy and tissue engineering in treating liver disease. Copyright © 2012 Wiley Periodicals, Inc.

Acute colonic pseudoobstruction in a child with sickle cell disease treated with neostigmine.

PubMed

Khosla, Arjun; Ponsky, Todd A

2008-12-01

Sickle cell disease is a disorder that produces significant morbidity and mortality. Vaso-occlusive pain crises are the most common presenting symptom associated with sickle cell patients. A rare, yet important to recognize, complication of sickle cell disease is acute colonic pseudoobstruction, also known as Ogilvie's syndrome. These patients may present with symptoms that are difficult to distinguish from other etiologies of abdominal pain, but a thorough diagnostic workup can provide important clues. Furthermore, there is no agreement on optimal treatment of pseudoobstruction. We report the first pediatric case of acute pseudoobstruction secondary to sickle cell disease that was treated successfully with neostigmine. Early recognition of this phenomenon is important as it alters patient management, can be treated medically, and may avoid unnecessary surgical intervention.

Using induced pluripotent stem cells to explore genetic and epigenetic variation associated with Alzheimer's disease.

PubMed

Imm, Jennifer; Kerrigan, Talitha L; Jeffries, Aaron; Lunnon, Katie

2017-11-01

It is thought that both genetic and epigenetic variation play a role in Alzheimer's disease initiation and progression. With the advent of somatic cell reprogramming into induced pluripotent stem cells it is now possible to generate patient-derived cells that are able to more accurately model and recapitulate disease. Furthermore, by combining this with recent advances in (epi)genome editing technologies, it is possible to begin to examine the functional consequence of previously nominated genetic variants and infer epigenetic causality from recently identified epigenetic variants. In this review, we explore the role of genetic and epigenetic variation in Alzheimer's disease and how the functional relevance of nominated loci can be investigated using induced pluripotent stem cells and (epi)genome editing techniques.

The clinical use of regenerative therapy in COPD

PubMed Central

Lipsi, Roberto; Rogliani, Paola; Calzetta, Luigino; Segreti, Andrea; Cazzola, Mario

2014-01-01

Regenerative or stem cell therapy is an emerging field of treatment based on stimulation of endogenous resident stem cells or administration of exogenous stem cells to treat diseases or injury and to replace malfunctioning or damaged tissues. Current evidence suggests that in the lung, these cells may participate in tissue homeostasis and regeneration after injury. Animal and human studies have demonstrated that tissue-specific stem cells and bone marrow-derived cells contribute to lung tissue regeneration and protection, and thus administration of exogenous stem/progenitor cells or humoral factors responsible for the activation of endogenous stem/progenitor cells may be a potent next-generation therapy for chronic obstructive pulmonary disease. The use of bone marrow-derived stem cells could allow repairing and regenerate the damaged tissue present in chronic obstructive pulmonary disease by means of their engraftment into the lung. Another approach could be the stimulation of resident stem cells by means of humoral factors or photobiostimulation. PMID:25548520

Inflammatory cells implicated in neoplasia development in idiopathic inflammatory bowel disease.

PubMed

Hashash, Jana G; Hartman, Douglas J

2017-11-10

The inflammatory mechanisms that lead to the clinical symptoms that are grouped under the term inflammatory bowel disease have not been fully characterized. Although a specific mechanism has not been identified, inflammatory bowel disease is believed to be related to an inability by the immune system to shut active inflammation within the intestine. Many contributing factors have been implicated in the disease process. Based on population studies, patients with inflammatory bowel disease have an increased risk for neoplastic development. Although no specific immune cell has been implicated in neoplastic development within this patient population, several immune cells have been implicated as possible etiologies in inflammatory bowel disease. In this review, we will review the clinical evidence about the risk for neoplastic development in inflammatory bowel disease and the current clinical guidelines to survey this patient population. We will also review the pathologic assessment of inflammation within this patient population as well the underlying immune cells and cytokines that have been implicated in the etiology of inflammatory bowel disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Renal cell carcinoma in a cat with polycystic kidney disease undergoing renal transplantation.

PubMed

Adams, Daniel J; Demchur, Jolie A; Aronson, Lillian R

2018-01-01

A 10-year-old spayed female American Shorthair cat underwent renal transplantation due to worsening chronic kidney disease secondary to polycystic kidney disease. During transplantation, the right kidney grossly appeared to be more diseased than the left and was firmly adhered to the surrounding tissues. An intraoperative fine-needle aspirate of the right native kidney revealed inflammatory cells but no evidence of neoplasia. To create space for the allograft, a right nephrectomy was performed. Following nephrectomy, the right native kidney was submitted for biopsy. Biopsy results revealed a renal cell carcinoma. Although the cat initially recovered well from surgery, delayed graft function was a concern in the early postoperative period. Significant azotemia persisted and the cat began to have diarrhea. Erythematous skin lesions developed in the perineal and inguinal regions, which were suspected to be secondary to thromboembolic disease based on histopathology. The cat's clinical status continued to decline with development of signs of sepsis, followed by marked obtundation with uncontrollable seizures. Given the postoperative diagnosis of renal cell carcinoma and the cat's progressively declining clinical status, humane euthanasia was elected. This case is the first to document renal cell carcinoma in a cat with polycystic kidney disease. An association of the two diseases has been reported in the human literature, but such a link has yet to be described in veterinary medicine. Given the association reported in the human literature, a plausible relationship between polycystic kidney disease and renal cell carcinoma in cats merits further investigation.

Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

PubMed Central

Green, Nancy S.; Ender, Katherine L.; Pashankar, Farzana; Driscoll, Catherine; Giardina, Patricia J.; Mullen, Craig A.; Clark, Lorraine N.; Manwani, Deepa; Crotty, Jennifer; Kisselev, Sergey; Neville, Kathleen A.; Hoppe, Carolyn; Barral, Sandra

2013-01-01

Background Fetal hemoglobin level is a heritable complex trait that strongly correlates swith the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. Methodology/Principal Findings In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. Conclusions/Significance These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease. PMID:23409025

Memory T cells: A helpful guard for allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease.

PubMed

Huang, Wei; Chao, Nelson J

2017-12-01

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHSCT) and the major cause of nonrelapse morbidity and mortality of AHSCT. In AHSCT, donor T cells facilitate hematopoietic stem cell (HSC) engraftment, contribute to anti-infection immunity, and mediate graft-versus-leukemia (GVL) responses. However, activated alloreactive T cells also attack recipient cells in vital organs, leading to GVHD. Different T-cell subsets, including naïve T (T N ) cells, memory T (T M ) cells, and regulatory T (T reg ) cells mediate different forms of GVHD and GVL; T N cells mediate severe GVHD, whereas T M cells do not cause GVHD, but preserve T-cell function including GVL. In addition, metabolic reprogramming controls T-cell differentiation and activation in these disease states. This minireview focuses on the role and the related mechanisms of T M cells in AHSCT, and the potential manipulation of T cells in AHSCT. Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.

Immunomodulatory activity of interleukin-27 in human chronic periapical diseases

PubMed Central

Li, Juan; Wang, Rong; Huang, Shi-Guang

2017-01-01

This study aims to observe expression of IL-27 on different cells in periapical tissues of different types of human chronic periapical diseases. Periapical tissue specimens of 60 donors, including healthy control (n=20), periapical granuloma group (n=20) and radicular cysts group (n=20), were fixed in 10% buffered formalin, stained with hematoxylin and eosin for histopathology. Then specimens were stained with double- immuno-fluorescence assay for identification of IL-27-tryptase (mast cells, MCs), IL-27-CD14 (mononuclear phagocyte cells, MPs) and IL-27-CD31 (endothelial cells, ECs) double-positive cells in periapical tissues. The results indicated that compared with healthy control, the densities (cells/mm2) of IL-27-tryptase, IL-27-CD14 and IL-27-CD31 double-positive cells were significantly increased in human chronic periapical diseases (periapical granuloma group and radicular cysts group) (P<0.001). The density of IL-27-tryptase double positive cells in radicular cysts group was significantly higher than those in periapical granuloma group (P<0.001). Densities of IL-27-CD14 and IL-27-CD31 double-positive cells in periapical granuloma group had no significant difference with those in radicular cysts group (P=0.170 and 0.138, respectively). IL-27-CD14 double positive cells density achieved to peak among three cell groups in radicular cysts groups. In conclusion, IL-27 expressed in MCs, MPs and ECs of human chronic periapical diseases with different degrees. IL-27-tryptase double-positive cells may participate in pathogenic mechanism of chronic periapical diseases, especially for formation of fibrous in periapical cysts. IL-27-CD14 and IL-27-CD31 double-positive cells may participate in immunologic response to resist periapical infection, and they may play an dual role in pathogenesis and localization of periapical diseases. PMID:28386371

Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease

PubMed Central

Blecharz, Kinga G; Frey, Dietmar; Schenkel, Tobias; Prinz, Vincent; Bedini, Gloria; Krug, Susanne M; Czabanka, Marcus; Wagner, Josephin; Fromm, Michael; Bersano, Anna

2016-01-01

Moyamoya disease is a rare steno-occlusive cerebrovascular disorder often resulting in hemorrhagic and ischemic strokes. Although sharing the same ischemic stimulus with atherosclerotic cerebrovascular disease, Moyamoya disease is characterized by a highly instable cerebrovascular system which is prone to rupture due to pathological neovascularization. To understand the molecular mechanisms underlying this instability, angiopoietin-2 gene expression was analyzed in middle cerebral artery lesions obtained from Moyamoya disease and atherosclerotic cerebrovascular disease patients. Angiopoietin-2 was significantly up-regulated in Moyamoya vessels, while serum concentrations of soluble angiopoietins were not changed. For further evaluations, cerebral endothelial cells incubated with serum from these patients in vitro were applied. In contrast to atherosclerotic cerebrovascular disease serum, Moyamoya disease serum induced an angiopoietin-2 overexpression and secretion, accompanied by loss of endothelial integrity. These effects were absent or inverse in endothelial cells of non-brain origin suggesting brain endothelium specificity. The destabilizing effects on brain endothelial cells to Moyamoya disease serum were partially suppressed by the inhibition of angiopoietin-2. Our findings define brain endothelial cells as the potential source of vessel-destabilizing factors inducing the high plasticity state and disintegration in Moyamoya disease in an autocrine manner. We also provide new insights into Moyamoya disease pathophysiology that may be helpful for preventive treatment strategies in future. PMID:27381827

Innate and adaptive immunity in experimental glomerulonephritis: a pathfinder tale.

PubMed

Artinger, Katharina; Kirsch, Alexander H; Aringer, Ida; Moschovaki-Filippidou, Foteini; Eller, Philipp; Rosenkranz, Alexander R; Eller, Kathrin

2017-06-01

The role of innate and adaptive immune cells in the experimental model of nephrotoxic serum nephritis (NTS) has been rigorously studied in recent years. The model is dependent on kidney-infiltrating T helper (TH) 17 and TH1 cells, which recruit neutrophils and macrophages, respectively, and cause sustained kidney inflammation. In a later phase of disease, regulatory T cells (Tregs) infiltrate the kidney in an attempt to limit disease activity. In the early stage of NTS, lymph node drainage plays an important role in disease initiation since dendritic cells present the antigen to T cells in the T cell zones of the draining lymph nodes. This results in the differentiation and proliferation of TH17 and TH1 cells. In this setting, immune regulatory cells (Tregs), namely, CCR7-expressing Tregs and mast cells (MCs), which are recruited by Tregs via the production of interleukin-9, exert their immunosuppressive capacity. Together, these two cell populations inhibit T cell differentiation and proliferation, thereby limiting disease activity by as yet unknown mechanisms. In contrast, the spleen plays no role in immune activation in NTS, but constitutes a place of extramedullary haematopoiesis. The complex interactions of immune cells in NTS are still under investigation and might ultimately lead to targeted therapies in glomerulonephritis.

Characterization of stem cells in Dupuytren's disease.

PubMed

Hindocha, S; Iqbal, S A; Farhatullah, S; Paus, R; Bayat, A

2011-02-01

Dupuytren's disease (DD) is a common fibroproliferative disease of unknown origin. The source of abnormal cells leading to DD formation remains underexplored. In addition to fascia, palmar skin and fat-derived cells may be a potential source of cells causing DD. This study aimed to profile haematopoietic and mesenchymal stem cells in different DD tissue components compared with tissue removed at carpal tunnel surgery (control). Biopsies were taken from the diseased cord, nodule, perinodular fat and skin overlying the nodule of ten patients with DD and compared with control tissue from seven patients having surgery for carpal tunnel syndrome. Fluorescence-activated cell sorting (FACS), immunohistochemistry and quantitative real-time polymerase chain reaction (QRT-PCR) were used to identify expression of selected stem cell markers. FACS and QRT-PCR analysis identified the highest RNA expression and number of cells positive for adipocyte stem cell markers (CD13 and CD29) in the DD nodule in comparison with carpal tunnel control tissue (P = 0·053). CD34 RNA was overexpressed, and a higher percentage of these cells was present in DD skin compared with carpal tunnel skin (P = 0·001). Each structural component of DD (cord, nodule, perinodular fat and skin) had distinct stem cell populations. These findings support the hypothesis that DD may result from mesenchymal progenitor cell expansion.

Potential of Induced Pluripotent Stem Cells (iPSCs) for Treating Age-Related Macular Degeneration (AMD).

PubMed

Fields, Mark; Cai, Hui; Gong, Jie; Del Priore, Lucian

2016-12-08

The field of stem cell biology has rapidly evolved in the last few decades. In the area of regenerative medicine, clinical applications using stem cells hold the potential to be a powerful tool in the treatment of a wide variety of diseases, in particular, disorders of the eye. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) are promising technologies that can potentially provide an unlimited source of cells for cell replacement therapy in the treatment of retinal degenerative disorders such as age-related macular degeneration (AMD), Stargardt disease, and other disorders. ESCs and iPSCs have been used to generate retinal pigment epithelium (RPE) cells and their functional behavior has been tested in vitro and in vivo in animal models. Additionally, iPSC-derived RPE cells provide an autologous source of cells for therapeutic use, as well as allow for novel approaches in disease modeling and drug development platforms. Clinical trials are currently testing the safety and efficacy of these cells in patients with AMD. In this review, the current status of iPSC disease modeling of AMD is discussed, as well as the challenges and potential of this technology as a viable option for cell replacement therapy in retinal degeneration.

Chronic Active Epstein–Barr Virus Disease

PubMed Central

Kimura, Hiroshi; Cohen, Jeffrey I.

2017-01-01

Chronic active Epstein–Barr virus (CAEBV) disease is a rare disorder in which persons are unable to control infection with the virus. The disease is progressive with markedly elevated levels of EBV DNA in the blood and infiltration of organs by EBV-positive lymphocytes. Patients often present with fever, lymphadenopathy, splenomegaly, EBV hepatitis, or pancytopenia. Over time, these patients develop progressive immunodeficiency and if not treated, succumb to opportunistic infections, hemophagocytosis, multiorgan failure, or EBV-positive lymphomas. Patients with CAEBV in the United States most often present with disease involving B or T cells, while in Asia, the disease usually involves T or NK cells. The only proven effective treatment for the disease is hematopoietic stem cell transplantation. Current studies to find a cause of this disease focus on immune defects and genetic abnormalities associated with the disease. PMID:29375552

Chronic Active Epstein-Barr Virus Disease.

PubMed

Kimura, Hiroshi; Cohen, Jeffrey I

2017-01-01

Chronic active Epstein-Barr virus (CAEBV) disease is a rare disorder in which persons are unable to control infection with the virus. The disease is progressive with markedly elevated levels of EBV DNA in the blood and infiltration of organs by EBV-positive lymphocytes. Patients often present with fever, lymphadenopathy, splenomegaly, EBV hepatitis, or pancytopenia. Over time, these patients develop progressive immunodeficiency and if not treated, succumb to opportunistic infections, hemophagocytosis, multiorgan failure, or EBV-positive lymphomas. Patients with CAEBV in the United States most often present with disease involving B or T cells, while in Asia, the disease usually involves T or NK cells. The only proven effective treatment for the disease is hematopoietic stem cell transplantation. Current studies to find a cause of this disease focus on immune defects and genetic abnormalities associated with the disease.

Parkinson's Disease: Leucine-Rich Repeat Kinase 2 and Autophagy, Intimate Enemies

PubMed Central

Bravo-San Pedro, José M.; Gómez-Sánchez, Rubén; Pizarro-Estrella, Elisa; Niso-Santano, Mireia; González-Polo, Rosa A.; Fuentes Rodríguez, José M.

2012-01-01

Parkinson's disease is the second common neurodegenerative disorder, after Alzheimer's disease. It is a clinical syndrome characterized by loss of dopamine-generating cells in the substancia nigra, a region of the midbrain. The etiology of Parkinson's disease has long been through to involve both genetic and environmental factors. Mutations in the leucine-rich repeat kinase 2 gene cause late-onset Parkinson's disease with a clinical appearance indistinguishable from Parkinson's disease idiopathic. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damage proteins and cytoplasmic organelles. This degradative process has been associated with cellular dysfunction in neurodegenerative processes including Parkinson's disease. We discuss the role of leucine-rich repeat kinase 2 in autophagy, and how the deregulations of this degradative mechanism in cells can be implicated in the Parkinson's disease etiology. PMID:22970411

Peripolesis followed by cytotoxicity in chronic idiopathic inflammatory bowel disease.

PubMed Central

Wilders, M M; Drexhage, H A; Kokjé, M; Verspaget, H W; Meuwissen, S G

1984-01-01

Antigen presenting veiled cells have recently been described in cell suspensions prepared from the gut wall of patients with chronic idiopathic inflammatory bowel disease (CIBD). The normal gut wall is virtually devoid of these cells. In this report we describe a phenomenon known as peripolesis studied by phase contrast cinematography. This is a process in which lymphocytes are seen to wander around larger target cells. These could be identified ultrastructurally as Ia positive veiled cells. In most cases peripolesis was followed by lysis of the target cell. Peripolesis was recorded in cell suspensions of three out of seven patients with ulcerative colitis and in three out of nine patients with Crohn's disease; furthermore peripolesis was observed in one out of two patients with non-classifiable CIBD. In four cell suspensions showing peripolesis, cell lysis could be recorded and was especially striking in ulcerative colitis. Peripolesis involving veiled cells was previously described in delayed hypersensitivity reactions. This study lends support to the concept that delayed allergic reactivity plays a part in chronic inflammatory bowel disease. The antigens involved are, however, completely unknown. Images Fig. 1 Fig. 2 Fig. 3 PMID:6380839

Stem Cell Therapies in Retinal Disorders.

PubMed

Garg, Aakriti; Yang, Jin; Lee, Winston; Tsang, Stephen H

2017-02-02

Stem cell therapy has long been considered a promising mode of treatment for retinal conditions. While human embryonic stem cells (ESCs) have provided the precedent for regenerative medicine, the development of induced pluripotent stem cells (iPSCs) revolutionized this field. iPSCs allow for the development of many types of retinal cells, including those of the retinal pigment epithelium, photoreceptors, and ganglion cells, and can model polygenic diseases such as age-related macular degeneration. Cellular programming and reprogramming technology is especially useful in retinal diseases, as it allows for the study of living cells that have genetic variants that are specific to patients' diseases. Since iPSCs are a self-renewing resource, scientists can experiment with an unlimited number of pluripotent cells to perfect the process of targeted differentiation, transplantation, and more, for personalized medicine. Challenges in the use of stem cells are present from the scientific, ethical, and political realms. These include transplant complications leading to anatomically incorrect placement, concern for tumorigenesis, and incomplete targeting of differentiation leading to contamination by different types of cells. Despite these limitations, human ESCs and iPSCs specific to individual patients can revolutionize the study of retinal disease and may be effective therapies for conditions currently considered incurable.

BJ-3105, a 6-Alkoxypyridin-3-ol Analog, Impairs T Cell Differentiation and Prevents Experimental Autoimmune Encephalomyelitis Disease Progression

PubMed Central

Timilshina, Maheshwor; Kang, Youra; Dahal, Ishmit; You, Zhiwei; Nam, Tae-gyu; Kim, Keuk-Jun

2017-01-01

CD4+ T cells are essential in inflammation and autoimmune diseases. Interferon-γ (IFN-γ) secreting T helper (Th1) and IL-17 secreting T helper (Th17) cells are critical for several autoimmune diseases. To assess the inhibitory effect of a given compound on autoimmune disease, we screened many compounds with an in vitro Th differentiation assay. BJ-3105, a 6-alkoxypyridin-3-ol analog, inhibited IFN-γ and IL-17 production from polyclonal CD4+ T cells and ovalbumin (OVA)-specific CD4+ T cells which were activated by T cell receptor (TCR) engagement. BJ-3105 ameliorated the experimental autoimmune encephalomyelitis (EAE) model by reducing Th1 and Th17 generation. Notably, Th cell differentiation was significantly suppressed by BJ-3105 treatment without inhibiting in vitro proliferation of T cells or inducing programmed cell death. Mechanistically, BJ-3105 inhibited the phosphorylation of JAK and its downstream signal transducer and activator of transcription (STAT) that is critical for Th differentiation. These results demonstrated that BJ-3105 inhibits the phosphorylation of STAT in response to cytokine signals and subsequently suppressed the differentiation of Th cell responses. PMID:28095433

The Plasma Concentration of the B Cell Activating Factor Is Increased in Children With Acute Malaria

PubMed Central

Nduati, Eunice; Gwela, Agnes; Karanja, Henry; Mugyenyi, Cleopatra; Langhorne, Jean; Marsh, Kevin

2011-01-01

Malaria-specific antibody responses in children often appear to be short-lived but the mechanisms underlying this phenomenon are not well understood. In this study, we investigated the relationship between the B-cell activating factor (BAFF) and its receptors expressed on B cells with antibody responses during and after acute malaria in children. Our results demonstrate that BAFF plasma levels increased during acute malarial disease and reflected disease severity. The expression profiles for BAFF receptors on B cells agreed with rapid activation and differentiation of a proportion of B cells to plasma cells. However, BAFF receptor (BAFF-R) expression was reduced on all peripheral blood B cells during acute infection, but those children with the highest level of BAFF-R expression on B cells maintained schizont-specific immunoglobin G (IgG) over a period of 4 months, indicating that dysregulation of BAFF-R expression on B cells may contribute to short-lived antibody responses to malarial antigens in children. In summary, this study suggests a potential role for BAFF during malaria disease, both as a marker for disease severity and in shaping the differentiation pattern of antigen-specific B cells. PMID:21849293

Rhinacanthus nasutus protects cultured neuronal cells against hypoxia induced cell death.

PubMed

Brimson, James M; Tencomnao, Tewin

2011-07-26

Rhinacanthus nasutus (L.) Kurz (Acanthaceae) is an herb native to Thailand and Southeast Asia, known for its antioxidant properties. Hypoxia leads to an increase in reactive oxygen species in cells and is a leading cause of neuronal damage. Cell death caused by hypoxia has been linked with a number of neurodegenerative diseases including some forms of dementia and stroke, as well as the build up of reactive oxygen species which can lead to diseases such as Huntington's disease, Parkinson's disease and Alzeheimer's disease. In this study we used an airtight culture container and the Mitsubishi Gas Company anaeropack along with the MTT assay, LDH assay and the trypan blue exlusion assay to show that 1 and 10 µg mL⁻¹ root extract of R. nasutus is able to significantly prevent the death of HT-22 cells subjected to hypoxic conditions, and 0.1 to 10 µg mL⁻¹ had no toxic effect on HT-22 under normal conditions, whereas 100 µg mL⁻¹ reduced HT-22 cell proliferation. We also used H₂DCFDA staining to show R. nasutus can reduce reactive oxygen species production in HT-22 cells.

Autophagy: controlling cell fate in rheumatic diseases.

PubMed

Rockel, Jason S; Kapoor, Mohit

2016-09-01

Autophagy, an endogenous process necessary for the turnover of organelles, maintains cellular homeostasis and directs cell fate. Alterations to the regulation of autophagy contribute to the progression of various rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), osteoarthritis (OA) and systemic sclerosis (SSc). Implicit in the progression of these diseases are cell-type-specific responses to surrounding factors that alter autophagy: chondrocytes within articular cartilage show decreased autophagy in OA, leading to rapid cell death and cartilage degeneration; fibroblasts from patients with SSc have restricted autophagy, similar to that seen in aged dermal fibroblasts; fibroblast-like synoviocytes from RA joints show altered autophagy, which contributes to synovial hyperplasia; and dysregulation of autophagy in haematopoietic lineage cells alters their function and maturation in SLE. Various upstream mechanisms also contribute to these diseases by regulating autophagy as part of their signalling cascades. In this Review, we discuss the links between autophagy, immune responses, fibrosis and cellular fates as they relate to pathologies associated with rheumatic diseases. Therapies in clinical use, and in preclinical or clinical development, are also discussed in relation to their effects on autophagy in rheumatic diseases.

Altered cell-matrix associated ADAM proteins in Alzheimer disease.

PubMed

Gerst, J L; Raina, A K; Pirim, I; McShea, A; Harris, P L; Siedlak, S L; Takeda, A; Petersen, R B; Smith, M A

2000-03-01

Alterations in cell-matrix 'contact' are often related to a disruption of cell cycle regulation and, as such, occur variously in neoplasia. Given the recent findings showing cell cycle alterations in Alzheimer disease, we undertook a study of ADAM-1 and 2 (A Disintegrin And Metalloprotease), developmentally-regulated, integrin-binding, membrane-bound metalloproteases. Our results show that whereas ADAM-1 and 2 are found in susceptible hippocampal neurons in Alzheimer disease, these proteins were not generally increased in similar neuronal populations in younger or age-matched controls except in association with age-related neurofibrillary alterations. This increase in both ADAM-1 and 2 in cases of Alzheimer disease was verified by immunoblot analysis (P < 0.05). An ADAM-induced loss of matrix integration would effectively "reset" the mitotic clock and thereby stimulate re-entry into the cell cycle in neurons in Alzheimer disease. Furthermore, given the importance of integrins in maintaining short-term memory, alterations in ADAM proteins or their proteolytic activity could also play a proximal role in the clinico-pathological manifestations of Alzheimer disease. Copyright 2000 Wiley-Liss, Inc.

Juvenile fibromyalgia in an adolescent patient with sickle cell disease presenting with chronic pain.

PubMed

Ramprakash, Stalin; Fishman, Daniel

2015-10-01

Juvenile fibromyalgia in children with sickle cell disease has not been reported in the literature. We report an adolescent patient with sickle cell whose pain symptoms progressed from having recurrent acute sickle cell pain crisis episodes to a chronic pain syndrome over several years. He was eventually diagnosed with juvenile fibromyalgia based on the clinical history and myofascial tender points and his pain symptoms responded better to multidisciplinary strategies for chronic fibromyalgia pain. Chronic pain in sickle cell disease is an area of poor research, and in addition there is inconsistency in the definition of chronic pain in sickle cell disease. Central sensitisation to pain is shown to occur after recurrent painful stimuli in a genetically vulnerable individual. In a chronic pain condition such as fibromyalgia central sensitisation is thought to play a key role. Fibromyalgia should be considered as one of the main differential diagnosis in any sickle cell patient with chronic pain. 2015 BMJ Publishing Group Ltd.

Induced Pluripotent Stem Cells in Huntington's Disease Research: Progress and Opportunity.

PubMed

Tousley, Adelaide; Kegel-Gleason, Kimberly B

2016-06-28

Induced pluripotent stem cells (iPSCs) derived from controls and patients can act as a starting point for in vitro differentiation into human brain cells for discovery of novel targets and treatments for human disease without the same ethical limitations posed by embryonic stem cells. Numerous groups have successfully produced and characterized Huntington's disease (HD) iPSCs with different CAG repeat lengths, including cells from patients with one or two HD alleles. HD iPSCs and the neural cell types derived from them recapitulate some disease phenotypes found in both human patients and animal models. Although these discoveries are encouraging, the use of iPSCs for cutting edge and reproducible research has been limited due to some of the inherent problems with cell lines and the technological differences in the way laboratories use them. The goal of this review is to summarize the current state of the HD iPSC field, and to highlight some of the issues that need to be addressed to maximize their potential as research tools.

The promise of human embryonic stem cells in aging-associated diseases

PubMed Central

Yabut, Odessa; Bernstein, Harold S.

2011-01-01

Aging-associated diseases are often caused by progressive loss or dysfunction of cells that ultimately affect the overall function of tissues and organs. Successful treatment of these diseases could benefit from cell-based therapy that would regenerate lost cells or otherwise restore tissue function. Human embryonic stem cells (hESCs) promise to be an important therapeutic candidate in treating aging-associated diseases due to their unique capacity for self-renewal and pluripotency. To date, there are numerous hESC lines that have been developed and characterized. We will discuss how hESC lines are derived, their molecular and cellular properties, and how their ability to differentiate into all three embryonic germ layers is determined. We will also outline the methods currently employed to direct their differentiation into populations of tissue-specific, functional cells. Finally, we will highlight the general challenges that must be overcome and the strategies being developed to generate highly-purified hESC-derived cell populations that can safely be used for clinical applications. PMID:21566262

Exosomes carrying immunoinhibitory proteins and their role in cancer.

PubMed

Whiteside, T L

2017-09-01

Recent emergence of exosomes as information carriers between cells has introduced us to a new previously unknown biological communication system. Multi-directional cross-talk mediated by exosomes carrying proteins, lipids and nucleic acids between normal cells, cells harbouring a pathogen or cancer and immune cells has been instrumental in determining outcomes of physiological as well as pathological conditions. Exosomes play a key role in the broad spectrum of human diseases. In cancer, tumour-derived exosomes carry multiple immunoinhibitory signals, disable anti-tumour immune effector cells and promote tumour escape from immune control. Exosomes delivering negative signals to immune cells in cancer, viral infections, autoimmune or other diseases may interfere with therapy and influence outcome. Exosomes can activate tissue cells to produce inhibitory factors and thus can suppress the host immune responses indirectly. Exosomes also promise to be non-invasive disease biomarkers with a dual capability to provide insights into immune dysfunction as well as disease progression and outcome. © 2017 British Society for Immunology.

Stem cell therapy: the great promise in lung disease.

PubMed

Siniscalco, Dario; Sullo, Nikol; Maione, Sabatino; Rossi, Francesco; D'Agostino, Bruno

2008-06-01

Lung injuries are leading causes of morbidity and mortality worldwide. Pulmonary diseases such as asthma or chronic obstructive pulmonary disease characterized by loss of lung elasticity, small airway tethers, and luminal obstruction with inflammatory mucoid secretions, or idiopathic pulmonary fibrosis characterized by excessive matrix deposition and destruction of the normal lung architecture, have essentially symptomatic treatments and their management is costly to the health care system.Regeneration of tissue by stem cells from endogenous, exogenous, and even genetically modified cells is a promising novel therapy. The use of adult stem cells to help with lung regeneration and repair could be a newer technology in clinical and regenerative medicine. In fact, different studies have shown that bone marrow progenitor cells contribute to repair and remodeling of lung in animal models of progressive pulmonary hypertension.Therefore, lung stem cell biology may provide novel approaches to therapy and could represent a great promise for the future of molecular medicine. In fact, several diseases can be slowed or even blocked by stem cell transplantation.

Mucosal-Associated Invariant T Cells in Regenerative Medicine

PubMed Central

Wakao, Hiroshi; Sugimoto, Chie; Kimura, Shinzo; Wakao, Rika

2017-01-01

Although antibiotics to inhibit bacterial growth and small compounds to interfere with the productive life cycle of human immunodeficiency virus (HIV) have successfully been used to control HIV infection, the recent emergence of the drug-resistant bacteria and viruses poses a serious concern for worldwide public health. Despite intensive scrutiny in developing novel antibiotics and drugs to overcome these problems, there is a dilemma such that once novel antibiotics are launched in markets, sooner or later antibiotic-resistant strains emerge. Thus, it is imperative to develop novel methods to avoid this vicious circle. Here, we discuss the possibility of using induced pluripotent stem cell (iPSC)-derived, innate-like T cells to control infection and potential application of these cells for cancer treatment. Mucosal-associated invariant T (MAIT) cells belong to an emerging family of innate-like T cells that link innate immunity to adaptive immunity. MAIT cells exert effector functions without priming and clonal expansion like innate immune cells and relay the immune response to adaptive immune cells through production of relevant cytokines. With these characteristics, MAIT cells are implicated in a wide range of human diseases such as autoimmune, infectious, and metabolic diseases, and cancer. Circulating MAIT cells are often depleted by these diseases and often remain depleted even after appropriate remedy because MAIT cells are susceptible to activation-induced cell death and poor at proliferation in vivo, which threatens the integrity of the immune system. Because MAIT cells have a pivotal role in human immunity, supplementation of MAIT cells into immunocompromised patients suffering from severe depletion of these cells may help recapitulate or recover immunocompetence. The generation of MAIT cells from human iPSCs has made it possible to procure MAIT cells lost from disease. Such technology creates new avenues for cell therapy and regenerative medicine for difficult-to-cure infectious diseases and cancer and contributes to improvement of our welfare. PMID:29250077

Predictors of osteoclast activity in patients with sickle cell disease

PubMed Central

Nouraie, Mehdi; Cheng, Kevin; Niu, Xiaomei; Moore-King, Evadne; Fadojutimi-Akinsi, Margaret F.; Minniti, Caterina P.; Sable, Craig; Rana, Sohail; Dham, Niti; Campbell, Andrew; Ensing, Gregory; Kato, Gregory J.; Gladwin, Mark T.; Castro, Oswaldo L.; Gordeuk, Victor R.

2011-01-01

Background Bone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. Design and Methods We examined tartrate-resistant acid phosphatase 5b concentrations in patients with sickle cell disease and normal controls of similar age and sex distribution at steady state. Serum tartrate-resistant acid phosphatase 5b concentration was measured using an immunocapture enzyme assay and plasma concentrations of other cytokines were assayed using the Bio-Plex suspension array system. Tricuspid regurgitation velocity, an indirect measure of systolic pulmonary artery pressure, was determined by echocardiography. Results Tartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively; P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=−0.28, P=0.031) concentrations, but not with serum ferritin concentration. Frequent blood transfusions (>10 units in life time) were not associated with higher tartrate-resistant acid phosphatase 5b levels in multivariate analysis. There were strong correlations among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). Conclusions Patients with sickle cell disease have increased osteoclast activity as reflected by serum tartrate-resistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease. PMID:21546502

Atypical memory B cells in human chronic infectious diseases: An interim report.

PubMed

Portugal, Silvia; Obeng-Adjei, Nyamekye; Moir, Susan; Crompton, Peter D; Pierce, Susan K

2017-11-01

Immunological memory is a remarkable phenomenon in which survival of an initial infection by a pathogen leads to life-long protection from disease upon subsequent exposure to that same pathogen. For many infectious diseases, long-lived protective humoral immunity is induced after only a single infection in a process that depends on the generation of memory B cells (MBCs) and long-lived plasma cells. However, over the past decade it has become increasingly evident that many chronic human infectious diseases to which immunity is not readily established, including HIV-AIDS, malaria and TB, are associated with fundamental alterations in the composition and functionality of MBC compartments. A common feature of these diseases appears to be a large expansion of what have been termed exhausted B cells, tissue-like memory B cells or atypical memory B cells (aMBCs) that, for simplicity's sake, we refer to here as aMBCs. It has been suggested that chronic immune activation and inflammation drive the expansion of aMBCs and that in some way aMBCs contribute to deficiencies in the acquisition of immunity in chronic infectious diseases. Although aMBCs are heterogeneous both within individuals and between diseases, they have several features in common including low expression of the cell surface markers that define classical MBCs in humans including CD21 and CD27 and high expression of genes not usually expressed by classical MBCs including T-bet, CD11c and a variety of inhibitory receptors, notably members of the FcRL family. Another distinguishing feature is their greatly diminished ability to be stimulated through their B cell receptors to proliferate, secrete cytokines or produce antibodies. In this review, we describe our current understanding of the phenotypic markers of aMBCs, their specificity in relation to the disease-causing pathogen, their functionality, the drivers of their expansion in chronic infections and their life span. We briefly summarize the features of aMBCs in healthy individuals and in autoimmune disease. We also comment on the possible relationship of human aMBCs and T-bet + , CD11c + age/autoimmune-associated B cells, also a topic of this review volume. Published by Elsevier Inc.

Neurotrophins in healthy and diseased skin.

PubMed

Raap, U; Kapp, A

2010-04-01

Understanding the complex mechanism of allergic inflammatory skin diseases has been a main challenge of clinical and experimental research for years. It is well known that the inflammatory response is also controlled by tissue resident cells including neurons and structural cells. Thus, allergic inflammation triggers neuronal dysfunction and structural changes in diseased skin. Prime candidates for the interaction between immune, structural, and neuronal cells are presented by neurotrophins. Neurotrophins have initially been described for their neurotrophic capacity. However, recent evidence emerges that neurotrophins display bidirectional interaction pathways in activating structural cells, immune cells in addition to neurons. Neurotrophins including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) are upregulated in allergic inflammatory skin diseases. Further, structural cells, neurons and tissue resident cells have not only been shown to be a target but also a source of neurotrophin. In this regard, eosinophil granulocytes which are key target effector cells in chronic inflammatory skin have been identified as a target of neurotrophins but are also capable of neurotrophin production. Thus, neuroimmune interaction mechanisms in allergic inflammatory skin display a novel pathophysiological aspect in which neurotrophins serve as prime candidates for bidirectional interaction mechanisms. In this review, we provide an actual overview of neurotrophins in healthy and diseased skin with special emphasis on atopic dermatitis and therapeutic implications.

Cell-type-specific, Aptamer-functionalized Agents for Targeted Disease Therapy

PubMed Central

Zhou, Jiehua; Rossi, John J.

2014-01-01

One hundred years ago, Dr. Paul Ehrlich popularized the “magic bullet” concept for cancer therapy in which an ideal therapeutic agent would only kill the specific tumor cells it targeted. Since then, “targeted therapy” that specifically targets the molecular defects responsible for a patient's condition has become a long-standing goal for treating human disease. However, safe and efficient drug delivery during the treatment of cancer and infectious disease remains a major challenge for clinical translation and the development of new therapies. The advent of SELEX technology has inspired many groundbreaking studies that successfully adapted cell-specific aptamers for targeted delivery of active drug substances in both in vitro and in vivo models. By covalently linking or physically functionalizing the cell-specific aptamers with therapeutic agents, such as siRNA, microRNA, chemotherapeutics or toxins, or delivery vehicles, such as organic or inorganic nanocarriers, the targeted cells and tissues can be specifically recognized and the therapeutic compounds internalized, thereby improving the local concentration of the drug and its therapeutic efficacy. Currently, many cell-type-specific aptamers have been developed that can target distinct diseases or tissues in a cell-type-specific manner. In this review, we discuss recent advances in the use of cell-specific aptamers for targeted disease therapy, as well as conjugation strategies and challenges. PMID:24936916

Assessment of cytologic evaluation of preputial epithelial cells as a diagnostic test for detection of adrenocortical disease in castrated ferrets.

PubMed

Protain, Holly J; Kutzler, Michelle A; Valentine, Beth A

2009-05-01

To determine whether results of cytologic evaluation of preputial epithelial cells correspond to results of a serum endocrine hormone assay and clinical signs associated with adrenocortical disease in castrated ferrets. 13 clinically normal ferrets and 8 ferrets with signs of adrenocortical disease. Blood and preputial lavage samples were collected from each ferret. Serum samples were submitted to the University of Tennessee Veterinary Diagnostic Laboratory for performance of an endocrine hormone assay. Differential epithelial cell counts were performed on preputial lavage samples to determine the percentage of cornified cells. Results of cytologic evaluation were compared with results of the endocrine hormone assay and clinical status of ferrets. The percentage of cornified preputial epithelial cells was not significantly correlated with serum 17B-estradiol or androstenedione concentration but was significantly correlated with serum 17-hydroxyprogesterone concentration (r = 0.60). The percentage of cornified preputial epithelial cells was higher in ferrets with clinical signs of adrenocortical disease (mean +/- SD, 71.3 +/- 16.9%) than in clinically normal ferrets (55.5 +/- 19.0%). Cornification of preputial epithelial cells was correlated with an increase in serum 17-hydroxyprogesterone concentration as well as clinical signs of adrenocortical disease in castrated ferrets. Additional investigation is needed to elucidate the mechanism of preputial epithelial cell cornification in castrated ferrets.

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.

PubMed

Uhlin, Michael; Wikell, Helena; Sundin, Mikael; Blennow, Ola; Maeurer, Markus; Ringden, Olle; Winiarski, Jacek; Ljungman, Per; Remberger, Mats; Mattsson, Jonas

2014-02-01

Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch (P<0.001), serological Epstein-Barr virus mismatch recipient-/donor+ (P<0.001), use of reduced intensity conditioning (P=0.002), acute graft-versus-host disease grade II to IV (P=0.006), pre-transplant splenectomy (P=0.008) and infusion of mesenchymal stromal cells (P=0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease (P<0.001). The study identifies patients at risk of post-transplant lymphoproliferative disease after transplantation in need of pre-emptive measures.

B cell subset distribution is altered in patients with severe periodontitis.

PubMed

Demoersman, Julien; Pochard, Pierre; Framery, Camille; Simon, Quentin; Boisramé, Sylvie; Soueidan, Assem; Pers, Jacques-Olivier

2018-01-01

Several studies have recently highlighted the implication of B cells in physiopathogenesis of periodontal disease by showing that a B cell deficiency leads to improved periodontal parameters. However, the detailed profiles of circulating B cell subsets have not yet been investigated in patients with severe periodontitis (SP). We hypothesised that an abnormal distribution of B cell subsets could be detected in the blood of patients with severe periodontal lesions, as already reported for patients with chronic inflammatory diseases as systemic autoimmune diseases. Fifteen subjects with SP and 13 subjects without periodontitis, according to the definition proposed by the CDC periodontal disease surveillance work group, were enrolled in this pilot observational study. Two flow cytometry panels were designed to analyse the circulating B and B1 cell subset distribution in association with the RANKL expression. A significantly higher percentage of CD27+ memory B cells was observed in patients with SP. Among these CD27+ B cells, the proportion of the switched memory subset was significantly higher. At the same time, human B1 cells, which were previously associated with a regulatory function (CD20+CD69-CD43+CD27+CD11b+), decreased in SP patients. The RANKL expression increased in every B cell subset from the SP patients and was significantly greater in activated B cells than in the subjects without periodontitis. These preliminary results demonstrate the altered distribution of B cells in the context of severe periodontitis. Further investigations with a larger cohort of patients can elucidate if the analysis of the B cell compartment distribution can reflect the periodontal disease activity and be a reliable marker for its prognosis (clinical trial registration number: NCT02833285, B cell functions in periodontitis).

B cell subset distribution is altered in patients with severe periodontitis

PubMed Central

Demoersman, Julien; Pochard, Pierre; Framery, Camille; Simon, Quentin; Boisramé, Sylvie; Soueidan, Assem

2018-01-01

Several studies have recently highlighted the implication of B cells in physiopathogenesis of periodontal disease by showing that a B cell deficiency leads to improved periodontal parameters. However, the detailed profiles of circulating B cell subsets have not yet been investigated in patients with severe periodontitis (SP). We hypothesised that an abnormal distribution of B cell subsets could be detected in the blood of patients with severe periodontal lesions, as already reported for patients with chronic inflammatory diseases as systemic autoimmune diseases. Fifteen subjects with SP and 13 subjects without periodontitis, according to the definition proposed by the CDC periodontal disease surveillance work group, were enrolled in this pilot observational study. Two flow cytometry panels were designed to analyse the circulating B and B1 cell subset distribution in association with the RANKL expression. A significantly higher percentage of CD27+ memory B cells was observed in patients with SP. Among these CD27+ B cells, the proportion of the switched memory subset was significantly higher. At the same time, human B1 cells, which were previously associated with a regulatory function (CD20+CD69-CD43+CD27+CD11b+), decreased in SP patients. The RANKL expression increased in every B cell subset from the SP patients and was significantly greater in activated B cells than in the subjects without periodontitis. These preliminary results demonstrate the altered distribution of B cells in the context of severe periodontitis. Further investigations with a larger cohort of patients can elucidate if the analysis of the B cell compartment distribution can reflect the periodontal disease activity and be a reliable marker for its prognosis (clinical trial registration number: NCT02833285, B cell functions in periodontitis). PMID:29447240

Modeling Huntington׳s disease with patient-derived neurons.

PubMed

Mattis, Virginia B; Svendsen, Clive N

2017-02-01

Huntington׳s Disease (HD) is a fatal neurodegenerative disorder caused by expanded polyglutamine repeats in the Huntingtin (HTT) gene. While the gene was identified over two decades ago, it remains poorly understood why mutant HTT (mtHTT) is initially toxic to striatal medium spiny neurons (MSNs). Models of HD using non-neuronal human patient cells and rodents exhibit some characteristic HD phenotypes. While these current models have contributed to the field, they are limited in disease manifestation and may vary in their response to treatments. As such, human HD patient MSNs for disease modeling could greatly expand the current understanding of HD and facilitate the search for a successful treatment. It is now possible to use pluripotent stem cells, which can generate any tissue type in the body, to study and potentially treat HD. This review covers disease modeling in vitro and, via chimeric animal generation, in vivo using human HD patient MSNs differentiated from embryonic stem cells or induced pluripotent stem cells. This includes an overview of the differentiation of pluripotent cells into MSNs, the established phenotypes found in cell-based models and transplantation studies using these cells. This review not only outlines the advancements in the rapidly progressing field of HD modeling using neurons derived from human pluripotent cells, but also it highlights several remaining controversial issues such as the 'ideal' series of pluripotent lines, the optimal cell types to use and the study of a primarily adult-onset disease in a developmental model. This article is part of a Special Issue entitled SI: Exploiting human neurons. Copyright © 2015 Elsevier B.V. All rights reserved.

The endothelin B receptor plays a crucial role in the adhesion of neutrophils to the endothelium in sickle cell disease

PubMed Central

Koehl, Bérengère; Nivoit, Pierre; El Nemer, Wassim; Lenoir, Olivia; Hermand, Patricia; Pereira, Catia; Brousse, Valentine; Guyonnet, Léa; Ghinatti, Giulia; Benkerrou, Malika; Colin, Yves; Le Van Kim, Caroline; Tharaux, Pierre-Louis

2017-01-01

Although the primary origin of sickle cell disease is a hemoglobin disorder, many types of cells contribute considerably to the pathophysiology of the disease. The adhesion of neutrophils to activated endothelium is critical in the pathophysiology of sickle cell disease and targeting neutrophils and their interactions with endothelium represents an important opportunity for the development of new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and investigated the involvement of the endothelin receptors in the interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on the mouse model and patients indicate that blocking endothelin receptors, particularly ETB receptor, strongly influences neutrophil recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils have functional ETB receptors with calcium signaling capability, leading to increased adhesion to the endothelium through effects on both endothelial cells and neutrophils. Intact ETB function was found to be required for tumor necrosis factor α-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1, which may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETB axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptors, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises in sickle cell patients. PMID:28385784

The emerging roles of B cells as partners and targets in periodontitis.

PubMed

Zouali, Moncef

2017-02-01

Initial studies of periodontal disease suggested that T cell-mediated immunity against oral Gram-negative microorganisms is a key player in the pathogenesis of this inflammatory disease. Recent investigations, however, revealed that B cells are also engaged. Given their chief role in innate-like and adaptive immune responses, B cells could exert protective functions in periodontitis. However, the periodontal bacteria-specific antibody response is generally unable to halt disease progression in affected subjects, suggesting that the antibodies produced could exhibit low anti-bacterial blocking functions or opsonophagocytic potential, and/or unfavorable effects. Moreover, although microbial antigens are involved in the induction of the inflammatory responses in human adult periodontitis, endogenous antigens also may contribute to the chronicity of this common disease. Not only antibodies to self-antigens, such as collagen, are locally produced, but the autoreactivities observed in aggressive periodontitis are more severe and diverse than those observed in chronic periodontitis, suggesting that autoimmune reactivity could play a role in the tissue destruction of periodontal disease. Further support for a pathological role of B cells in periodontitis comes from the finding that B cell-deficient mice are protected from bacterial infection-induced alveolar bone loss. Studies in patients indicate that B cells and plasma cells, together with osteoclastogenic factors (RANKL and osteoprotegerin) and specific cytokines involved in their growth and differentiation (BAFF and APRIL) participate in the induction of the pathological bone loss in periodontitis. This novel insight suggests that selective targeting of B cells could represent a future therapeutic avenue for severe periodontal disease.

Role of innate immunity and the microbiota in liver fibrosis: crosstalk between the liver and gut

PubMed Central

Seki, Ekihiro; Schnabl, Bernd

2012-01-01

Liver fibrosis occurs as a wound-healing scar response following chronic liver inflammation including alcoholic liver disease, non-alcoholic steatohepatitis, viral hepatitis, cholestatic liver disease and autoimmune liver diseases. The liver has a unique vascular system within the gastrointestinal tract, as the majority of the liver's blood supply comes from the intestine through the portal vein. When the intestinal barrier function is disrupted, an increase in intestinal permeability leads to the translocation of intestine-derived bacterial products such as lipopolysaccharide (LPS) and unmethylated CpG containing DNA to the liver via the portal vein. These gut-derived bacterial products stimulate innate immune receptors, namely Toll-like receptors (TLRs), in the liver. TLRs are expressed on Kupffer cells, endothelial cells, dendritic cells, biliary epithelial cells, hepatic stellate cells, and hepatocytes. TLRs activate these cells to contribute to acute and chronic liver diseases. This review summarizes recent studies investigating the role of TLRs, intestinal microbiota and bacterial translocation in liver fibrosis, alcoholic liver disease and non-alcoholic steatohepatitis. PMID:22124143

The Deadly Dance of B Cells with Trypanosomatids.

PubMed

Silva-Barrios, Sasha; Charpentier, Tania; Stäger, Simona

2018-02-01

B cells are notorious actors for the host's protection against several infectious diseases. So much so that early vaccinology seated its principles upon their long-term protective antibody secretion capabilities. Indeed, there are many examples of acute infectious diseases that are combated by functional humoral responses. However, some chronic infectious diseases actively induce immune deregulations that often lead to defective, if not deleterious, humoral immune responses. In this review we summarize how Leishmania and Trypanosoma spp. directly manipulate B cell responses to induce polyclonal B cell activation, hypergammaglobulinemia, low-specificity antibodies, limited B cell survival, and regulatory B cells, contributing therefore to immunopathology and the establishment of persistent infections. Copyright © 2017 Elsevier Ltd. All rights reserved.

Circulating anti-double-stranded DNA antibody-secreting cells in patients with systemic lupus erythematosus: a novel biomarker for disease activity.

PubMed

Hanaoka, H; Okazaki, Y; Satoh, T; Kaneko, Y; Yasuoka, H; Seta, N; Kuwana, M

2012-10-01

Antibodies against double-stranded DNA (dsDNA) are widely used to diagnose systemic lupus erythematosus (SLE) and evaluate its activity in patients. This study was undertaken to examine the clinical utility of circulating anti-dsDNA antibody-secreting cells for evaluating SLE patients. Anti-dsDNA antibody-secreting cells quantified using an enzyme-linked immunospot assay were detected in the spleen, bone marrow and peripheral blood from MRL/lpr but not in control BALB/c mice. Circulating anti-dsDNA antibody-secreting cells were detected in 29 (22%) of 130 patients with SLE, but in none of 49 with non-SLE connective-tissue disease or 18 healthy controls. The presence of circulating anti-dsDNA antibody-secreting cells was associated with persistent proteinuria, high SLE disease activity index and systemic lupus activity measures, and a high serum anti-dsDNA antibody titre measured with an enzyme-linked immunosorbent assay. The positive predictive value for active disease was 48% for circulating anti-dsDNA antibody-secreting cells versus 17% for serum anti-dsDNA antibodies. A prospective cohort of patients with circulating anti-dsDNA antibodies and inactive SLE showed that the cumulative disease flare-free rate was significantly lower in patients with than without circulating anti-dsDNA antibody-secreting cells (p < 0.001). Circulating anti-dsDNA antibody-secreting cells are a useful biomarker for assessing disease activity in SLE patients.

Exacerbation of spontaneous autoimmune nephritis following regulatory T cell depletion in B cell lymphoma 2‐interacting mediator knock‐out mice

PubMed Central

Wang, Y. M.; Zhang, G. Y.; Wang, Y.; Hu, M.; Zhou, J. J.; Sawyer, A.; Cao, Q.; Wang, Y.; Zheng, G.; Lee, V. W. S.; Harris, D. C. H.

2017-01-01

Summary Regulatory T cells (Tregs) have been recognized as central mediators for maintaining peripheral tolerance and limiting autoimmune diseases. The loss of Tregs or their function has been associated with exacerbation of autoimmune disease. However, the temporary loss of Tregs in the chronic spontaneous disease model has not been investigated. In this study, we evaluated the role of Tregs in a novel chronic spontaneous glomerulonephritis model of B cell lymphoma 2‐interacting mediator (Bim) knock‐out mice by transient depleting Tregs. Bim is a pro‐apoptotic member of the B cell lymphoma 2 (Bcl‐2) family. Bim knock‐out (Bim–/–) mice fail to delete autoreactive T cells in thymus, leading to chronic spontaneous autoimmune kidney disease. We found that Treg depletion in Bim–/– mice exacerbated the kidney injury with increased proteinuria, impaired kidney function, weight loss and greater histological injury compared with wild‐type mice. There was a significant increase in interstitial infiltrate of inflammatory cells, antibody deposition and tubular damage. Furthermore, the serum levels of cytokines interleukin (IL)−2, IL‐4, IL‐6, IL‐10, IL‐17α, interferon (IFN)‐γ and tumour necrosis factor (TNF)‐α were increased significantly after Treg depletion in Bim–/– mice. This study demonstrates that transient depletion of Tregs leads to enhanced self‐reactive T effector cell function followed by exacerbation of kidney disease in the chronic spontaneous kidney disease model of Bim‐deficient mice. PMID:28152566

Analysis of neural crest cells from Charcot-Marie-Tooth disease patients demonstrates disease-relevant molecular signature.

PubMed

Kitani-Morii, Fukiko; Imamura, Keiko; Kondo, Takayuki; Ohara, Ryo; Enami, Takako; Shibukawa, Ran; Yamamoto, Takuya; Sekiguchi, Kazuya; Toguchida, Junya; Mizuno, Toshiki; Nakagawa, Masanori; Inoue, Haruhisa

2017-09-06

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The majority of CMT is demyelinating type (demyelinating CMT) caused by Schwann cell involvement. Although a large number of genes responsible for demyelinating CMT have been found, the common molecular target of the pathophysiology caused by these different genes in demyelinating CMT is still unknown. We generated induced pluripotent stem cells (iPSCs) from healthy controls and patients with demyelinating CMT caused by duplication in peripheral myelin protein 22 kDa (PMP22) or point mutations in myelin protein zero (MPZ) or early growth response 2 (EGR2). iPSCs were differentiated into neural crest cells, progenitors of Schwann cells, followed by purification using the neural crest cell markers p75 and human natural killer-1. To identify a disease-relevant molecular signature at the early stage of demyelinating CMT, we conducted global gene expression analysis of iPSC-derived neural crest cells and found that a glutathione-mediated detoxification pathway was one of the related pathways in demyelinating CMT. mRNA expression of glutathione S-transferase theta 2 (GSTT2), encoding an important enzyme for glutathione-mediated detoxification, and production of reactive oxygen species were increased in demyelinating CMT. Our study suggested that patient-iPSC-derived neural crest cells could be a cellular model for investigating genetically heterogeneous disease CMT and might provide a therapeutic target for the disease.

The role of necroptosis in pulmonary diseases.

PubMed

Mizumura, Kenji; Maruoka, Shuichiro; Gon, Yasuhiro; Choi, Augustine M K; Hashimoto, Shu

2016-11-01

By regulating the cell number and eliminating harmful cells, programmed cell death plays a critical role in development, homeostasis, and disease. While apoptosis is a recognized form of programmed cell death, necrosis was considered a type of uncontrolled cell death induced by extreme physical or chemical stress. However, recent studies have revealed the existence of a genetically programmed and regulated form of necrosis, termed necroptosis. Necroptosis is defined as necrotic cell death that is dependent on receptor-interacting protein kinase 3 (RIPK3). RIPK3, receptor-interacting protein kinase 1 (RIPK1), and a mixed-lineage kinase domain-like protein (MLKL) form a multiprotein complex called a necrosome. Although necroptosis generally provides a cell-autonomous host defense, on the other hand, cell rupture caused by necroptosis induces inflammation through the release of damage-associated molecular patterns, such as mitochondrial DNA, HMGB1, and IL-1. Previously, necroptosis was considered an alternative to apoptosis, but it is becoming increasingly clear that necroptosis itself is relevant to clinical disease, independent of apoptosis. According to some recent studies, autophagy, a cellular process for organelle and protein turnover, regulates necroptosis. This review outlines the principal components of necroptosis and provides an overview of the emerging importance of necroptosis in the pathogenesis of pulmonary disease, including chronic obstructive pulmonary disease, lung cancer, infection, and sepsis. We also discuss the molecular relationship between necroptosis and autophagy. Strategies targeting necroptosis may yield novel therapies for pulmonary diseases. Copyright © 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Myofibroblasts in interstitial lung diseases show diverse electron microscopic and invasive features.

PubMed

Karvonen, Henna M; Lehtonen, Siri T; Sormunen, Raija T; Harju, Terttu H; Lappi-Blanco, Elisa; Bloigu, Risto S; Kaarteenaho, Riitta L

2012-09-01

The characteristic features of myofibroblasts in various lung disorders are poorly understood. We have evaluated the ultrastructure and invasive capacities of myofibroblasts cultured from small volumes of diagnostic bronchoalveolar lavage (BAL) fluid samples from patients with different types of lung diseases. Cells were cultured from samples of BAL fluid collected from 51 patients that had undergone bronchoscopy and BAL for diagnostic purposes. The cells were visualized by transmission electron microscopy and immunoelectron microscopy to achieve ultrastructural localization of alpha-smooth muscle actin (α-SMA) and fibronectin. The levels of α-SMA protein and mRNA and fibronectin mRNA were measured by western blot and quantitative real-time reverse transcriptase polymerase chain reaction. The invasive capacities of the cells were evaluated. The cultured cells were either fibroblasts or myofibroblasts. The structure of the fibronexus, and the amounts of intracellular actin, extracellular fibronectin and cell junctions of myofibroblasts varied in different diseases. In electron and immunoelectron microscopy, cells cultured from interstitial lung diseases (ILDs) expressed more actin filaments and α-SMA than normal lung. The invasive capacity of the cells obtained from patients with idiopathic pulmonary fibrosis was higher than that from patients with other type of ILDs. Cells expressing more actin filaments had a higher invasion capacity. It is concluded that electron and immunoelectron microscopic studies of myofibroblasts can reveal differential features in various diseases. An analysis of myofibroblasts cultured from diagnostic BAL fluid samples may represent a new kind of tool for diagnostics and research into lung diseases.

Current status of treating neurodegenerative disease with induced pluripotent stem cells.

PubMed

Pen, A E; Jensen, U B

2017-01-01

Degenerative diseases of the brain have proven challenging to treat, let alone cure. One of the treatment options is the use of stem cell therapy, which has been under investigation for several years. However, treatment with stem cells comes with a number of drawbacks, for instance the source of these cells. Currently, a number of options are tested to produce stem cells, although the main issues of quantity and ethics remain for most of them. Over recent years, the potential of induced pluripotent stem cells (iPSCs) has been widely investigated and these cells seem promising for production of numerous different tissues both in vitro and in vivo. One of the major advantages of iPSCs is that they can be made autologous and can provide a sufficient quantity of cells by culturing, making the use of other stem cell sources unnecessary. As the first descriptions of iPSC production with the transcription factors Sox2, Klf4, Oct4 and C-Myc, called the Yamanaka factors, a variety of methods has been developed to convert somatic cells from all germ layers to pluripotent stem cells. Improvement of these methods is necessary to increase the efficiency of reprogramming, the quality of pluripotency and the safety of these cells before use in human trials. This review focusses on the current accomplishments and remaining challenges in the production and use of iPSCs for treatment of neurodegenerative diseases of the brain such as Alzheimer's disease and Parkinson's disease. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Generating induced pluripotent stem cell derived endothelial cells and induced endothelial cells for cardiovascular disease modelling and therapeutic angiogenesis.

PubMed

Clayton, Z E; Sadeghipour, S; Patel, S

2015-10-15

Standard therapy for atherosclerotic coronary and peripheral arterial disease is insufficient in a significant number of patients because extensive disease often precludes effective revascularization. Stem cell therapy holds promise as a supplementary treatment for these patients, as pre-clinical and clinical research has shown transplanted cells can promote angiogenesis via direct and paracrine mechanisms. Induced pluripotent stem cells (iPSCs) are a novel cell type obtained by reprogramming somatic cells using exogenous transcription factor cocktails, which have been introduced to somatic cells via viral or plasmid constructs, modified mRNA or small molecules. IPSCs are now being used in disease modelling and drug testing and are undergoing their first clinical trial, but despite recent advances, the inefficiency of the reprogramming process remains a major limitation, as does the lack of consensus regarding the optimum transcription factor combination and delivery method and the uncertainty surrounding the genetic and epigenetic stability of iPSCs. IPSCs have been successfully differentiated into vascular endothelial cells (iPSC-ECs) and, more recently, induced endothelial cells (iECs) have also been generated by direct differentiation, which bypasses the pluripotent intermediate. IPSC-ECs and iECs demonstrate endothelial functionality in vitro and have been shown to promote neovessel growth and enhance blood flow recovery in animal models of myocardial infarction and peripheral arterial disease. Challenges remain in optimising the efficiency, safety and fidelity of the reprogramming and endothelial differentiation processes and establishing protocols for large-scale production of clinical-grade, patient-derived cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Novel paths towards neural cellular products for neurological disorders.

PubMed

Daadi, Marcel M

2011-11-01

The prospect of using neural cells derived from stem cells or from reprogrammed adult somatic cells provides a unique opportunity in cell therapy and drug discovery for developing novel strategies for brain repair. Cell-based therapeutic approaches for treating CNS afflictions caused by disease or injury aim to promote structural repair of the injured or diseased neural tissue, an outcome currently not achieved by drug therapy. Preclinical research in animal models of various diseases or injuries report that grafts of neural cells enhance endogenous repair, provide neurotrophic support to neurons undergoing degeneration and replace lost neural cells. In recent years, the sources of neural cells for treating neurological disorders have been rapidly expanding and in addition to offering therapeutic potential, neural cell products hold promise for disease modeling and drug discovery use. Specific neural cell types have been derived from adult or fetal brain, from human embryonic stem cells, from induced pluripotent stem cells and directly transdifferentiated from adult somatic cells, such as skin cells. It is yet to be determined if the latter approach will evolve into a paradigm shift in the fields of stem cell research and regenerative medicine. These multiple sources of neural cells cover a wide spectrum of safety that needs to be balanced with efficacy to determine the viability of the cellular product. In this article, we will review novel sources of neural cells and discuss current obstacles to developing them into viable cellular products for treating neurological disorders.

Applications of Raman micro-spectroscopy to stem cell technology: label-free molecular discrimination and monitoring cell differentiation.

PubMed

Ghita, Adrian; Pascut, Flavius C; Sottile, Virginie; Denning, Chris; Notingher, Ioan

Stem cell therapy is widely acknowledged as a key medical technology of the 21st century which may provide treatments for many currently incurable diseases. These cells have an enormous potential for cell replacement therapies to cure diseases such as Parkinson's disease, diabetes and cardiovascular disorders, as well as in tissue engineering as a reliable cell source for providing grafts to replace and repair diseased tissues. Nevertheless, the progress in this field has been difficult in part because of lack of techniques that can measure non-invasively the molecular properties of cells. Such repeated measurements can be used to evaluate the culture conditions during differentiation, cell quality and phenotype heterogeneity of stem cell progeny. Raman spectroscopy is an optical technique based on inelastic scattering of laser photons by molecular vibrations of cellular molecules and can be used to provide chemical fingerprints of cells or organelles without fixation, lysis or use of labels and other contrast enhancing chemicals. Because differentiated cells are specialized to perform specific functions, these cells produce specific biochemicals that can be detected by Raman micro-spectroscopy. This mini-review paper describes applications of Raman micro-scpectroscopy to measure moleculare properties of stem cells during differentiation in-vitro. The paper focuses on time- and spatially-resolved Raman spectral measurements that allow repeated investigation of live stem cells in-vitro.

Sickle cell disease diagnosis based on spatio-temporal cell dynamics analysis using 3D printed shearing digital holographic microscopy.

PubMed

Javidi, Bahram; Markman, Adam; Rawat, Siddharth; O'Connor, Timothy; Anand, Arun; Andemariam, Biree

2018-05-14

We present a spatio-temporal analysis of cell membrane fluctuations to distinguish healthy patients from patients with sickle cell disease. A video hologram containing either healthy red blood cells (h-RBCs) or sickle cell disease red blood cells (SCD-RBCs) was recorded using a low-cost, compact, 3D printed shearing interferometer. Reconstructions were created for each hologram frame (time steps), forming a spatio-temporal data cube. Features were extracted by computing the standard deviations and the mean of the height fluctuations over time and for every location on the cell membrane, resulting in two-dimensional standard deviation and mean maps, followed by taking the standard deviations of these maps. The optical flow algorithm was used to estimate the apparent motion fields between subsequent frames (reconstructions). The standard deviation of the magnitude of the optical flow vectors across all frames was then computed. In addition, seven morphological cell (spatial) features based on optical path length were extracted from the cells to further improve the classification accuracy. A random forest classifier was trained to perform cell identification to distinguish between SCD-RBCs and h-RBCs. To the best of our knowledge, this is the first report of machine learning assisted cell identification and diagnosis of sickle cell disease based on cell membrane fluctuations and morphology using both spatio-temporal and spatial analysis.