Publications
104 results found
Cooper N, Bussel JB, 2010, The Long-term Impact of Rituximab for Childhood Immune Thrombocytopenia, Current Rheumatology Reports, Vol: 12, Pages: 94-100, ISSN: 1523-3774
Cooper N, Arnold DM, 2010, The effect of rituximab on humoral and cell mediated immunity and infection in the treatment of autoimmune diseases, British Journal of Haematology, Vol: 149, Pages: 3-13, ISSN: 0007-1048
<jats:title>Summary</jats:title><jats:p>Depletion of B lymphocytes using the anti‐CD20 monoclonal antibody rituximab has wide‐spread use in the treatment of patients with autoimmune disorders. As haematopoietic progenitor cells and only a fraction of differentiated plasma express CD20, the effect of rituximab on immune function appears to be minimal. However, hypogammagobulinaemia can occur with repeated doses and emerging data from large studies suggest a subtle increase in the risk of infection. Reactivation of latent JC virus, resulting in progressive multifocal leucoencephalopathy, and hepatitis B virus, resulting in hepatoxicity, have been documented in patients receiving rituximab; although confounding effects of concomitant immunosuppressive therapies and immune dysregulation due to the underlying disease make causal associations of infections problematic. This review discusses the efficacy of B cell depletion therapy in the treatment of autoimmune diseases, the effect of B cell depletion on infection and immunity including the role of the B cell in autoimmunity, and identifies areas of controversy.</jats:p>
Cooper N, 2009, Intravenous Immunoglobulin and Anti-RhD Therapy in the Management of Immune Thrombocytopenia, Hematology/Oncology Clinics of North America, Vol: 23, Pages: 1317-1327, ISSN: 0889-8588
Cooper N, Cotter FE, 2009, Multipotential cord blood cells. Are they the future?, British Journal of Haematology, Vol: 147, Pages: 159-160, ISSN: 0007-1048
Himoudi N, Yan M, Bouma G, et al., 2009, Migratory and Antigen Presentation Functions of IFN-Producing Killer Dendritic Cells, Cancer Research, Vol: 69, Pages: 6598-6606, ISSN: 0008-5472
<jats:title>Abstract</jats:title> <jats:p>The CD11cint B220+ NK1.1+ CD49+ subset of cells has recently been described as IFN-producing killer dendritic cells (IKDC), which share phenotypic and functional properties with both dendritic cells and natural killer cells. We have previously shown that IKDCs within murine bone marrow–derived DC preparations are essential for the antitumor activity of unpulsed DCs. Here we show that bone marrow–derived IKDCs (BM-IKDC) migrate in vivo into tumors and thence to tumor draining lymph nodes, where they highly express MHC class II and costimulatory molecules. In vitro, freshly isolated BM-IKDCs, fluorescence-activated cell sorted to homogeneity, have no intrinsic antigen presentation function unless cocultured with tumor target cells. On killing of target cells, they can cross-present antigens to stimulate antigen-primed CD8 T cells and can also present antigens to antigen-primed CD4 cells. In vivo, in mice lacking class I–restricted antigen-presenting cell function, robust proliferation of antigen-specific T cells is achieved after adoptive transfer of BM-IKDCs at an injection site distant to the tumor site. Therefore, BM-IKDCs are capable of cytotoxic killing of tumor targets and also of potent antigen presentation after encountering antigen in the context of a viable target cell. [Cancer Res 2009;69(16):6598–606]</jats:p>
Rodeghiero F, Stasi R, Gernsheimer T, et al., 2009, Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group, Blood, Vol: 113, Pages: 2386-2393, ISSN: 0006-4971
<jats:p>Diagnosis and management of immune thrombocytopenic purpura (ITP) remain largely dependent on clinical expertise and observations more than on evidence derived from clinical trials of high scientific quality. One major obstacle to the implementation of such studies and in producing reliable meta-analyses of existing data is a lack of consensus on standardized critical definitions, outcome criteria, and terminology. Moreover, the demand for comparative clinical trials has dramatically increased since the introduction of new classes of therapeutic agents, such as thrombopoietin receptor agonists, and innovative treatment modalities, such as anti-CD 20 antibodies. To overcome the present heterogeneity, an International Working Group of recognized expert clinicians convened a 2-day structured meeting (the Vicenza Consensus Conference) to define standard terminology and definitions for primary ITP and its different phases and criteria for the grading of severity, and clinically meaningful outcomes and response. These consensus criteria and definitions could be used by investigational clinical trials or cohort studies. Adoption of these recommendations would serve to improve communication among investigators, to enhance comparability among clinical trials, to facilitate meta-analyses and development of therapeutic guidelines, and to provide a standardized framework for regulatory agencies.</jats:p>
Stasi R, Sarpatwari A, Segal JB, et al., 2009, Effects of eradication of Helicobacter pylori infection in patients with immune thrombocytopenic purpura: a systematic review, Blood, Vol: 113, Pages: 1231-1240, ISSN: 0006-4971
<jats:title>Abstract</jats:title><jats:p>Whether the eradication of Helicobacter pylori infection can increase the platelet count in patients with immune thrombocytopenic purpura (ITP) is still a controversial issue. To provide evidence-based guidance, we performed a systematic review of the literature published in English, selecting articles reporting 15 or more total patients. We identified 25 studies including 1555 patients, of whom 696 were evaluable for the effects of H pylori eradication on platelet count. The weighted mean complete response (platelet count ≥ 100 × 109/L) and overall response (platelet count ≥ 30 × 109/L and at least doubling of the basal count) were 42.7% (95% confidence interval [CI], 31.8%-53.9%) and 50.3% (95% CI, 41.6%-59.0%), respectively. In 222 patients with a baseline platelet count less than 30 × 109/L, the complete response rate was 20.1% (95% CI, 13.5%-26.7%) and the overall response rate was 35.2% (95% CI, 28.0%-42.4%). The response rate tended to be higher in countries with a high background prevalence of H pylori infection and in patients with milder degrees of thrombocytopenia. These findings suggest that the detection and eradication of H pylori infection should be considered in the work-up of patients with seemingly typical ITP.</jats:p>
Stasi R, Cooper N, Del Poeta G, et al., 2008, Analysis of regulatory T-cell changes in patients with idiopathic thrombocytopenic purpura receiving B cell–depleting therapy with rituximab, Blood, Vol: 112, Pages: 1147-1150, ISSN: 0006-4971
<jats:title>Abstract</jats:title><jats:p>The effects of B-cell depletion with rituximab on regulatory T cells (Tregs) have not been determined. We investigated Tregs in patients receiving rituximab for chronic idiopathic thrombocytopenic purpura (ITP). The peripheral blood Tregs, identified as CD4+FOXP3+ T cells, were measured by flow cytometry prior to and after the immunotherapy. In addition, Tregs were analyzed for their usage of the T-cell receptor (TCR) β-variable (VB) region gene as well as their regulatory function as assessed by cell proliferation assays. Pretreatment data revealed a reduced number and a defective suppressive capacity of Tregs in ITP patients compared with control individuals. In addition, Tregs showed a polyclonal spectratype. Patients, particularly responders, showed restored numbers of Tregs as well as a restored regulatory function upon treatment with rituximab. These results indicate that patients with active ITP have a defective T regulatory cell compartment that can be modulated by a B cell–targeted therapy.</jats:p>
Gratwohl A, 2008, Allogeneic hematopoietic stem cell transplantation for severe autoimmune diseases, Autoimmunity, Vol: 41, Pages: 673-678, ISSN: 0891-6934
Stasi R, Del Poeta G, Stipa E, et al., 2007, Response to B-cell–depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura, Blood, Vol: 110, Pages: 2924-2930, ISSN: 0006-4971
<jats:title>Abstract</jats:title><jats:p>Rituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as idiopathic thrombocytopenic purpura (ITP). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of different peripheral blood T-cell subsets, the apoptosis profile, as well as the changes of T-cell receptor (TCR) β-variable (VB) region gene usage of CD4+ and CD8+ T-cell subpopulations following rituximab therapy. The study involved 30 patients with chronic ITP who received rituximab, of whom 14 achieved a durable (> 6 months) response. Compared with the control group, pretreatment abnormalities of T cells in ITP patients included an increase of the Th1/Th2 ratio and of the Tc1/Tc2 ratios (P < .001), increased expression of Fas ligand on Th1 and Th2 cells (P < .001), increased expression of Bcl-2 mRNA (P = .003) and decreased expression of bax mRNA (P = .025) in Th cells, and expansion of oligoclonal T cells with no preferential use of any TCR VB subfamily. These abnormalities were reverted in responders at 3 and 6 months after treatment, whereas they remained unchanged in nonresponders. Our findings indicate that in patients with ITP, response to B-cell depletion induced by rituximab is associated with significant changes of the T-cell compartment.</jats:p>
Cooper N, Bussel J, 2006, The pathogenesis of immune thrombocytopaenic purpura, British Journal of Haematology, Vol: 133, Pages: 364-374, ISSN: 0007-1048
<jats:title>Summary</jats:title><jats:p>Immune thrombocytopaenic purpura (ITP) is an autoimmune bleeding disease that is rarely fatal. However, in many adults treatment is unsatisfactory, with as much morbidity from the immunosuppressive effects of treatment as from bleeding. Identifying the underlying disease process should help us to identify more targeted therapies and improve not only the treatment but also the quality of life of patients with this disorder.</jats:p>
Cooper N, Rao K, Gilmour K, et al., 2006, Stem cell transplantation with reduced-intensity conditioning for hemophagocytic lymphohistiocytosis, Blood, Vol: 107, Pages: 1233-1236, ISSN: 0006-4971
<jats:title>Abstract</jats:title><jats:p>Allogeneic stem cell transplantation (SCT) is curative for hemophagocytic lymphohistiocytosis (HLH). However, patients frequently have significant morbidity before transplantation and there is high transplant-related mortality (TRM). Because first-degree HLH is caused by immune dysregulation, a reduced-intensity conditioned (RIC) regimen might be sufficient for cure while decreasing the TRM. Twelve patients with HLH underwent RIC SCT from a matched family/unrelated or haploidentical donor. Eleven were conditioned with fludarabine/melphalan with additional busulphan for haploidentical grafts. One received fludarabine and 2-Gy total body irradiation (TBI). All patients showed engraftment at a median of 14 days. Nine of 12 (75%) are alive and in complete remission (CR) a median of 30 months (range, 9-73 months) after SCT. Two patients died from pneumonitis and one from hepatic rupture. Four patients developed acute graft-versus-host disease (GVHD) and 3 have chronic GVHD. Three of 9 survivors have mixed chimerism but remain free of disease. In summary, RIC compares favorably to conventional SCT with long-term disease control in surviving patients despite a significant incidence of mixed chimerism.</jats:p>
Cooper N, Stasi R, CunninghamRundles S, et al., 2004, The efficacy and safety of B‐cell depletion with anti‐CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura, British Journal of Haematology, Vol: 125, Pages: 232-239, ISSN: 0007-1048
<jats:title>Summary</jats:title><jats:p>Because of its B‐cell depleting effect, rituximab has entered clinical trials in several autoimmune conditions. This study assesses the efficacy and safety of rituximab in 57 adults with chronic immune thrombocytopenic purpura (ITP). All patients had platelet counts <30 × 10<jats:sup>9</jats:sup>/l, all had received two or more previous ITP treatments and 31 had undergone splenectomy. Patients received rituximab 375 mg/m<jats:sup>2</jats:sup> weekly for 4 weeks. Thirty‐one patients (54%) responded, achieving a platelet count >50 × 10<jats:sup>9</jats:sup>/l: 18 achieved a complete response (CR: platelet count >150 × 10<jats:sup>9</jats:sup>/l) and 13 a partial response (PR: platelet count 50–150 × 10<jats:sup>9</jats:sup>/l). Twenty‐nine responses occurred within 8 weeks of the first infusion. Sixteen of 18 CR patients (28% overall), including eight who had failed splenectomy, continued in CR after a median of 72·5 weeks; 15 of 16 are >1 year from the first infusion. Only two of 13 maintained a PR. Thirty‐three patients experienced grade 1–2 adverse events and one a grade 3 event, but they all completed treatment. Circulating B cells fell to <0·03 × 10<jats:sup>9</jats:sup>/l. No changes in immunoglobulin levels or infectious complications were seen. In summary, rituximab was well tolerated with no immediate complications and induced a lasting, substantial response in 32% of adults with chronic ITP.</jats:p>
Michel M, Cooper N, Jean C, et al., 2004, Does Helicobater pylori initiate or perpetuate immune thrombocytopenic purpura?, Blood, Vol: 103, Pages: 890-896, ISSN: 0006-4971
<jats:title>Abstract</jats:title> <jats:p>To determine the prevalence of Helicobacter pylori (H pylori) infection in North American patients with immune thrombocytopenic purpura (ITP) and the effect of H pylori eradication on the platelet count, a prospective study was performed. Seventy-four patients aged 10 years and older (mean age of 41 years) with chronic ITP and a platelet count below 60 × 109/L were enrolled. H pylori infection was found in 22% of patients by means of a breath test and could not be predicted by gastrointestinal symptoms. H pylori–positive patients (52.5 years of age) were older than H pylori–negative patients (38.5 years of age; P = .0035). Fifteen of the 16 H pylori–positive patients were treated and the bacteria was eradicated in 14 (93%). After 3 months, a significant response (platelet count &gt; 50 × 109/L and doubling the initial count) was observed in only one patient. After a median follow-up of 11.5 months, none of the 14 patients had responded. Ten H pylori–negative patients treated with the same regimen also did not increase their platelet counts. In conclusion, unlike several previous reports, this study does not implicate H pylori in the pathogenesis of ITP since the prevalence of H pylori infection was low and eradication of H pylori did not positively influence the course of the ITP.</jats:p>
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