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Biomedical subjects

Elling Ulvestad

Publications and source records attributed to Elling Ulvestad.

15 recordsLinked to original sources
PubMed2006

T cells remaining after intensive chemotherapy for acute myelogenous leukemia show a broad cytokine release profile including high levels of interferon-gamma that can be further increased by a novel protein kinase C agonist PEP005.

Cytokines are released during T cell activation, including the potentially anti-leukemic interferon-gamma (IFNgamma), but also the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) that enhance proliferation and inhibit apoptosis of acute myelogenous leukemia (AML) cells. In the present study we investigated the release of IFNgamma and GM-CSF by circulating T cells in AML patients with chemotherapy-induced cytopenia. T cells were activated with anti-CD3 plus anti-CD28 in a whole-blood assay in the presence of their natural cytokine network. We examined 63 samples derived from 16 AML patients during 28 chemotherapy cycles. Activated T cells showed a broad cytokine release profile, but IFNgamma and GM-CSF levels showed a significant correlation and were generally higher than the other cytokine levels. Higher IFNgamma and GM-CSF responses were associated with a low CD4:CD8 ratio, older patient age and no ongoing chemotherapy indicating potential utility of T cell activation regimes for the older AML patient. The cytokine levels could be further increased by the novel protein kinase C agonist PEP005, which also induced significant production of IL2 and TNFalpha which could contribute to anti-tumor effects in AML patients. We conclude that remaining T cells after intensive AML therapy show a broad cytokine release profile including high and significantly correlated levels of potentially anti-leukemic IFNgamma and the AML growth factor GM-CSF. The final outcome of an AML-initiated T cell cytokine response will thus depend on the functional characteristics of the AML cells, in particular the relative expression of IFNgamma and GM-CSF receptors which differs between AML patients.

Adult↗
PubMed2006

Effects of interferon gamma on native human acute myelogenous leukaemia cells.

T cell targeting immunotherapy is now considered a possible strategy in acute myelogenous leukaemia (AML), and IFNgamma release may then contribute to the antileukaemic effects. We investigated the effects of IFNgamma on native human AML cells. Normal T cells could be activated to release IFNgamma in the presence of AML cells. Furthermore, high levels of CD119 (IFNgamma receptor alpha chain) expression were observed for all 39 patients examined. Receptor expression was decreased after exposure to exogenous IFNgamma, and receptor ligation caused Stat1 phosphorylation but no phosphorylation of the alternative messengers Erk1/2. The effect of exogenous IFNgamma on AML blast proliferation was dependent on the local cytokine network and IFNgamma (1) inhibited proliferation in the presence of exogenous IL1beta, GM-CSF, G-CSF and SCF; (2) had divergent effects in the presence of IL3 and Flt3 (65 patients examined); (3) inhibited proliferation in the presence of endothelial cells but had divergent effects in the presence of fibroblasts, osteoblasts and normal stromal cells (65 patients examined). IFNgamma increased stress-induced (spontaneous) in vitro apoptosis as well as cytarabine-induced apoptosis only for a subset of patients. Furthermore, IFNgamma decreased the release of proangiogenic CXCL8 and increased the release of antiangiogenic CXCL9-11. We conclude that IFNgamma can be released in the presence of native human AML cells and affect AML cell proliferation, regulation of apoptosis and the balance between pro- and antiangiogenic chemokine release.

Adult↗
PubMed2006

Presence of activated T lymphocytes in peripheral blood of head and neck squamous cell carcinoma patients predicts impaired prognosis.

CONCLUSIONS: The results indicate that a high level of peripheral blood (PB) T-lymphocyte activation in vivo predicts impaired prognosis with and without adjustment for TNM stage in head and neck squamous cell carcinoma (HNSCC). OBJECTIVE: To determine if PB T-lymphocyte activation in vivo is associated with the presence of, stage of and prognosis of HNSCC. MATERIALS AND METHODS: Sixty-two patients with newly diagnosed HNSCC and 15 control patients were studied. PB T-lymphocyte activation was assessed by measuring by flow cytometry the percentage of PB T lymphocytes (CD3 + ) showing the early activation-related cell surface epitopes CD69+ or CD71+ (transferrin receptor) or the late activation epitopes CD25+ (IL-2 receptor) or HLA-DR+. RESULTS: There was no significant difference in expression of T-lymphocyte activation markers between HNSCC patients and control patients, or any difference dependent on TNMG stage. In HNSCC patients a high percentage of CD71+ T lymphocytes predicted worse prognosis with a relative risk (RR) of 2.38 (confidence interval (CI): 1.04-5.47). A high mean value of the early (CD69 + /CD71 + ) (RR 2.37; CI: 1.06-5.29) or late (CD25 + /HLA-DR + ) (RR 3.31; CI: 1.39-7.88) activation markers also predicted worse prognosis. Following adjustment for TNM stage, high mean value of the early activation epitopes CD71+ (RR 2.89; CI: 1.22-6.85), the mean value of CD69 + /CD71+ (RR 2.58; CI: 1.12-5.91) and CD25 + /HLA-DR+ (RR 2.75; CI: 1.14-6.62) predicted worse prognosis.

Carcinoma, Squamous Cell↗
PubMed2006

Primary chronic cold agglutinin disease: a population based clinical study of 86 patients.

BACKGROUND AND OBJECTIVES: Our knowledge of primary chronic cold agglutinin disease (CAD) is incomplete. The aim of this study was to collect comprehensive and precise data the on epidemiology, clinical and pathological features, course, and therapy of CAD. DESIGN AND METHODS: We performed a population-based retrospective follow-up study of as many as possible of all CAD patients in Norway. Eighty-six patients were studied. RESULTS: The prevalence of primary CAD was 16 cases per million inhabitants. The incidence rate was 1 per million per year. The median age at onset was 67 years (range, 30-92) and the male to female ratio was 0.55. The median survival was 12.5 years from onset. Autoimmune diseases other than CAD were reported in 8% of patients, cold-induced circulatory symptoms in 91%, and exacerbation of hemolytic anemia during febrile illness in 74%. At least 51% had received red blood cell transfusions. The mean initial hemoglobin level was 9.2 g/dL (range, 4.5-15.6) and the median monoclonal immunoglobulin level 4.0 g/L (range, 0.0-47.3). Most laboratory findings did not change significantly during a median follow-up of 5 years. Monoclonal IgM was detected in 90%; IgG and IgA in 3.5% each; with kappa light chains in 94%. An abnormal kappa/lambda ratio in bone marrow was found in 90%, lymphoma in 76%, and lymphoplasmacytic lymphoma in 50%. Transformation to aggressive lymphoma occurred in 3.5% during 10 years. Rituximab therapy was the only treatment showing acceptable response rates (60%). INTERPRETATION AND CONCLUSIONS: Primary CAD represents a spectrum of clonal lymphoproliferative bone marrow disorders, in most cases with morphological signs of lymphoma. Despite a favorable prognosis for survival, the disease is not indolent in terms of clinical manifestations.

Adult↗
PubMed2005

CD34 expression in native human acute myelogenous leukemia blasts: differences in CD34 membrane molecule expression are associated with different gene expression profiles.

BACKGROUND: The stem cell marker CD34 is expressed by leukemia blasts only for a subset of patients with acute myelogenous leukemia (AML). It is still controversial as to whether CD34 expression (defined as at least 10-20% positive cells) has any prognostic effect in patients with AML who receive intensive chemotherapy. The present study investigated whether gene expression profiling could be used to further subclassify CD34(+) AML cell populations. METHODS: AML blasts derived from 25 patients were examined; these patients were randomly selected from a larger consecutive group of patients. CD34 protein expression was determined by flow cytometry and expressed as the percentage of positive cells. Gene expression profiles were determined by complementary DNA microarrays. RESULTS: By unsupervised hierarchical clustering our patients could be grouped into two or three major subsets depending on the methodologic approach before clustering analysis (filtering or flooring of data, respectively). However, both approaches identified a cluster characterized by high gene expression and membrane molecule level of CD34. When using the floored expression profiles, the patient cluster characterized by increased CD34 gene expression was also characterized by a high percentage of CD34(+) cells (median 82%, range 56-100%) compared with the two other major clusters (median 19%, range <1-55%), but three of four outpatients also showed a high percentage of CD34(+) cells. CONCLUSION: A major proportion of patients with AML and high CD34 expression (usually >80% CD34(+) cells; nearly all patients had >50% positive cells) showed similarities in gene expression profile. In contrast, patients with lower CD34 expression often had a profile similar to those of patients regarded as CD34(-) according to conventional criteria. Our results suggest that the possible prognostic effect of CD34 expression should be reevaluated in clinical studies using additional or alternative cutoff values to describe CD34 expression.

Adult↗
PubMed2004

Population-based hematologic and immunologic reference values for a healthy Ugandan population.

To assess the validity of the reference values for hematologic and immunologic indices currently used in Africa, we evaluated blood samples from 3,311 human immunodeficiency virus (HIV)-negative Ugandans aged 1 week to 92 years. Erythrocyte, hemoglobin, and hematocrit levels and mean corpuscular volume all significantly increased with age (P < 0.001) and were independent of gender until the age of 13 years, after which the levels were higher in males than in females (P < 0.001). White blood cell, neutrophil, lymphocyte, basophil, and monocyte counts significantly declined with age until the age of 13 years (P < 0.001), with no differences by gender, while platelet counts declined with age (P < 0.001) and showed differences by gender only among adults older than age 24 years. CD4+- and CD8+-cell counts declined with age until the age of 18 years; thereafter, females had higher counts than males. The absolute values for many of these parameters differed from those reported for populations outside Africa, suggesting that it may be necessary to develop tables of reference values for hematologic and immunologic indices specific for the African population. This may be particularly important with regard to CD4+-cell counts among children because significant differences in absolute and percent CD4+-cell counts exist between the values for Western populations and the values for the population evaluated in our study. These differences could influence the decision to initiate antiretroviral therapy among children infected with HIV.

Adolescent↗
PubMed2003

Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients.

Conventional therapies for primary chronic cold agglutinin disease (CAD) are ineffective, but remissions after treatment with the anti-CD20 antibody rituximab have been described in a small, prospective trial and in some case reports. In this study we report on 37 courses of rituximab administered prospectively to 27 patients. Fourteen of 27 patients responded to their first course of rituximab, and 6 of 10 responded to re-treatment. In both groups combined, responses were achieved after 20 of 37 courses, giving an overall response rate of 54%. We observed 1 complete and 19 partial responses. Two nonresponders and 3 patients who experienced relapse received second-line therapy with interferon-alpha combined with a new course of rituximab, and 1 nonresponder and 2 patients who experienced relapse achieved partial responses. Responders achieved a median increase in hemoglobin levels of 40 g/L (4 g/dL). Median time to response was 1.5 months, and median observed response duration was 11 months. We conclude that rituximab is an effective and well-tolerated therapy for CAD. Histologic and flow cytometric findings suggest that some of the effect may be mediated by mechanisms other than the elimination of clonal lymphocytes. We were unable to predict responses from the hematologic, immunologic, or histologic parameters before therapy.

Anemia, Hemolytic, Autoimmune↗
PubMed2003

Changes in immunoglobulin isotypes and immunoglobulin G (IgG) subclasses during highly active antiretroviral therapy: anti-p24 IgG1 closely parallels the biphasic decline in plasma viremia.

SUMMARY: The effects of highly active antiretroviral therapy (HAART) on immunoglobulin isotypes and immunoglobulin G (IgG) subclasses were studied in 12 patients in early stages of HIV-1 infection. Blood samples were obtained at enrollment and 2, 4, 8, 12, 24, 48, and 120 weeks after initiation of HAART. Immunoglobulin concentrations were determined by nephelometry, and anti-p24-specific IgG and IgG1 levels were determined by an enzyme immunoassay. Overall time changes were analyzed in analysis of variance models. IgG and IgG1 levels showed a marked overall decline, whereas other immunoglobulin isotypes and IgG subclasses did not change significantly. Anti-p24-specific IgG1 levels decreased considerably and significantly more in virus isolation-negative patients than in virus isolation-positive patients, as defined according to the ability to isolate HIV-1 from their CD4+ T cells after initiation of therapy. Anti-p24 IgG levels showed a similar but overall weaker decline in the two groups. However, the anti-p24 IgG1 level followed the biphasic decline in plasma viremia more closely than the anti-p24 IgG level, with an initial sharp decline that leveled off with time. These findings suggest that the main reduction in immunoglobulin levels is caused by reduced HIV-1-specific antigen stimulation rather than a general reduction in immune activation. Using anti-p24 IgG1 as a parameter of response to the effect of HAART merits further investigation.

Adult↗
PubMed2003

Human acute lymphoblastic leukemia (ALL) blasts as accessory cells during T-cell activation: differences between patients in costimulatory capacity affect proliferative responsiveness and cytokine release by activated T cells.

The ability of acute lymphoblastic leukemia (ALL) blasts to mediate costimulatory signals during T-lymphocyte activation was investigated in an experimental model in which monoclonal T-cell populations were stimulated with standardized activation signals (anti-CD3 and anti-CD28 monoclonal antibodies; phytohemagglutinin, PHA). Leukemia cells from 12 consecutive ALL patients with high peripheral blood blast counts were studied. Proliferative T-cell responses were detected for a majority of these patients when irradiated leukemia blasts were used as accessory cells during activation. T-cell cytokine release was also observed for most patients when using nonirradiated ALL accessory cells. Low or undetectable cytokine levels were usually observed for CD8+ clones, whereas the CD4+ clones often showed a broad cytokine response with release of interleukin-2 (IL-2), IL-4, IL-10, IL-13 and interferon gamma(IFN-gamma) in the presence of the ALL accessory cells. ALL blasts were also able to function as allostimulatory cells for normal peripheral blood mononuclear responder cells. However, both T-cell proliferation and cytokine release showed a wide variation between ALL patients. The accessory cell function of ALL blasts showed no correlation with the release of immunomodulatory mediators (IL-2, IL-10, IL-15) or the expression of any single adhesion/costimulatory membrane molecule (CD54, CD58, CD80, CD86) by the blasts. We conclude that for a majority of patients, native ALL blasts can mediate costimulatory signals needed for accessory cell-dependent T-cell activation, but differences in costimulatory capacity between ALL patients affects both the proliferative responsiveness and cytokine release by activated T cells.

Adolescent↗
PubMed2003

In vitro culture of human acute lymphoblastic leukemia (ALL) cells in serum-free media; a comparison of native ALL blasts, ALL cell lines and virus-transformed B cell lines.

The aim of this study was to standardize in vitro culture conditions for human acute lymphoblastic leukemia (ALL) cells. The cells were cultured in medium containing 10% fetal calf serum (FCS) and in the four serum-free media X-vivo 10, X-vivo 15, X-vivo 20 and Stem Span. Native ALL blasts could proliferate in all four serum-free media, but the strongest responses were usually observed with Stem Span. Native leukemia blasts were also cultured in the presence of various single cytokines or cytokine combinations. The highest proliferation was usually observed in the presence of Flt3-Ligand (Flt3-L) when single cytokines were examined, and these responses could be further increased especially by combining Flt3-L with interleukin 3 (IL3), IL7 or stem cell factor (SCF). Proliferation could also be increased when ALL blasts were cultured in the presence of two commercially available fibroblast cell lines (Hs27 and HFL1). Based on these results we suggest that in vitro culture conditions for native human ALL blasts can be standardized by using serum-free culture media supplemented with exogenous Flt3-L+IL3+SCF, and the use of accessory cells can also be standardized by using well-characterized fibroblast cell lines. Detectable ALL blast proliferation can then be observed for most patients. Our experimental model can thereby be used for in vitro evaluation of possible antileukemic treatment strategies, and it will then allow comparison of experimental results between different studies.

Adolescent↗
PubMed2003

Performance characteristics of a glycoprotein G based oligopeptide (peptide 55) and two different methods using the complete glycoprotein as assays for detection of anti-HSV-2 antibodies in human sera.

Assays for serological diagnosis of HSV-2 infection in clinical settings have been generally available only recently. We wanted to investigate and compare the diagnostic utility of three different ELISAs for detection of anti-HSV-2 IgG antibodies, using intact glycoprotein G or an oligopeptide from a portion of the protein as antigens. HSV-1 negative/HSV-2 negative sera (n = 32), HSV-1 positive/HSV-2 negative sera (n = 30) and sera from HSV-2 culture positive individuals (n = 36), collected at least 6 months after culture verified HSV-2 genital infection were examined. Cut-off values were determined according to the manufacturer's instructions, and also by establishing new cut-off values at the level of highest diagnostic efficiency. Sensitivities and specificities were compared for each assay. In addition, test accuracies were compared using receiver-operating characteristics (ROC) methodology. Establishment of new cut-off values increased the performance characteristics for all three tests. At similarly set cut-off values, the peptide 55 assay showed the highest diagnostic sensitivity (100%) and specificity (98%). All three assays displayed high efficiency and also high agreement between the tests (kappa > 0.85 for all comparisons). The performance of all three assays were satisfactory although the highest efficiency and accuracy was obtained with the peptide 55 assay.

Antibodies, Viral↗
PubMed2002

Effects of cytarabine and various anthracyclins on platelet activation: characterization of in vitro effects and their possible clinical relevance in acute myelogenous leukemia.

Previous in vitro studies have demonstrated that normal platelets and platelet-released mediators can alter in vitro characteristics of human acute myelogenous leukemia (AML) blasts. To further investigate whether platelets can be expected to adhere to and thereby affect AML blasts through their release of soluble mediators into a common microenvironment, we investigated (i) the effects on platelet activation by cytotoxic drugs commonly used in AML therapy; (ii) the occurrence of circulating activated platelets in acute leukemia patients; and (iii) the in vivo and in vitro adherence of platelets to AML blasts. The anthracyclins daunorubicin and idarubicin increased the expression of activation-associated membrane molecules (GPIIb/IIIa, CD62P, CD63) by normal platelets, daunorubicin then having the strongest effect. In contrast, cytarabine, epirubicin, doxorubicin and mitoxantrone had no significant effects. Although AML patients did not show increased levels of activated platelets in the circulation, adhesion of platelets to AML blasts was demonstrated both in vivo and in vitro. These results suggest that platelets and AML blasts may locate to common in vivo microenvironments, and platelet-derived soluble mediators may thereby affect the functional characteristics of the leukemia cells.

Adult↗