Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Visilizumab is a humanized anti-CD3 monoclonal antibody characterized by a mutated IgG2 isotype, lack of binding to Fcgamma-receptors, and ability to induce apoptosis selectively in activated T cells. To test pharmacokinetics, safety, and immunosuppressive activity of visilizumab, 17 patients with glucocorticoid-refractory acute graft-versus-host disease (GVHD) were enrolled in a phase 1 study. Six patients were given 7 doses of visilizumab (0.25 or 1.0 mg/m(2)) on days 1, 3, 5, 7, 9, 11, and 13. Because multiple doses of 1 mg/m(2) caused delayed visilizumab accumulation and prolonged lymphopenia, the next 11 patients received a single dose of 3.0 mg/m(2) on day 1. GVHD improved in all patients; 15 were evaluable through day 42. Multiple dosing resulted in 1 of 6 complete responses (CRs) and 5 partial responses (PRs), but all 6 patients died at a median of 87 days after starting visilizumab therapy. Single dosing resulted in 6 of 9 CRs, 3 PRs, and 7 of 11 patients surviving after 260 to 490 days (median, 359 days; P =.03). There were no allergic reactions and 3 grade 1 acute infusional toxicities. Plasma Epstein-Barr virus (EBV) DNA titers more than 1000 copies/mL and posttransplant lymphoproliferative disease (PTLD) developed in 2 of the first 7 patients. Based on rising EBV DNA titers, 5 of the next 10 patients were given the B cell-specific monoclonal antibody, rituximab. EBV DNA became undetectable and no overt PTLD developed. Visilizumab is well tolerated and has activity in advanced GVHD. A phase 2 study incorporating preemptive therapy for PTLD is warranted to determine the efficacy of visilizumab in GVHD.
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PMID:A humanized non-FcR-binding anti-CD3 antibody, visilizumab, for treatment of steroid-refractory acute graft-versus-host disease. 1192 57

Immune reconstitution was studied prospectively in 66 children who underwent 77 haematopoietic cell transplantations (HCT): 46 autologous HCTs in 39 patients and 31 allogeneic HCTs in 27 patients. We studied the dynamic analysis of immune recovery with regard to potential factors affecting its speed, including age, type of HCT, diagnosis, graft-versus-host disease (GvHD) and cytomegalovirus (CMV) infection reactivation. Absolute counts of different lymphocyte subsets and immunoglobulin serum levels were determined in peripheral blood of patients on d -7 and +16, and then at various intervals up to 24 months post transplant. Common patterns of immune recovery after both allogeneic and autologous HCT were identified: (i) CD4+CD45RO+ peripheral T-cell expansion on d +16; (ii) inverted CD4+:CD8+ ratio from d +30 onwards; (iii) rapid natural killer (NK) cell (CD16+/-CD56+) count normalization. We observed prolonged T-cell lymphopenia (CD3+, CD3+CD4+, CD4+CD45RA+) until 24 months after autologous HCT, whereas in the allogeneic setting CD3+CD4+ cells, including naive CD45RA+ cells, returned to normal values at 9 months post transplant. Age > 10 years and coexistence of GvHD and CMV reactivation were associated with a substantial delay in T- (CD4+, including CD45RA+) and B-cell recovery after allogeneic HCT. Multidrug GvHD prophylaxis resulted in impaired T- (CD4+, CD4+CD45RA+) and B-cell reconstitution only in the early phase after allogeneic HCT (up to 4 months). Our results demonstrated that T-cell recovery was severely impaired in children after autologous HCT. It should be emphasized that specific approaches to enhance immune reconstitution are necessary to control minimal residual disease and avoid the risk of infectious complications in the autologous setting. Thymic involution after allogeneic HCT seems to be associated with age and coexistence of GvHD and CMV reactivation.
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PMID:Immune reconstitution after haematopoietic cell transplantation in children: immunophenotype analysis with regard to factors affecting the speed of recovery. 1210 Jan 30

The extravasation of leukocytes at sites of inflammation critically depends on initial shear-resistant adhesive interactions between leukocytes in blood flow and target tissue endothelium. Dermal lymphocytic infiltrates are a hallmark feature of acute cutaneous graft-versus-host disease (acGVHD) following allogeneic hematopoietic stem cell (allo-HSC) transplantation. These infiltrates occur commonly during periods of profound lymphopenia, suggesting that the dermal endothelial adhesive mechanism(s) promoting lymphocyte emigration in acGVHD are highly efficient. To examine this issue, we performed Stamper-Woodruff assays on frozen sections of biopsy specimens of cutaneous lesions occurring within 100 days of HSC transplantation in 22 autologous hematopoietic stem cell transplant (auto-HSCT) and 25 allo-HSCT recipients. By using this shear-based assay, we observed lymphocyte adherence to papillary dermal vascular structures in all punch biopsy specimens of allo-HSCT recipients who had clinicohistologic evidence of acGVHD and who were not receiving steroids, whereas no lymphocyte adherence was observed within skin specimens from allo-HSCT recipients who did not develop acGVHD. Within the group of auto-HSCT recipients, 2 of 22 skin biopsies demonstrated lymphocyte binding to dermal vessels. Among allo-HSCT patients receiving steroid therapy for acGVHD, lymphocyte binding to dermal endothelium was abrogated prior to resolution of rash in those who responded, yet binding was persistent in skin from one patient whose rash did not respond to steroid therapy. Collectively, these data indicate that the papillary endothelium of skin in acGVHD displays heightened capacity to support lymphocyte adhesion under shear stress conditions and suggest that down-modulation of this endothelial adhesive capability may be one mechanism by which steroids abrogate acGVHD reactions.
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PMID:In vitro adherence of lymphocytes to dermal endothelium under shear stress: implications in pathobiology and steroid therapy of acute cutaneous GVHD. 1239 84

The incidence of postengraftment invasive aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients increased during the 1990s. We determined risks for IA and outcomes among 1682 patients who received HSCTs between January 1993 and December 1998. Risk factors included host variables (age, underlying disease), transplant variables (stem cell source), and late complications (acute and chronic graft-versus-host disease [GVHD], receipt of corticosteroids, secondary neutropenia, cytomegalovirus [CMV] disease, and respiratory virus infection). We identified risk factors associated with IA early after transplantation (<or= 40 days) and after engraftment (41-180 days). Older patient age was associated with an increased risk during both periods. Chronic myelogenous leukemia (CML) in chronic phase was associated with low risk for early IA compared with other hematologic malignancies, aplastic anemia, and myelodysplastic syndrome. Multiple myeloma was associated with an increased risk for postengraftment IA. Use of human leukocyte antigen (HLA)-matched related (MR) peripheral blood stem cells conferred protection against early IA compared with use of MR bone marrow, but use of cord blood increased the risk of IA early after transplantation. Factors that increased risks for IA after engraftment included receipt of T cell-depleted or CD34-selected stem cell products, receipt of corticosteroids, neutropenia, lymphopenia, GVHD, CMV disease, and respiratory virus infections. Very late IA (> 6 months after transplantation) was associated with chronic GVHD and CMV disease. These results emphasize the postengraftment timing of IA; risk factor analyses verify previously recognized risk factors (GVHD, receipt of corticosteroids, and neutropenia) and uncover the roles of lymphopenia and viral infections in increasing the incidence of postengraftment IA in the 1990s.
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PMID:Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. 1239 25

Ganciclovir effectively prevents cytomegalovirus (CMV) disease in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT), but late-onset CMV disease is increasingly observed. We designed a prospective cohort study to define the incidence and risk factors for late CMV infection in patients who undergo HSCT. CMV-seropositive patients were studied prospectively for CMV infection (quantitative pp65 antigenemia, quantitative CMV-DNA, blood culture), T-cell immunity (CMV-specific CD4(+) T-helper and CD8(+) cytotoxic T-lymphocyte responses, CD4 and CD8 T-cell count, absolute lymphocyte count), and other transplantation-related factors. Univariate and multivariable analyses were used to assess the risk for late CMV infection and disease and to assess overall survival. Late CMV disease developed in 26 of 146 (17.8%) patients a median of 169 days after transplantation (range, 96-784 days); the mortality rate was 46%. Thirty-eight percent of patients surviving late disease had a second episode a median of 79 days after the first episode. At 3 months after transplantation, preceding detection of CMV pp65 antigenemia, CD4 T-cell counts lower than 50 cells/mm(3), postengraftment absolute lymphopenia levels lower than 100 lymphocytes/mm(3), undetectable CMV-specific T-cell responses, and graft-versus-host disease (GVHD) were associated with late CMV disease or death. After 3 months, continued detection of pp65 antigenemia or CMV DNA in plasma or peripheral blood leukocytes and lymphopenia (fewer than 300 lymphocytes/mm(3)) were strong predictors of late CMV disease and death. In conclusion, CMV viral load, lymphopenia, and CMV-specific T-cell immunodeficiency are predictors of late CMV disease and death after allogeneic stem cell transplantation. Prevention strategies should be targeted at patients in whom CMV reactivated during the first 3 months and those with poor CMV-specific immunity or low CD4 counts.
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PMID:Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. 1239 59

Fusarium species frequently implicated in human infections include F. solani, F. oxysporum and F. moniliforme. Among immunocompetent patients, tissue breakdown (as caused by trauma, severe burns or foreign body) is the risk factor for fusariosis. Infections include keratitis, onychomycosis and occasionally peritonitis and cellulitis. Treatment is usually successful and requires removal of the foreign body as well as antifungal therapy. Among immunocompromised patients, mainly patients with haematological malignancies, Fusarium spp. are the second most common pathogenic mould. Risk factors for disseminated fusariosis include severe immunosuppression (neutropenia, lymphopenia, graft-versus-host disease, corticosteroids), colonisation, tissue damage, and receipt of a graft from an HLA-mismatched or unrelated donor. Clinical presentation includes refractory fever (> 90%), skin lesions and sino-pulmonary infections ( approximately 75%). Type of skin lesions includes ecthyma-like, target, and multiple subcutaneous nodules. Skin lesions lead to diagnosis in > 50% of patients and precede fungemia by approximately 5 days. In contrast to disseminated aspergillosis, disseminated fusariosis can be diagnosed by blood cultures in 40% of patients. Histopathology reveals hyaline acute-branching septate hyphae similar to those found in aspergillosis. Mortality from fusarial infections in immunocompromised patients ranges from 50% to 80%. Host immune status is the single most important factor predicting outcome. Persistent neutropenia and corticosteroid therapy significantly affect survival. Optimal treatment has not been established. Anecdotal successes have been reported with various agents (high-dose amphotericin B, lipid-based amphotericin B formulations, itraconazole, voriconazole) and with cytokine-stimulated granulocyte transfusions. Preventing fusariosis relies on detection and treatment of cutaneous damage prior to commencing immunosuppression and decreasing environmental exposure to Fusaria (via air and water).
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PMID:Human fusariosis. 1474 3

Patients with sickle cell disease (N = 3) and thalassemia (N = 1) with high-risk features received hematopoietic stem cell transplantations (HCT) to induce stable (full or partial) donor engraftment. Patients were 9-30 years of age. Fludarabine, rabbit anti-thymocyte globulin (ATG), and 200 cGy total body irradiation were administered pre-transplant. Patients received bone marrow (N = 3) or peripheral blood stem cells (N = 1) from HLA-identical siblings, followed by mycophenolate mofetil and cyclosporine for post-grafting immunosuppression. Significant lymphopenia, but only moderate neutropenia and thrombocytopenia developed post transplant. No grade IV nonhematological toxicities or acute graft-versus-host disease (GVHD) were observed. At 3 months after transplantation, three of four patients had evidence of donor myeloid chimerism (range, 15-100%). However, after post transplant immunosuppression was discontinued, graft rejection occurred in all but one patient. This patient is now doing well 27 months post transplant with full donor engraftment. One patient died after a second transplant, and another patient experienced a stroke as her graft was being rejected. These results suggest that stable donor engraftment after nonmyeloablative HCT is difficult to achieve among immunocompetent patients with hemoglobinopathies and that new approaches will need to be developed before wider application of this transplantation method for hemoglobinopathies.
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PMID:Hematopoietic stem cell transplantation for multiply transfused patients with sickle cell disease and thalassemia after low-dose total body irradiation, fludarabine, and rabbit anti-thymocyte globulin. 1553 1

Pentostatin (deoxycoformycin), is one of a number of purine analogues. The drug was originally designed to mimic a form of severe combined immune deficiency, characterised by marked T lymphopenia but variable B cell function. Clinically, the drug has been used primarily to treat a rare type of leukaemia - hairy cell leukaemia. Recently, the drug has seen increasing attention as an immunosuppressant. This review will cover the basic pharmacology and immunological effects of pentostatin. The clinical use of this agent in prevention and treatment of graft-versus-host disease will be examined. Although many of these studies are ongoing, this agent has promise as a novel immunosuppressive agent with a new mechanism of action.
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PMID:Pentostatin - pharmacology, immunology, and clinical effects in graft-versus-host disease. 1557 77

Bone marrow transplantation (BMT) benefits nonmalignant diseases but is limited by regimen-related toxicity, graft-versus-host disease (GVHD), donor availability, and graft rejection (GR). To overcome some of these barriers, we developed a new conditioning strategy for these patients. In total, 16 patients received Campath-1H (33/48 mg; days -21 to -19), fludarabine (150 mg/m(2); days -8 to -4), melphalan (140/70 mg/m(2); day -3), and transplant using related/unrelated stem cells. GVHD prophylaxis included cyclosporine/methylprednisolone for cord cells. Other recipients also received methotrexate. Risk factors for GR included multiple transfusions (6), low stem cell numbers (1), and immunologic/metabolic disorders (3). Donor engraftment was present in 14/16 recipients. Neutrophils (ANC>0.5 x 10(9)/l) and platelets (>50 x 10(9)/l) engrafted at a median of 13 and 24 days. Two patients died of Pseudomonas sepsis prior to engraftment, one of CMV disease, and another of intracranial hemorrhage. With median follow-up of 281 days (78-907), 12/16 are stable/improved, or cured. Acute GVHD was absent (n=10) or mild and transient (grade1-2 skin) (n=4). There was no chronic GVHD. Toxicities were predominantly early infections within 100 days, and correlated with lymphopenia (CD4+ T and B cells). Stable engraftment and low incidence of significant GVHD, irrespective of age or stem cell source, make this reduced-intensity regimen attractive for nonmalignant disorders.
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PMID:A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders. 1559 91

Thymus-dependent T-cell regeneration is a major pathway for immune reconstitution after stem cell transplantation in children. Therefore, we prospectively assessed T-cell dynamics and thymic function in 164 pediatric patients between 1 and 124 months after transplantation by measuring T-cell receptor recombination excision circles and spontaneous expression of Ki67 in peripheral T-cell subsets. We analyzed the effect of recipient age, conditioning regimen, type of donor and graft, stem cell dose, and graft-versus-host disease on the onset and the plateau of thymic output. A high rate of spontaneous proliferation in early-reconstituting naive and memory T cells inversely correlated with total T-cell numbers. Accordingly, T-cell receptor recombination excision circle content was diminished in early-appearing naive T cells. A multivariate analysis revealed that the onset of thymic recovery was inversely correlated only with recipient age ( P < .0002), whereas the plateau of thymic output was higher in patients receiving increased stem cell numbers ( P < .0022). Donor type, stem cell source, and conditioning regimen influenced none of the analyzed parameters. In conclusion, lymphopenia-driven proliferation is important for T-cell homeostasis in children early after stem cell transplantation, but it might result in underestimation of thymic function. Onset and plateau of thymic activity are independently regulated by different transplant-related factors.
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PMID:Onset of thymic recovery and plateau of thymic output are differentially regulated after stem cell transplantation in children. 1574 38


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