Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The authors have studied the case of a female patient with rheumatoid polyarthritis, who developed a lymphocytic proliferation in the blood, the marrow, and the liver, associated with a neutropenia. Several similar cases have been recently reported in the literature. The cellular proliferation is made of large granulous lymphocytes and the study of membrane markers enables to find the following homogeneous phenotype: E rosette+, CD8+, HNK-1+, FcR+, CD4-luminal diameter "divided by degrees - -, IgS-, HLA class II-. This lymphocytic sub-population produces little interleukin-2, responds weakly to mitogens (PHA, CON A, PWM), and inhibits the response of normal lymphocytes to the same mitogens. These lymphocytes have a weak natural killer activity but, on the contrary, develop a very strong cytotoxic activity which is antibody-dependent. Clinically, splenomegaly, anemia and infections are frequent and hepatomegaly or thrombopenia more rare. Adenopathies are never present. The evolution is chronic in nature and not very aggressive, although the lymphocytic proliferation is monoclonal in origin, as demonstrated in molecular biology studies. The neutropenia might be secondary to an inhibiting effect of lymphocytes on the granular precursors of the bone marrow. There is a definite association between this lympho-proliferative syndrome and rheumatoid polyarthritis, and this association appears to be different from the Felty's syndrome.
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PMID:[Characterization of chronic lymphocytic proliferation in a female patient having rheumatoid polyarthritis with neutropenia]. 361 55

We have investigated a case of lymphoproliferative disease of large granular lymphocytes (LDGL) occurring in association with celiac disease, anemia, neutropenia, and carcinomas of the endometrium, breast, and skin. The large granular lymphocyte (LGL) proliferation was monoclonal, T cell in origin, with T cell receptor beta-chain gene rearrangement, and a CD3+, CD8+, CD16+/- phenotype. In spite of the high frequency of LGL, natural killer (NK) cell activity was absent. Stimulation with interleukin-2 in vitro, however, resulted in high lymphokine-activated killer (LAK) cell activity against NK-resistant targets. The T-cell nature of the LAK precursor cells is in contrast to the majority seen in normal peripheral blood. Therapeutic trials of cyclosporin A, low-dose cyclophosphamide, and levamisole were unsuccessful in reducing transfusion requirements. This case is unique in the association of LDGL with celiac disease. It is also unique in that the patient had been followed for several years prior to the onset of the LDGL. The case extends the list of lymphoproliferative disorders documented to be associated with celiac disease and, conversely, adds to our knowledge of lymphoproliferative disorder of LGL and its "dysimmune" manifestations.
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PMID:Lymphoproliferative disease of "LAK cell" precursor large granular lymphocytes in association with celiac disease. 834 38

Analysis of the events that regulate development of red blood cells or granulocytes has led to therapies altering clinical conditions associated with anemia or neutropenia. The development of therapeutic approaches to target conditions associated with lymphopenia, such as AIDS, has been thwarted by limited techniques for studying T-lymphocyte development. We describe an in vitro system in which human bone marrow CD34+ cells proliferate, acquire the expression of the lymphoid-specific RAG-2 gene and a broad repertoire of rearranged T-cell receptor genes, develop the ability to produce T cell-specific interleukin-2 and achieve a range of T-cell immunophenotypes. The cells also become susceptible to infection with the T-lymphotropic strain of human immunodeficiency virus-1, HIV-1IIIB. This culture system induces human T lymphopoiesis and may permit further analysis of the events regulating human T-lineage differentiation. It provides a preclinical model for screening stem cell gene therapies directed toward AIDS.
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PMID:Generation of human T lymphocytes from bone marrow CD34+ cells in vitro. 856 38

Autologous transplantation can induce extended remission in some patients with advanced breast cancer and lymphoma yet nearly 80% and 50%, respectively, will ultimately relapse. In vitro studies suggest that activated natural killer cells (NK) mediate lytic activity against breast cancer and lymphoma cell lines. Therefore, immunotherapy with interleukin-2 (IL-2, Amgen) to activate NK may improve long-term disease-free survival when administered in a post-transplant minimal residual disease setting. To determine the feasibility of administering IL-2 and activation of NK post-transplant, twelve patients (6 breast cancer, 6 lymphoma) were enrolled on a phase I dose escalation study after autologous transplantation (median day + 94, range 50-166). IL-2 was self administered at 0.25 x 10(6) (n = 6) or 0.5 x 10(6) (n = 6) U/m2/day subcutaneously for 84 consecutive days. The best tolerated dose was 0.25 x 10(6) U/m2/day (75% of planned doses given vs. 48% at the higher dose). Dose limiting toxicity occurred in 6 patients (n = 2 at 0.25 x 10(6) U/m2/day, n = 4 at 0.5 x 10(6) U/m2/day) consisting of decreased performance status (n = 2), thrombocytopenia (n = 3, 1 at the lower dose), and mild neutropenia (n = 1 at the lower dose). However, all symptoms resolved within a week following discontinuation of IL-2 and no patient required hospitalization. Circulating soluble IL-2 receptor levels were significantly increased in all patients receiving IL-2. Patients receiving at least 28 days of IL-2 exhibited a greater than 10-fold increment in circulating CD56+bright/CD3- NK. Furthermore, lytic function was increased against NK resistant targets, MCF-7 (breast cancer), and Raji (lymphoma). In vivo IL-2 primed NK cells obtained by lymphapheresis were activated in large-scale ex vivo incubation in high dose IL-2 (1,000 U/mL) at high cell density (10 x 10(6)/mL), in gas permeable bags, and using serum-free media. NK lytic function against MCF-7 and Raji targets was further enhanced. We conclude that low dose subcutaneous IL-2 based immunotherapy is feasible, relatively safe, can be administered in an outpatient setting and hypothesize that additional ex vivo incubation in IL-2 may be used to generate NK cells with potent antitumor effects in vivo.
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PMID:Low dose subcutaneous interleukin-2 after autologous transplantation generates sustained in vivo natural killer cell activity. 920 39

Multilineage hematopoietic defects occur in patients with human immunodeficiency virus (HIV) infection and affect therapy of the disease and of associated opportunistic infections and neoplasms. Anemia and neutropenia are common in HIV patients, and can occur as a result of HIV-related myelosuppression or complications or may be secondary effects of antiretroviral or other agents used in management of the disease. With the advent of combination drug therapy for the treatment of HIV infection and prophylaxis and treatment of infectious complications, myelosuppression is frequently encountered and may be treated with synthetic hematopoietic growth factors. Erythropoietin has been shown to increase mean hematocrit levels and to reduce transfusion requirements in anemic HIV-infected patients receiving zidovudine. Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor have been shown to increase neutrophil counts in patients with AIDS-related bone marrow failure and those receiving zidovudine, interferon-alpha, or ganciclovir. Although recent research using interleukin-2 (IL-2) has shown that use of this cytokine in AIDS patients can lead to increases in CD4 cell counts that appear to be functional, further study is needed to determine whether cytokines can play a role other than palliation in HIV-infected patients.
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PMID:Cytokine use in the management of HIV disease. 938 9

Mice lacking interleukin-2 (IL-2) developed a severe hematopoietic disorder characterized by the abnormal development of myeloid cells and neutropenia. Analysis of the bone marrow of IL-2-deficient (IL-2(-/-)) mice showed that the number of mature polymorphonuclear cells was decreased by 65% to 75%, and granulocyte/macrophage precursor cells were reduced by 50%. Bone marrow cells from IL-2(-/-) mice were unable to sustain myelopoiesis in lethally irradiated mice and in long-term bone marrow cultures (LTBMC). The addition of exogenous IL-2 to LTBMC of IL-2(-/-) cells partially restored hematopoietic progenitor activity. In the bone marrow of wild-type mice, immature (Mac-1(lo)) myeloid cells, including myeloblasts and promyelocytes, constitutively expressed the beta-chain of the IL-2R, and the number of Mac-1(lo)IL-2Rbeta+ cells was increased by twofold to threefold in IL-2(-/-) mice. During culture in the presence of IL-2 and the absence of stromal cells, Mac-1(lo)IL-2Rbeta+ immature myeloid cells proliferated and gave rise to mature granulocytes and macrophages. Collectively, these observations indicate that defective myelopoiesis in IL-2(-/-) mice is at least in part a consequence of their direct dependency on IL-2, and by regulating the growth of immature myeloid cells, IL-2 plays an important role in the homeostatic regulation of myelocytic cell generation.
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PMID:Abnormal myelocytic cell development in interleukin-2 (IL-2)-deficient mice: evidence for the involvement of IL-2 in myelopoiesis. 953 4

Natural killer cell activity (Nka) of peripheral blood mononuclear cells (PBMCs) against K562 cell targets was assessed in 66 patients with chronic idiopathic neutropenia of adults (CINA) using the 16-h 51Cr-release assay. It was found that CINA patients exhibited significantly lower Nkr than normal subjects, which strongly correlated with the degree of neutropenia and the numbers of circulating neutrophils. Patients' NKa was increased by recombinant human interleukin-2 (rhIL-2) or recombinant human interferon-alpha (rhIFN-alpha), but the values obtained did not reach the respective NKa values found in normals. However, percentages of cytokine-induced rises of NKa did not differ statistically between patients and normal subjects. No serum inhibitors of NKa were demonstrated in our patients. CINA patients had low numbers of circulating NK cells as defined by the expression of NK-cell-related surface markers CD16, CD56, and CD57. CD16+ and CD56+, but not CD57+, cells correlated with the values of baseline NKa. The numbers of all these cell subsets correlated with the degree of neutropenia and the numbers of circulating neutrophils. Using CD56+-enriched PBL suspensions, it was shown that patients' NK cells displayed normal tumor cell binding capacity and produced in vitro normal amounts of natural killer cytotoxic factor(s) against K562 cell targets upon activation with rhIFN-alpha. Finally, percentages of perforin-expressing and granzyme B-expressing CD16+ cells did not differ statistically between patients and normal controls. Based on all these observations, we concluded that CINA patients display low NKa probably because they have low numbers of circulating NK cells. No functional abnormalities of NK cells were demonstrated. The cause and the underlying mechanisms leading to NK-cell depletion in these patients remain to be clarified.
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PMID:Defective natural killer cell activity of peripheral blood lymphocytes correlates with the degree of neutropenia in patients with chronic idiopathic neutropenia of adults. 961 29

Despite of suppression of HIV-viremia antiretroviral therapy is not able to achieve a complete reconstitution of the immune system in advanced HIV-1-infected patients. In addition, drug therapy can be limited over time by side effects and emergence of drug resistance. This has evoked growing interest in developing immune based therapies of HIV-1 infection. Current strategies for immune reconstitution are focusing on cytokines such as interleukin-2 (IL-2) and "Colony stimulating factors" (CSF). Combinations of IL-2 with antiretroviral drug combinations can induce a significant increase of CD4-counts. However, it has not been proven yet, that IL-2 can restore functional immunocompetence and that it can influence the clinical course of HIV-1-infection. Polyvalent immunoglobulins have been successfully used for the treatment of recurrent bacterial infections. Colony stimulating factors (CSF) can improve neutropenia in HIV-1-infection and there is growing evidence that CSF are useful in the treatment of bacterial infections in patients even with normal leucocyte counts. A variety of different therapeutic vaccines are currently tested in clinical trials. These vaccines could enhance HIV-1-specific immunological effector mechanisms, but so far they had no effect on HIV-1-viremia or on the course of disease. Further studies are necessary to test whether new vaccination strategies in combination with potent antiretroviral drug therapies can contribute to a better long-term control of HIV-1.
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PMID:[Immunotherapy of HIV infection]. 1018 87

Based on the likelihood of antitumor interactions between cytokines and cytotoxic drugs, we designed a pilot study to evaluate feasibility, clinical, pharmacologic, and immunologic effects of concomitantly administered subcutaneous (SQ) recombinant interleukin-2 (r-IL-2) and doxorubicin (ADR) in patients with advanced solid tumors (AST). Patients received one injection of ADR alone (70 mg/m2) and 3 weeks later a combination of r-IL-2 (18 MIU/m2 days 1-5 s.q.) and ADR at the same dose either 3-4 h after the first r-IL-2 injection (arm 1) or 2 days after the last r-IL-2 injection (arm 2). The same combination was repeated every 4 weeks according to the evolution of the disease. Pharmacokinetics were assessed over 48 h after injection of ADR alone and after the first ADR-IL-2 cycle and immunologic monitoring at days 1 and 8 of the first ADR-IL-2 cycle. Tumors were measured at baseline, after ADR alone, and after each ADR-IL-2 cycle until progression. Twenty-one adult patients with various AST including 14 soft-tissue sarcomas (STS) entered the study, 11 in arm 1 and 10 in arm 2. All patients were heavily pretreated; 16 had received an anthracycline-containing chemotherapy regimen. Eleven patients were ADR refractory and 1 ADR resistant. Grade 4 neutropenia occurred in 28, 82, and 40% of patients after ADR alone, ADR-IL-2 in arm 1 and ADR-IL-2 in arm 2, respectively. Mucitis was higher in arm 1 (7 of 11 patients) compared with arm 2 (0 of 10) and ADR alone (0 of 21). SQ injections of r-IL-2 did not affect ADR pharmacokinetics. ADR injection in arm 1 prevented IL-2-induced lymphocyte rebounds in all patients but did not alter qualitatively non-major histocompatibility complex-restricted cytotoxicity. There was no response after ADR alone. Two patients, one in each arm, experienced a prolonged (8 and 5 months) objective response after ADR-IL-2. Both had ADR-refractory STS with a local relapse and metastatic metastases. Interestingly, both patients had unusually elevated TNF-alpha levels before and after the first ADR cycle. Combination ADR-IL-2, although toxic, is feasible and manageable with routine clinical support. r-IL-2 enhanced ADR hematologic and extrahematologic toxicities. The two objective responses observed in these heavily pretreated patients refractory to ADR supports the hypothesis of a modulation of ADR resistance, possibly mediated by means of a mechanism involving TNF-alpha. Elevated baseline TNF-alpha levels could be predictive of response to ADR-IL-2 and deserves further investigation.
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PMID:Combination interleukin-2 and doxorubicin in advanced adult solid tumors: circumvention of doxorubicin resistance in soft-tissue sarcoma? 1033 87

To develop a T-cell-based therapy for carcinomas, the superantigen staphylococcal enterotoxin A (SEA) was supplied with tumor specificity by means of a recombinant fusion of the Fab fragment of the monoclonal antibody C242 recognizing human colorectal (CRC) and pancreatic carcinomas (PC). Using this Fab-SEA fusion protein (PNU-214565), potent cytotoxicity by activation of T cells can be obtained in the targeted area. Twenty-one patients with CRC and 3 with PC were treated with single, escalating doses of PNU-214565 to establish the maximum tolerated dose (MTD) and to define toxicities. The doses ranged from 0.01 ng/kg to 4.0 ng/kg with three patients at each dose level, except for the dose of 1.5 ng/kg with which six patients were treated because of dose-limiting toxicity. Adverse events (AE) were transient: 13 patients experienced mild to moderate fever. In one patient, a grade 3 fever was followed by a grade 2 hypotension. Other mild or moderate AEs were fatigue, nausea, vomiting, diarrhea, and abdominal pain. No significant hematological toxicity occurred. Immune activation was highly variable with strong activity in peripheral blood seen only in two patients at the dosage level 1.5 ng/kg. They showed pronounced elevations of interleukin-2 (IL-2), IL-6, tumor necrosis factor-alpha, and interferon-gamma, 3-5 hours after the start of infusion. In one patient, IL-2 and IL-6 increased substantially (2,925 U/mL and 32,000 U/mL) concomitantly with grade 3 fever and transient grade 2 neutropenia, grade 2 lymphopenia, and grade 2 monocytopenia. In conclusion, a single 3-hour infusion of PNU-214565 could be safely administered up to 4 ng/kg. MTD was not determined. Instead, a repeat-dose trial was initiated starting at 0.5 ng/kg, considered safe in this trial, with the objective of defining the MTD.
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PMID:Phase I study of single, escalating doses of a superantigen-antibody fusion protein (PNU-214565) in patients with advanced colorectal or pancreatic carcinoma. 1068 47


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