Long‐term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group

Immunosuppressive therapy has been employed as the initial treatment for acquired chronic pure red cell aplasia (PRCA), such as idiopathic, thymoma‐associated, or large granular lymphocyte (LGL) leukaemia‐associated PRCA, which is thought to be immune‐mediated. To explore the overall long‐term outcome following immunosuppression and to identify the risk factors for death in these disorders, we conducted nationwide surveys in Japan 2004 and 2006, and identified a total of 185 patients with acquired chronic PRCA, including 72 idiopathic, 41 thymoma‐associated and 14 LGL leukaemia‐associated cases of PRCA for whom data was available. The present study evaluated 127 patients with these three subsets of PRCA. The median overall survival has not yet been reached in idiopathic PRCA. The estimated median overall survival times in patients with thymoma‐associated and LGL leukaemia‐associated PRCA were 142·1 and 147·8 months, respectively. Twenty‐two deaths were reported, and the response to induction therapy and relapse of anaemia were found to be associated with death. The major causes of death were infection in seven patients and organ failure in another seven patients. The results suggest that maintenance therapy and the management of infectious complications are crucial for improving the prognosis of chronic PRCA.     

Pure red cell aplasia with thymoma: Evidence of T-cell clonal disorder

Pure red cell aplasia (PRCA) sometimes accompanies thymoma. Herein, we report a PRCA patient with thymoma with a clonal disorder of T cells. A 55-year-old man presented with anemia and anterior mediastinum tumor. The laboratory study revealed hemoglobin 8.2 g/dl; leukocytes 15.8 × 10⁹/L with 76.5% neutrophils, 20.0% lymphocytes, and reticulocytes 0.0%. Bone marrow aspirate smears and biopsy sections revealed normal myeloid and megakaryocyte differentiation and contained no erythroid precursors. We made the diagnosis of PRCA. The size of the lymphocytes was small without any granules in the cytoplasm. The surface marker of peripheral blood mononuclear cells demonstrated increased CD2⁺, CD3⁺, CD4⁻, and CD8⁺ populations. The mediastinal tumor was resected and a thymoma diagnosed. A monoclonal rearrangement of T-cell receptor (TCR)- β-chain gene was found using Southern blot analysis of the mononuclear cells in both peripheral blood and thymoma. Treatment with prednisolone, thymectomy, and cyclophosphamide exerted no beneficial effect. After initiation of the Cyclosporin A therapy, the patient developed reticulocytosis. This PRCA case seems to present a neoplastic proliferation of CD8⁺ T cells in peripheral blood and thymus with a monoclonal rearrangement of the TCR- β-chain gene. Am. J. Hematol. 54:324–328, 1997. © 1997 Wiley-Liss, Inc.     

Distribution and functional plasticity of peripheral blood Th(c)17 and Th(c)1 in rheumatoid arthritis

With the discovery of Th17 cells, it became unclear whether rheumatoid arthritis (RA) is a Th1-mediated and/or a Th17-mediated disease. Objective: The aim of this study was to identify and characterize the pro-inflammatory function of IL-17-producing T cell subsets (Th(c)17) in RA. Flow cytometry analysis was performed on peripheral blood from RA patients with inactive or low disease activity (LDA, n = 19) and moderate to high disease activity (HDA, n = 13) to analyze the number and functional activity of Th(c)17 and Th(c)1 cell subsets according to the frequency of IL-2-, TNF-α- and IFN-γ-producers cells, as well as, their cytokine amount. Additionally, 13 age-matched healthy volunteers were added to the study. Our data point to a slight increase in Tc17 frequency in RA patients, more evident in HDA, and a higher ability of Th17 to produce IL-17, whereas a lower production of TNF-α was noted either in Th17 or Tc17 cells, particularly from HDA. A similar decrease was observed in Th(c)1 for almost all studied pro-inflammatory cytokines, with the exception of IL-2, which was increased in Tc1 from LDA patients. Analysing the proportion of pro-inflammatory cytokines-producing cells, a polarization to a Tc1 phenotype seemed to occur in CD8 T cells, while CD4 T cells appear to be decreased in their frequency of IFN-γ-producing cells. Taken together, the functional plasticity features of Th17 and Tc17 cells suggest a particular contribution to the local cytokine production, pointing an underestimated role, namely of Tc1 and Tc17 cells, in the RA pathophysiology.     

康艾注射液对代偿期肝硬化患者Th1/Th2及相关细胞因子的影响

目的研究康艾注射液对代偿期肝硬化患者Th1/Th2细胞及相关细胞因子的影响。方法采用流式细胞仪检测康艾注射液治疗代偿期肝硬化患者治疗前、后血清Th1、Th2细胞的变化,用ELISA法检测两组患者治疗前、后血清IFN-γ、IL-10的变化。结果两组治疗前后血清Th1、Th2细胞均明显高于健康对照组(P<0.01),Th1/Th2比值均明显低于健康对照组(P<0.01)。治疗后两组Th1、Th2细胞均较治疗前明显下降(P<0.01),Th1/Th2比值均较治疗前明显上升(P<0.01),治疗组Th1/Th2比值明显高于对照组(P<0.01)。两组患者IL-10治疗后明显下降(P<0.01),治疗组低于对照组(P<0.05);两组患者IFN-γ治疗后明显上升(P<0.01),治疗组高于对照组(P<0.01)。结论康艾注射液可以促使代偿期肝硬化患者Th1/Th2平衡向Th1优势漂移,从而促进炎症吸收,促进病情尽早康复。     

Treatment of pure red cell aplasia with ciclosporin: suppression of activated T suppressor/cytotoxic and NK-like cells in marrow and blood correlates with haematological response

In pure red cell aplasia (PRCA), suppression of erythropoiesis is most probably effected by cellular and/or antibody-mediated immune mechanisms. We have prospectively investigated the patterns of activated T-lymphocyte subsets and natural killer (NK)-like cells in the bone marrow (BM) and peripheral blood (PB) of 6 PRCA patients prior to and during treatment with the T-cell selective immunosuppressive drug Ciclosporin (CS; Cyclosporin-A). Before CS therapy, large proportions of circulating activated HLA-DR+ T-suppressor/cytotoxic cells (28%, 11-41; median and range), DR+ T-helper cells (7%, 4-13) and cytoplasmic interferon-gamma+ (IFN-gamma) lymphocytes (20%, 9-33) were found in PRCA, but were barely detectable in healthy controls. Similarly, high levels of activated T cells were present in patient marrows. Initiation of CS therapy resulted in rapidly decreasing levels of activated T cells and NK cells both in PB and in BM. During follow-up of individual patients, an inverse relationship was observed between the haematological response to CS and the levels of activated T-suppressor/cytotoxic cells, IFN-gamma+ lymphocytes (in PB and BM) and NK-like cells (in BM). The present correlations indicate a pathogenetic role of phenotypically activated T-suppressor/cytotoxic cells and possibly NK-like cells in PRCA. During successful treatment with CS, these cell types are reduced in numbers but reappear in relapse. Our results also pinpoint the clinical value of monitoring activated T-cell subsets for the prediction of immunological remission in PRCA and related disorders.     

High Th1/Th2 ratio in patients with chronic idiopathic thrombocytopenic purpura

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by increased platelet clearance because of antiplatelet antibodies. It was recently reported that the balance of T helper 1 (Th1) and T helper 2 (Th2) subsets has been implicated in the regulation of many immune responses. In this study, the intracellular interleukin-4 and interferon-gamma production in CD4+ T-lymphocytes activated by phorbol 12-myristate 13-acetate and ionomycin was assessed via flow cytometry in order to determine the clinical significance of the Th1/Th2 ratio in 42 patients with ITP. The study cohort included 28 untreated patients, seven postprednisolone therapy patients and seven postsplenectomy patients. The mean level of the Th1/Th2 ratio in the untreated group was 36.9 (95% CI 25.8-47.9), and significantly higher than in the control group (mean 12.8, 95% CI 9.5-16.1). The mean levels of the Th1/Th2 ratio in the postprednisolone therapy and postsplenectomy groups were 20.5 (95% CI 8.4-32.6) and 16.4 (95% CI 3.1-29.7), respectively, but were no significant differences as compared with control subjects. When untreated patients were divided into two subgroups by Th1/Th2 ratio, the mean level of platelet associated IgG in the high Th1/Th2 subgroup (higher than upper limit of control group) tended to be higher than in the normal Th1/Th2 subgroup. In conclusion, the high Th1/Th2 ratio was closely related to the etiology and disease status of chronic ITP.     

Spectrum of pure red cell aplasia in adult population of north-west India

Abstract

Pure red cell aplasia (PRCA) is a rare haematological disorder characterised by selective inhibition of red cell precursors in the bone marrow. We conducted a retrospective analysis of nine cases of PRCA seen in our adult haematology clinic from January 2000 to December 2003. All patients had baseline hemogram, bone marrow examination, CT scan of chest, autoimmune and infectious disease markers. The diagnosis of PRCA was made on bone marrow examination showing normal granulocytic and megakaryocytic series with erythroblastopenia. The age range was 14–68 years (median: 40 years) and a male to female ratio of 3 : 1. In five patients, the aetiology of PRCA could not be identified with available investigations and were labelled as primary PRCA. The secondary causes of PRCA included three cases of thymoma and one case of non-Hodgkin lymphoma. Out of nine patients, three patients had died and two lost to follow-up. At the last available follow-up till December 2006, three patients (one secondary and two primary PRCA) are maintaining normal haemoglobin and one patient still has active disease. The retrospective review shows that causes and outcome of PRCA in the developing world are different to those seen in the West.     

The balance of Th1/Th2 cytokines in rheumatoid arthritis

It has been suggested that rheumatoid inflammation is mediated by activated pro-inflammatory T helper type I cells. In contrast, immunomodulatory T helper type 2 cells and their cytokines, in particular interleukin-4, are rarely found. This chapter reviews the concept of the Th1/Th2 dichotomy and summarizes the functions of the signature cytokines of the T helper subsets. We discuss current knowledge of the immunopathogenesis of rheumatoid arthritis and its related animal model, collagen induced arthritis, with regard to the Th1/Th2 paradigm. The accumulating evidence for a T helper type 1 driven inflammation and the implications for future therapy are delineated.     

Th1 and Th2 T-helper cells exert opposite regulatory effects on procoagulant activity and tissue factor production by human monocytes

The role of T-cell subsets in the induction of tissue factor (TF) production by human monocytes in vitro was investigated. Mitogen stimulation enabled both unfractionated T cells and their CD4+ or CD8+ subsets to promote procoagulant activity (PCA). After mitogen or antigen activation, all seven T-cell clones with Th1 cytokine profile, but none of seven Th2 clones, induced TF production and PCA. T-cell blasts from four Th1 activated clones were fixed with paraformaldehyde and added to monocytes in the presence of medium alone or their supernatants. Addition of either fixed Th1 cells or their supernatants induced low TF production (0.2 to 0.6 ng/mL), whereas addition of both resulted in much higher TF synthesis (1.8 to 3.4 ng/mL). Among Th1-type cytokines, only interferon-gamma (IFN-gamma) induced minimal TF production (0.1 to 0.4 ng/mL). No TF synthesis was induced by activated and fixed Th2 cells and/or their supernatants, whereas combined addition of fixed Th2 cells and Th1 supernatants or IFN-gamma induced noticeable TF production. The addition of either anti-IFN-gamma antibody or Th2 supernatants to monocytes stimulated with activated and fixed Th1 cells plus their supernatant resulted in a dose-dependent inhibition of TF synthesis, which was partially restored by neutralization of interleukin-4 (IL-4) or IL-10. Addition of recombinant IL-4, IL-13, or IL-10, but not IL-5, inhibited the Th1- induced TF production by monocytes. Data indicate that both CD8+ and CD4+ Th1, but not Th2, T cells can help TF production and PCA. Both cell-to-cell contact with activated T cells and Th1-type cytokines, in particular IFN-gamma, are required for optimal TF synthesis, whereas Th2-derived cytokines (IL-4, IL-13, and IL-10) are inhibitory. This may be of potential interest for future therapeutic strategies.     

人工肝支持系统对慢性重型乙型肝炎Th1/Th2、Tc1/Tc2亚群的影响

目的 研究人工肝支持系统治疗慢性重型乙型肝炎对机体Th1/Th2、Tc1/Tc2亚群的影响.方法 采用流式细胞仪检测人工肝支持系统治疗慢性重型乙型肝炎前、后患者Th1/Th2、Tc1/Tc2亚群的变化.结果 患者Th1/Th2、Tc1/Tc2亚群明显高于对照组,经治疗后有所下降,但仍高于对照组.结论 慢性重型乙型肝炎患...     

Th1/Th2平衡关系与IgA肾病临床、病理表现的相关性分析

目的探讨辅助性T（Th）1/Th2细胞平衡与IgA肾病（IgAN）临床、肾脏病理表现的相关性。方法采用流式细胞术检测40例IgAN患者与20例健康人对照组外周血Th1、Th2值;收集IgAN患者慢性扁桃体炎史和反复发作性肉眼血尿史,血清胆固醇（Tch）、三酰甘油（TG）、IgG、IgA、内生肌酐清除率（Ccr）,24 h尿蛋白及肾脏病理表现;并了解IgAN患者以上情况与Th1/Th2比例的相关性。结果 IgAN患者外周血中Th2细胞比例为（1.77±0.90）%,较健康对照组的（1.18±0.15）%升高（P〈0.01）。慢性扁桃体炎对Th1/Th2比例无明显影响;有反复发作性肉眼血尿的IgAN患者Th1细胞比例（8.50±4.68）%及Th1/Th2值（4.10±2.01）均较无反复发作性肉眼血尿IgAN患者高（P〈0.05）,24 h尿蛋白定量大于1.0 g/d IgAN患者的Th1细胞比例（2.55±1.20）%及Th1/Th2值（1.58±0.43）均较小于1.0 g/d的患者（P〈0.01）;多元线性回归分析显示IgAN患者外周血Th1/Th2比值与血清中IgG/IgA值存在着正相关关系。结论 IgAN患者存在Th2细胞型免疫表达增强,可能与IgA肾病的免疫机制有关;反复发作性肉眼血尿及24 h尿蛋白小于1.0 g/d的IgAN患者外周血的Th细胞亚群呈Th1偏移;IgAN患者的血清中IgG/IgA值对外周血中Th1/Th2比值存在着正相关影响。     

Spectrum of pure red cell aplasia in adult population of north-west India

Pure red cell aplasia (PRCA) is a rare haematological disorder characterised by selective inhibition of red cell precursors in the bone marrow. We conducted a retrospective analysis of nine cases of PRCA seen in our adult haematology clinic from January 2000 to December 2003. All patients had baseline hemogram, bone marrow examination, CT scan of chest, autoimmune and infectious disease markers. The diagnosis of PRCA was made on bone marrow examination showing normal granulocytic and megakaryocytic series with erythroblastopenia. The age range was 14-68 years (median: 40 years) and a male to female ratio of 3 : 1. In five patients, the aetiology of PRCA could not be identified with available investigations and were labelled as primary PRCA. The secondary causes of PRCA included three cases of thymoma and one case of non-Hodgkin lymphoma. Out of nine patients, three patients had died and two lost to follow-up. At the last available follow-up till December 2006, three patients (one secondary and two primary PRCA) are maintaining normal haemoglobin and one patient still has active disease. The retrospective review shows that causes and outcome of PRCA in the developing world are different to those seen in the West.     

Deferasirox treatment improved hematopoiesis and led to complete remission in a patient with pure red cell aplasia

A 64-year-old woman developed pure red cell aplasia (PRCA) 4 years after thymectomy for thymoma. During anti-thymocyte globulin treatment, the patient developed cytomegalovirus pneumonia and was thus unable to continue immunosuppressive therapy and became transfusion dependent. Deferasirox was started for treatment with iron overload when serum ferritin increased to >1000 ng/mL. Seven months after initiation of deferasirox treatment, serum ferritin level decreased the normal range and the patient has remained transfusion independent thereafter. Deferasirox was discontinued when serum ferritin level decreased below 500 ng/mL, and she has maintained in complete remission over the last 15 months. Hypotheses have been raised regarding the improvement of hematopoiesis by deferasirox treatment, but the mechanism whereby this might be achieved remains unclear. Deferasirox treatment may be clinically beneficial both by reducing iron overload and by improving hematopoiesis in patients with PRCA.     

All-trans-retinoic acid shifts Th1 towards Th2 cell differentiation by targeting NFAT1 signalling to ameliorate immune-mediated aplastic anaemia

Severe acquired aplastic anaemia (AA) is a serious disease characterised by autoreactive T cells attacking haematopoietic stem cells, leading to marrow hypoplasia and pancytopenia. Immunosuppressive therapy combined with antithymocyte globulin and ciclosporin can rescue most patients with AA. However, the relapse after ciclosporin withdrawal and the severe side effects of long-term ciclosporin administration remain unresolved. As such, new strategies should be developed to supplement current therapeutics and treat AA. In this study, the possibility of all-trans-retinoic acid (ATRA) as an alternative AA treatment was tested by using an immune-mediated mouse model of AA. Results revealed that ATRA inhibited T-cell proliferation, activation and effector function. It also restrained the Fas/Fasl pathway, shifted Th1 towards Th2 cell development, rebalanced T-cell subsets at a relatively high level and corrected the Th1/Th2 ratio by targeting NFAT1 signalling. In addition, ATRA inhibited Th17 cell differentiation and promoted regulatory T-cell development. Therefore, ATRA was an effective agent to improve AA treatment outcomes.     

Th1/Th2 balance alteration in the clinical course of a patient with acute viral myocarditis.

Cytokines have an important role in the pathogenesis and pathophysiology of myocarditis. In this study, subsets of peripheral helper T lymphocytes (Th) in a patient with acute viral myocarditis were analyzed by 3-color flow cytometry. During the clinical course of myocarditis, the Th1/Th2 ratio of peripheral lymphocytes changed. Th1 was dominant in the acute inflammatory phase during which levels of creatine kinase (CK) increased (day 6), then Th2 levels overtook those of Th1 in the recovery phase during which levels of CK decreased (day 13 and 20). At the time of discharge (day 35), Th1 and Th2 had normalized. Thus, it was speculated that the induction of lymphocytic myocarditis was associated with Th1 dominant status, and recovery was related to Th2 polarity. Th subset imbalances may play an important role in the pathogenesis of acute viral myocarditis and these analyses may be useful for understanding the disease activity of myocarditis.     

Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis

OBJECTIVE: To elucidate the involvement of the regulatory CD4+ T cells that produce high levels of interleukin-10 (IL-10) and low levels of IL-4 and IL-2 in the pathogenesis of rheumatoid arthritis (RA), we investigated whether the frequency of this type of CD4+ T cell subset in peripheral blood lymphocytes (PBL) or synovial lymphocyte infiltrates of patients with RA correlated with disease severity and histologic features in rheumatoid synovium. METHODS: PBL and synovial lymphocyte infiltrates were isolated from peripheral blood samples and synovial tissues obtained from 25 patients with RA. Control specimens were obtained from 18 patients with osteoarthritis (OA) and 10 patients with traumatic injuries of the knee joint. CD4+ T cell subsets were categorized as Th1 (production of interferon-gamma [IFNgamma], but not IL-4), Th2 (production of IL-4, but not IFNgamma), or CD4+ T cell subsets producing IL-10, IL-2, or IL-4. The percentages of these T helper subsets among PBL and among synovial infiltrating lymphocytes were determined by an intracellular staining assay with flow cytometric analysis. RESULTS: The level of expression of CD4+ T cells producing IL-10 but not IL-2 and IL-4 in the peripheral blood and synovial tissue was significantly lower in RA patients than in OA patients and trauma patients. In RA patients, the frequency of this type of CD4+ T cell subset among synovial infiltrating CD4+ T cells was inversely correlated with the frequency of Th1 cells and the Th1/Th2 balance in synovial lymphocytes, serum C-reactive protein value, disease activity score, and the degree of synovial lining hyperplasia and lymphocyte infiltration in rheumatoid synovium. There was a reciprocal relationship between the frequency of Thl cells and CD4+ T cells producing IL-10 but not IL-2 and IL-4 in the peripheral blood of RA patients. CONCLUSION: In RA, reduced expression of the CD4+ T cell subset producing IL-10 but not IL-2 and IL-4 may be responsible for the dominance of Th1 over Th2 cells at sites of inflamed synovium and in the peripheral blood. Decreases in this type of CD4+ T cell subset may induce the down-regulation of T cell tolerance and exacerbate the inflammatory process in RA.     

L’érythroblastopénie : diagnostic,classification, traitement

Pure red cell aplasia (PRCA) is a rare anemia characterised by profound reticulocytopenia caused by a marked reduction in bone marrow erythroblasts, without abnormalities in other blood lineages. Blackfan-Diamond anemia is an inherited ribosomopathy responsible for a hereditary form of PRCA. Acquired PRCA are separated in primary and secondary forms, including Parvovirus B19 infection, thymoma, lymphoproliferative disorders, autoimmune diseases (lupus) and drug-induced PRCA. The pathophysiology of PRCA is not fully understood and involves both humoral and T lymphocyte autoreactive cells. In Parvovirus B19-related PRCA, treatment is based on polyvalent immunoglobulins. Thymectomy for thymoma is mandatory but results in prolonged remission in a limited number of cases. The therapeutic strategy is based on expert opinion: corticosteroids in monotherapy provide few sustained responses. The choice of an additional immunosuppressant drug is guided by the presence of an underlying disease. In most cases, cyclosporine A is the first choice providing the best response rate but requires a concentration monitoring (150 to 250 ng/mL). The second choice is cyclophosphamide in large granular lymphocyte leukaemia. Sirolimus (mTOR inhibitor) seems to be a promising option especially in refractory cases. Transfusion independence is the main objective. If the patient receives numerous red blood cell transfusions (> 20 packs), iron overload assessment is crucial to initiate an iron chelation. A retrospective and prospective national cohort (EPIC-F) has been set up and is now available to include each case of PRCA to improve the knowledge of this disease and to optimize the therapeutic strategy.     

T1/ST2 is preferentially expressed on murine Th2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for Th2 effector function

T helper (Th) cells can be categorized according to their cytokine expression. The differential induction of Th cells expressing Th1 and/or Th2 cytokines is key to the regulation of both protective and pathological immune responses. Cytokines are expressed transiently and there is a lack of stably expressed surface molecules, significant for functionally different types of Th cells. Such molecules are of utmost importance for the analysis and selective functional modulation of Th subsets and will provide new therapeutic strategies for the treatment of allergic or autoimmune diseases. To this end, we have identified potential target genes preferentially expressed in Th2 cells, expressing interleukin (IL)-4, IL-5, and/or IL-10, but not interferon-γ. One such gene, T1/ST2, is expressed stably on both Th2 clones and Th2-polarized cells activated in vivo or in vitro. T1/ST2 expression is independent of induction by IL-4, IL-5, or IL-10. T1/ST2 plays a critical role in Th2 effector function. Administration of either a mAb against T1/ST2 or recombinant T1/ST2 fusion protein attenuates eosinophilic inflammation of the airways and suppresses IL-4 and IL-5 production in vivo following adoptive transfer of Th2 cells.     

Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17

Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD.