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

R24 is a mouse IgG3 monoclonal antibody that reacts with the ganglioside GD3 expressed by melanoma cells and other cells of neuroectodermal origin (e.g. adrenal medulla). Antitumour activity of R24 was demonstrated in initial phase I and pilot trials, but treatment was limited by urticaria at cumulative doses of 400 mg/m2. A trial exploring intensification of the dose of R24 was conducted in eight patients. Planned doses of R24 antibody were 800 and 1200 mg/m2 over 6-8 days by continuous i.v. infusion. All patients received concomitant therapy with hydroxyzine hydrochloride and cimetidine to minimize urticaria. One patient developed anaphylaxis, after which no further therapy was given. All patients developed peripheral blood lymphopenia and marked decreases in serum complement values during treatment, suggesting depletion of two possible effector mechanisms of the antitumour effects of R24. A vascular leak syndrome, manifested by weight gain, oedema and hypotension, was evident in seven patients during the initial 24-36 h of treatment. Serum sickness syndrome was observed in six of seven evaluable patients between days 5 and 8, coincident with the onset of the human anti-globulin response to R24. One patient given 1200 mg/m2 had a minor response (38% reduction in pelvic nodes) lasting 12 months. There was no detectable increase (by immunohistochemical staining) in deposition of R24 within tumour sites at doses used in this trial compared to that observed at doses of 240 and 400 mg/m2. The maximum tolerated dose was 800 mg/m2. Dose-limiting toxicity was manifest as reversible hypertension with end-organ symptoms (chest pain or visual field defects) in patients treated with a dose of 1200 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Treatment with high dose mouse monoclonal (anti-GD3) antibody R24 in patients with metastatic melanoma. 129 83

The incidence of B cell leukaemia in 186 consecutive untreated patients with histologically defined B cell neoplasms is described. The lymphomas were classified by the Kiel convention. B cell leukaemia in the context of this paper refers to the situation where a neoplastic clone of B cells in the blood greatly outnumbers normal blood B cells. It is defined as an absolute blood B cell count greater than 0.75 X 10(9)1(-1) where either greater than 90% B cells express kappa immunoglobulin light chains or greater than 80% express lambda light chains. This was found in several patients where the total blood lymphocyte count was within normal limits. All patients with diffuse lymphocytic lymphoma with the histological appearances of B cell chronic lymphocytic leukaemia (ML-BCLL) were found to have B cell leukaemia. However, more than half these patients had blood B cell counts less than 10 X 10(9)1(-1). B cell leukaemia was also a feature in approximately 33% of patients with follicle centre cell tumours and 33% of those with lymphoplasmacytoid tumours. B cell leukaemia was not detected in 34/35 patients with myelomatosis. The 35th patient had plasma cell leukaemia. Only 3/22 patients with high grade lymphoma had B cell leukaemia. In the three principal tumour types associated with B cell leukaemia mu + delta was the most common immunoglobulin heavy chain phenotype. Spontaneous mouse red cell rosette formation also characterised leukaemic B cells in these three groups but high proportions of mouse rosetting cells were seen only in association with ML-BCLL. None of 4 cases of prolymphocytic leukaemia showed mouse red cell rosetting. HLA-DR alpha chain was found on the leukaemic cells of all patients except one with ML-BCLL. B cell lymphopenia was a frequent finding in all histological groups in those patients who did not have B cell leukaemia.
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PMID:The incidence of B cell leukaemia and lymphopenia in B cell neoplasia in adults: a study using the Kiel classification of non-Hodgkin's lymphoma. 660 60

Cryptococcus neoformans is an encapsulated fungus that is a major cause of meningitis in patients with AIDS. In immunocompetent mice, administration of IgG1 mAb protects against cryptococcal infection, whereas administration of IgG3 is not protective and can accelerate the infection. In beige mice with impaired natural killer cell function, the effects of IgG1 and IgG3 are similar to those observed in immunocompetent mice, suggesting that natural killer cells are not crucial for antibody-mediated modulation of cryptococcal infection. In mice lacking CD4+ T cells, IgG1 is not protective and IgG3 accelerates infection, indicating that CD4+ T cells are required for antibody-mediated protection. In mice lacking CD8+ T cells, both IgG1 and IgG3 antibodies prolong survival, indicating that acceleration of the disease process by IgG3 involves CD8+ T cells. Both IgG1-mediated protection and IgG3-mediated acceleration of infection require interferon gamma. These results reveal a functional dependence of passively administered antibody on cellular immunity in cryptococcal infection in mice and have implications for antibody-based therapies in humans in the setting of CD4+ lymphopenia.
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PMID:T cells cooperate with passive antibody to modify Cryptococcus neoformans infection in mice. 912 21

Fludarabine is a highly effective chemotherapeutic agent for chronic lymphocytic leukemia/small lymphocytic lymphoma and is also active in other B-cell lymphoproliferative disorders. Although highly efficacious in destroying the malignant B-cells, fludarabine also causes T-cell lymphopenia and immunosuppression. We present five patients given fludarabine for low-grade B-cell lymphoproliferative disorders who showed transformation of the primary neoplasm to a higher grade tumor. Immunohistologic antibody studies were performed on paraffin-embedded tissue sections of the initial tissue (when available) and on the follow-up biopsy specimens for CD20, CD3, CD45RO, CD43, CD30, CD15, and latent membrane protein (LMP-1) for Epstein-Barr virus (EBV). The initial diagnoses in these five patients included chronic lymphocytic leukemia/small lymphocytic lymphoma (three cases), follicle center lymphoma (one case), and Waldenstrom's macroglobulinemia (one case). All of the follow-up biopsy specimens showed scattered Hodgkin's-like cells, and two of the five also showed foci of large-cell transformation. The Hodgkin's-like cells showed CD30 immunoreactivity in four of the five cases and CD15 immunoreactivity in three of the five. Strong immunoreactivity of the large, atypical, Hodgkin's-like cells for LMP-1 of EBV was noted in four cases; in the remaining case, this finding was equivocal. In situ hybridization for EBV-encoded RNA was positive in four of the five cases. Molecular studies by polymerase chain reaction (PCR) showed the presence of EBV in three of the five cases. PCR for detection of immunoglobulin heavy chain demonstrated identical monoclonal rearrangements in the original lymphoma and transformation in one case with available material. The CD4 lymphocyte count in each patient was less than 550/microL, indicating cellular dysfunction. Transformation of low-grade non-Hodgkin's lymphomas after fludarabine therapy might be associated with EBV and severe immunosuppression.
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PMID:Detection of Epstein-Barr virus in transformations of low-grade B-cell lymphomas after fludarabine treatment. 938 67

In vivo administration of anti-CD3 Ab induces both immune tolerance and undesirable side-effects resulting from nonspecific proinflammatory cytokine production. In the current study, we investigated the therapeutic potential of two structurally altered forms of the anti-CD3 Ab in ameliorating established experimental autoimmune encephalomyelitis. Administration of either a chimeric (NM-IgG3) or digestion product (NM-F(ab')2) form of the anti-CD3 Ab during established experimental autoimmune encephalomyelitis conferred significant protection from clinical disease progression and was associated with decreased Ag-specific T cell proliferation, cytokine production, and CNS inflammation. Interestingly, while this protection correlated with an increase in the frequency of CD4(+)CD25(+) regulatory T cells, neither prior depletion of regulatory T cells nor anti-TGF-beta treatment abrogated the treatment's efficacy. Importantly, both treatments induced normal levels of intracellular Ca(2+)-flux, but significantly diminished levels of TCR signaling. Consequent to this decreased level of TCR-mediated signaling were alterations in the level of apoptosis and CD4+ T cell trafficking resulting in a profound lymphopenia. Collectively, these results indicate that nonmitogenic anti-CD3 directly induces a state of immune unresponsiveness in primed pathogenic autoreactive effector cells via mechanisms that may involve the induction of T cell tolerance, apoptosis, and/or alterations in cell trafficking.
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PMID:Treatment with nonmitogenic anti-CD3 monoclonal antibody induces CD4+ T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis. 1581 73

Influenza virus can cause an acute respiratory illness of variable intensity. In our study, we describe the clinical and immunological characteristics of pregnant and nonpregnant women who were hospitalized with 2009 H1N1 influenza and pneumonia in Shenyang, China, from November 2009 to January 2010. Forty-two female patient infected with H1N1 were divided into groups according to pregnancy. Clinical data were collected. Cytokines and anti-H1N1 IgG subclasses were detected. We observed significant lymphopenia, hypoproteinemia, reduced CD4(+)T cell counts and CD4(+)/CD8(+) ratios, reduced anti-H1N1 IgG subclasses IgG2 and IgG3 constituent ratios, elevated C reactive protein and interleukin-10 levels with regard to nonpregnant H1N1 group. Compared with the healthy pregnant group, the pregnant H1N1 group showed elevated aspartate aminotransferase and glutamic alanine aminotransferase levels, an increased interferon-gamma and interleukin-10 levels and reduced anti-H1N1 IgG subclasses IgG2, IgG3 and IgG4 combination ratios. There was a statistically significant association between imbalanced anti-H1N1 immunoglobulin subclasses and dysregulated cytokines in pregnant women with H1N1 infection.
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PMID:Imbalanced anti-H1N1 immunoglobulin subclasses and dysregulated cytokines in hospitalized pregnant women with 2009 H1N1 influenza and pneumonia in Shenyang, China. 2275 May 37

Activated PI3K-delta syndrome (APDS) is an immunodeficiency caused by gain-of-function mutations in PIK3CD. This disease exhibits complex immune phenotypes including increased IgM, recurrent infection, and impaired vaccine responses. To better understand the impact of B cells in this disease, we generated an inducible model of the common APDS mutation (hPIK3CD-E1021K; referred to as aPIK3CD) and intercrossed these mice with B cell-specific Cre models. Mb1-aPIK3CD mice exhibited bone marrow B lymphopenia and, conversely, expansion of the peripheral innate B1a and MZ B cell compartments. aPIK3CD B cells manifest increased pS6 and increased survival at several stages, without alterations in cycling, and baseline increases in plasma cells, natural IgM, and IgG3. Finally, Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses, and both AID- and CD21-aPIK3CD mice displayed reduced class-switched antibodies following T cell-dependent immunization. Thus, aPIK3CD alters B cell development and function and is counter-productive during immune responses, providing insight into B cell-intrinsic contributions to the APDS phenotype.
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PMID:Activated PIK3CD drives innate B cell expansion yet limits B cell-intrinsic immune responses. 3019 67

SARS-CoV-2 infection causes an abrupt response by the host immune system, which is largely responsible for the outcome of COVID-19. We investigated whether the specific immune responses in the peripheral blood of 276 patients associated to severity and progression of COVID-19. At admission, dramatic lymphopenia of T, B and NK cells associated to severity. Conversely, the proportion of B cells, plasmablasts, circulating follicular helper T cells (cTfh) and CD56-CD16+ NK-cells increased. Regarding humoral immunity, levels of IgM, IgA and IgG were unaffected, but when degrees of severity were considered, IgG was lower in severe patients. Compared to healthy donors, complement C3 and C4 protein levels were higher in mild and moderate, but not in severe patients, while the activation peptide of C5 (C5a) increased from the admission in every patient, regardless their severity. Moreover, total IgG, the IgG1 and IgG3 isotypes and C4 decreased from day 0 to day 10 in patients who were hospitalized for more than two weeks, but not in patients who were discharged earlier. Our study provides important clues to understand the immune response observed in COVID-19 patients, associating severity with an imbalanced humoral response and identifying new targets for therapeutic intervention. This article is protected by copyright. All rights reserved.
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PMID:Deregulated cellular circuits driving immunoglobulins and complement consumption associate with the severity of COVID-19 patients. 3325 5