Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia.
TL;DR: Results indicate that a minor population of PNH-type cells represents a reliable marker of a positive IST response and a favorable prognosis among patients with AA, and immune attack against hematopoietic stem cells that allows PNH clonal expansion might occur only at the onset of AA.
About: This article is published in Blood.The article was published on 2006-02-15 and is currently open access. It has received 266 citations till now. The article focuses on the topics: Aplastic anemia & Bone marrow failure.
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TL;DR: The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways.
748 citations
TL;DR: Information is provided on how to identify and treat the signs and symptoms of central nervous system disease in children and young people with learning difficulties.
Abstract: King’s College Hospital, St Mary’s Hospital, Barts and The London Hospital, London, Birmingham Children’s Hospital, Birmingham, Barts and The London School of Medicine and Dentistry, St George’s Hospital, London, Queen Elizabeth Hospital, King’s Lynn, Norfolk, Ashford Hospital, Middlesex, London, Patient representative, St Helier Hospital, Carshalton, Surrey, Royal Bournemouth Hospital, Dorset, Chesterfield Royal Hospital, Derbyshire, and Manchester Royal Infirmary, Manchester, UK.
488 citations
TL;DR: The authors thank Sally B. Killick, Nick Bown, Jamie Cavenagh, Inderjeet Dokal, Theodora Foukaneli, Peter Hillmen, Robin Ireland, Austin Kulasekararaj, Ghulam Mufti, John A Snowden, Sujith Samarasinghe and Anna Wood for their help.
Abstract: Sally B. Killick (Writing Group Chair), Nick Bown, Jamie Cavenagh, Inderjeet Dokal, Theodora Foukaneli, Peter Hillmen, Robin Ireland, Austin Kulasekararaj, Ghulam Mufti, John A Snowden, Sujith Samarasinghe, Anna Wood (BCSH Task Force Member), Judith C.W. Marsh on behalf of the British Society for Standards in Haematology. The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, Northern Genetics Service, Newcastle upon Tyne, St Bartholomew’s Hospital, Barts Health NHS Trust, London, Barts and The London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, Addenbrooks Hospital, University of Cambridge, Cambridge, Leeds Teaching Hospitals, Leeds, Kings College Hospital NHS Foundation Trust, London, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield Great Ormond Street Hospital for Children NHS Foundation Trust, London, West Hertfordshire NHS Trust, Watford.
464 citations
Cites background from "Minor population of CD55-CD59- bloo..."
...Analysis of GPI-anchored proteins is a sensitive and quantitative test for PNH, enabling the detection of small PNH clones which occur in up to 50% of AA patients, the proportion depending on the sensitivity of the flow cytometric analysis used (Dunn et al, 1999; Sugimori et al, 2006)....
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TL;DR: Key aspects of differential diagnosis, considerations in the choice of first- and second-line therapies, and the management of patients after immunosuppression are reviewed based on both a critical review of the recent literature and large personal and research protocol experience of bone marrow failure in the Hematology Branch of the National Heart, Lung, and Blood Institute.
361 citations
TL;DR: This update emphasizes developments in the understanding of immune mechanisms and hematopoietic stem cell biology and new clinical approaches to stem cell stimulation as a therapy, alone and in combination with conventional suppression of the aberrant immune system.
Abstract: Historically viewed in isolation as an odd, rare, and invariably fatal blood disease, aplastic anemia is now of substantial interest for its immune pathophysiology, its relationship to constitutional BM failure syndromes and leukemia, and the success of both stem cell transplantation and immunosuppressive therapies in dramatically improving survival of patients. Once relegated to a few presentations in the red cell and anemia sessions of the ASH, the Society now sponsors multiple simultaneous sessions and plenary and scientific committee presentations on these topics. This update emphasizes developments in our understanding of immune mechanisms and hematopoietic stem cell biology and new clinical approaches to stem cell stimulation as a therapy, alone and in combination with conventional suppression of the aberrant immune system.
347 citations
Additional excerpts
...Mexico City106 2000-2005 23 25 (4-65) 26 17 26 88 at 4 y...
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...Seattle104,105 1988-2004 94 26 (2-59) 4 24 26 88 at 6 y...
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...86; MMUD: 51 Various 16 (1-55) 48 for MUD 29 for MUD 39 at 5 y for MUD...
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References
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Book•
01 Jan 1984
TL;DR: In this article, the authors present a survey of the advantages of using logit models in regression models for Ordinal Probabilities, Scores, and Odds Ratios, as well as their drawbacks.
Abstract: Preface. 1. Introduction. 1.1. Ordinal Categorical Scales. 1.2. Advantages of Using Ordinal Methods. 1.3. Ordinal Modeling Versus Ordinary Regession Analysis. 1.4. Organization of This Book. 2. Ordinal Probabilities, Scores, and Odds Ratios. 2.1. Probabilities and Scores for an Ordered Categorical Scale. 2.2. Ordinal Odds Ratios for Contingency Tables. 2.3. Confidence Intervals for Ordinal Association Measures. 2.4. Conditional Association in Three-Way Tables. 2.5. Category Choice for Ordinal Variables. Chapter Notes. Exercises. 3. Logistic Regression Models Using Cumulative Logits. 3.1. Types of Logits for An Ordinal Response. 3.2. Cumulative Logit Models. 3.3. Proportional Odds Models: Properties and Interpretations. 3.4. Fitting and Inference for Cumulative Logit Models. 3.5. Checking Cumulative Logit Models. 3.6. Cumulative Logit Models Without Proportional Odds. 3.7. Connections with Nonparametric Rank Methods. Chapter Notes. Exercises. 4. Other Ordinal Logistic Regression Models. 4.1. Adjacent-Categories Logit Models. 4.2. Continuation-Ratio Logit Models. 4.3. Stereotype Model: Multiplicative Paired-Category Logits. Chapter Notes. Exercises. 5. Other Ordinal Multinomial Response Models. 5.1. Cumulative Link Models. 5.2. Cumulative Probit Models. 5.3. Cumulative Log-Log Links: Proportional Hazards Modeling. 5.4. Modeling Location and Dispersion Effects. 5.5. Ordinal ROC Curve Estimation. 5.6. Mean Response Models. Chapter Notes. Exercises. 6. Modeling Ordinal Association Structure. 6.1. Ordinary Loglinear Modeling. 6.2. Loglinear Model of Linear-by-Linear Association. 6.3. Row or Column Effects Association Models. 6.4. Association Models for Multiway Tables. 6.5. Multiplicative Association and Correlation Models. 6.6. Modeling Global Odds Ratios and Other Associations. Chapter Notes. Exercises. 7. Non-Model-Based Analysis of Ordinal Association. 7.1. Concordance and Discordance Measures of Association. 7.2. Correlation Measures for Contingency Tables. 7.3. Non-Model-Based Inference for Ordinal Association Measures. 7.4. Comparing Singly Ordered Multinomials. 7.5. Order-Restricted Inference with Inequality Constraints. 7.6. Small-Sample Ordinal Tests of Independence. 7.7. Other Rank-Based Statistical Methods for Ordered Categories. Appendix: Standard Errors for Ordinal Measures. Chapter Notes. Exercises. 8. Matched-Pairs Data with Ordered Categories. 8.1. Comparing Marginal Distributions for Matched Pairs. 8.2. Models Comparing Matched Marginal Distributions. 8.3. Models for The Joint Distribution in A Square Table. 8.4. Comparing Marginal Distributions for Matched Sets. 8.5. Analyzing Rater Agreement on an Ordinal Scale. 8.6. Modeling Ordinal Paired Preferences. Chapter Notes. Exercises. 9. Clustered Ordinal Responses: Marginal Models. 9.1. Marginal Ordinal Modeling with Explanatory Variables. 9.2. Marginal Ordinal Modeling: GEE Methods. 9.3. Transitional Ordinal Modeling, Given the Past. Chapter Notes. Exercises. 10. Clustered Ordinal Responses: Random Effects Models. 10.1. Ordinal Generalized Linear Mixed Models. 10.2. Examples of Ordinal Random Intercept Models. 10.3. Models with Multiple Random Effects. 10.4. Multilevel (Hierarchical) Ordinal Models. 10.5. Comparing Random Effects Models and Marginal Models. Chapter Notes. Exercises. 11. Bayesian Inference for Ordinal Response Data. 11.1. Bayesian Approach to Statistical Inference. 11.2. Estimating Multinomial Parameters. 11.3. Bayesian Ordinal Regression Modeling. 11.4. Bayesian Ordinal Association Modeling. 11.5. Bayesian Ordinal Multivariate Regression Modeling. 11.6. Bayesian Versus Frequentist Approaches to Analyzing Ordinal Data. Chapter Notes. Exercises. Appendix Software for Analyzing Ordinal Categorical Data. Bibliography. Example Index. Subject Index.
1,678 citations
TL;DR: Analysis of activation of naive proteolipid protein (PLP)139–151-specific T cells in SJL mice undergoing PLP178–191-induced R-EAE or TMEV-IDD suggests that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.
Abstract: Chronic progression of two T cell–mediated central nervous system (CNS) demyelinating models of multiple sclerosis, relapsing EAE (R-EAE) and Theiler's murine encephalomyelitis virus–induced demyelinating disease (TMEV-IDD) is dependent on the activation of T cells to endogenous myelin epitopes (epitope spreading). Using transfer of carboxyfluorescein succinyl ester (CFSE)-labeled T-cell receptor (TCR)-transgenic T cells and mixed bone marrow chimeras, we show that activation of naive proteolipid protein (PLP)139–151-specific T cells in SJL mice undergoing PLP178–191-induced R-EAE or TMEV-IDD occurs directly in the CNS and not in the cervical lymph nodes or other peripheral lymphoid organs. Examination of the antigen-presentation capacity of antigen-presenting cell (APC) populations purified from the CNS of mice with PLP178–191-induced R-EAE shows that only F4/80−CD11c+CD45hi dendritic cells (DCs) efficiently present endogenous antigen to activate naive PLP139–151-specific T cells in vitro. In contrast, DCs as well as F4/80+CD45hi macrophages and F4/80+CD45lo microglia activate a PLP139–151-specific helper T cell line. The data suggest that naive T cells enter the inflamed CNS and are activated by local APCs, possibly DCs, to initiate epitope spreading.
652 citations
Additional excerpts
...Median hemoglobin level, g/L (range) 67 ( 32-140 ) 67 (40-108) .92 Mean corpuscular volume, fL (range) 101.5 (84.2-123.5) 98.5 (77.2-118.0) .13 Median platelet count, 109/L (range) 14.0 (2.0-60.0) 16.0 (1.0-87.0) .65...
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...No. of patients 83 39 NA Median age, y (range) 57 ( 13-83 ) 54 (12-83) .16 Sex, M/F 36/47 19/20 .58 Severity, severe/moderate 53/30 22/17 .43 Chromosome abnormality, no. of patients 7 3 .88 7 01 8 21 Y 30...
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...No. of patients 83 39 NA Median age, y (range) 57 (13-83) 54 ( 12-83 ) .16 Sex, M/F 36/47 19/20 .58 Severity, severe/moderate 53/30 22/17 .43 Chromosome abnormality, no. of patients 7 3 .88 7 01 8 21 Y 30...
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TL;DR: Compared to nontransplant regimens, early marrow transplantation more effectively restores normal marrow function and decreases the acute mortality of severe marrow aplasia.
531 citations
TL;DR: In conclusion, immunosuppressive treatment of aplastic anemia with antilymphocyte globulin, methylprednisolone, and cyclosporine appears to be more effective than a regimen of antiliesmphocytes globulin and methylpredisonsolone without cyclosporaine and may represent a treatment of choice for patients who are not eligible for bone marrow transplantation.
Abstract: Background and Methods. Immunosuppression is the most effective treatment for patients with aplastic anemia, except for bone marrow transplantation. The best results are achieved with antilymphocyte globulin or cyclosporine. Patients have been treated successfully with a combination of both agents, but there has been no controlled evaluation of its efficacy. We conducted a randomized, multicenter trial in 84 patients not eligible for bone marrow transplantation, comparing treatment with antilymphocyte globulin and methylprednisolone (41 patients — control group) with antilymphocyte globulin, methylprednisolone, and cyclosporine (43 patients — the cyclosporine group). Results. At three months significantly more patients in the cyclosporine group had a complete or partial remission in response to treatment than did patients in the control group (65 percent vs. 39 percent, P<0.03); this difference was confirmed at six months (70 percent vs. 46 percent, P<0.05). The superior results of the regimen in...
384 citations
TL;DR: Using flow cytometric analysis of granulocytes, it is identified cells that have the PNH phenotype, and PNH red blood cells also were identified, showing clearly that PIG-A gene mutations are not sufficient for the development of PNH.
Abstract: In paroxysmal nocturnal hemoglobinuria (PNH), acquired somatic mutations in the PIG-A gene give rise to clonal populations of red blood cells unable to express proteins linked to the membrane by a glycosylphosphatidylinositol anchor. These proteins include the complement inhibitors CD55 and CD59, and this explains the hypersensitivity to complement of red cells in PNH patients, manifested by intravascular hemolysis. The factors that determine to what extent mutant clones expand have not yet been pinpointed; it has been suggested that existing PNH clones may have a conditional growth advantage depending on some factor (e.g., autoimmune) present in the marrow environment of PNH patients. Using flow cytometric analysis of granulocytes, we now have identified cells that have the PNH phenotype, at an average frequency of 22 per million (range 10–51 per million) in nine normal individuals. These rare cells were collected by flow sorting, and exons 2 and 6 of the PIG-A gene were amplified by nested PCR. We found PIG-A mutations in six cases: four missense, one frameshift, and one nonsense mutation. PNH red blood cells also were identified at a frequency of eight per million. Thus, small clones with PIG-A mutations exist commonly in normal individuals, showing clearly that PIG-A gene mutations are not sufficient for the development of PNH. Because PIG-A encodes an enzyme essential for the expression of a host of surface proteins, the PIG-A gene provides a highly sensitive system for the study of somatic mutations in hematopoietic cells.
371 citations