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Biomedical subjects

D Kvale

Publications and source records attributed to D Kvale.

At least 19 recordsLinked to original sources
PubMed2002

Predictive value of immunologic parameters and HIV RNA in relation to humoral pneumococcal polysaccharide vaccine responses in patients with HIV infection.

In the study presented here immunologic markers and HIV RNA were related to specific antibody responses in 50 HIV-infected patients who had moderate immunodeficiency (median CD4+, 295) and were vaccinated with a pneumococcal polysaccharide vaccine. Low responses were associated with low IgG2 or high IgM levels ( P=0.01) and good responses with high IgG4 ( P=0.05) or IgG2 ( P=0.07) or low beta(2) microglobulin ( P=0.04) levels. A combination of IgG2 levels >1.0 g/l and IgM <1.6 g/l at baseline significantly predicted a twofold or better response in logistic regression analysis ( P=0.025). Neither CD4+ lymphocyte counts nor HIV RNA levels were predictive, but it should be noted that good antibody responses were not restricted to patients with high CD4+ cell counts or low HIV RNA levels.

Adult↗
PubMed2002

Immunophenotypic analyses of CD34(+) cell subsets in bone marrow from HIV-infected patients during highly- active antiretroviral therapy.

BACKGROUND: Because increased bone marrow lymphopoiesis might contribute to immunologic reconstitution during highly-active antiretroviral therapy (HAART), we examined the effect of HAART on CD34(+) cell subsets in bone marrow from HIV-infected patients. MATERIALS AND METHODS: In 12 HIV-infected patients, bone marrow and peripheral blood were collected before then 4 and 26 weeks after initiating HAART. Bone marrow in 28 HIV-seronegative controls was also examined. Immunophenotypic analyses of CD34(+) cell subsets in bone marrow were performed by flow cytometry. RESULTS: Our main findings in bone marrow were: (i) HIV-infected patients had increased proportions of CD34(+)cells expressing T- and B-cell markers before initiating HAART; (ii) in contrast, these patients had decreased proportions of CD34(+) cells expressing myeloid-associated markers; (iii) although HAART induced an increase in peripheral T-cell counts, the percentage of CD34(+)cells expressing T-cell markers tended to decrease during such therapy; (iv) HAART induced a decrease in serum IgG accompanied by a slight decrease in the proportion of CD34(+)cells expressing B-cell markers; (v) in contrast, HAART induced a significant increase in peripheral granulocyte counts, accompanied by a slightly increased proportion of CD34(+) cells expressing myeloid-associated molecules. CONCLUSION: Our findings are compatible with an HIV-related block in T-cell differentiation, leading to accumulation of T-cell progenitors in bone marrow, and such a block may be removed by HAART.

Adult↗
PubMed2002

Cytomegalovirus DNA concentration in plasma predicts development of cytomegalovirus disease in kidney transplant recipients.

The clinical significance of cytomegalovirus (CMV) DNA detection in post-kidney transplantation infection surveillance was examined by comparing the performance of three assays for detection of CMV in blood: the test for CMV-pp65-antigen in leukocytes, which is routinely employed in our laboratory, the quantitative plasma CMV-DNA-polymerase chain reaction (PCR; Cobas Amplicor CMV Monitor test) and the qualitative plasma CMV-DNA-PCR (Amplicor CMV test). Thirteen kidney transplant recipients were monitored with serial samples taken over a period of 3 months following transplantation. The quantitative CMV-PCR was the test with highest sensitivity, 95.9%, vs. 88.9% and 76.9% for the CMV-pp65 antigen assay and qualitative CMV-PCR, respectively. The virus load in the first positive specimens, assessed as DNA-copies/mL, was significantly associated with CMV disease because five of the six patients who developed disease, but only one of the seven who did not develop disease, had more than 3000 CMV-DNA-copies/mL. The number of CMV-pp65 antigen-positive cells in the first positive specimens did not have predictive value for development of CMV disease. Assessment of CMV in plasma by the quantitative CMV-PCR is especially useful since it has a high sensitivity and the amount of CMV DNA in plasma is a good predictor of CMV disease.

Cytomegalovirus↗
PubMed2000

Human intestinal endothelium shows high susceptibility to cytomegalovirus and altered expression of adhesion molecules after infection.

Human cytomegalovirus (HCMV) causes gastro intestinal disease with ulcerations, apparently as a consequence of cytopathic damage to endothelial cells (EC) and subsequent microvascular obliteration. In this study we showed that cultured human intestinal microvascular endothelial cells (HIMEC) are much more susceptible to HCMV infection than human umbilical vein endothelial cells (HUVEC). When both cell types were challenged with a clinical isolate of HCMV (10 pfu per cell), 30% of HIMEC expressed HCMV immediate early proteins, but only 10% of HUVEC. Enhanced susceptibility was also reflected in the expression of early and late HCMV proteins. In addition, the interleukin-1beta (IL-1beta)-induced cellular expression of adhesion molecules differed between HIMEC and HUVEC after HCMV-infection. E-selectin was unaffected in HUVEC but increased in HIMEC, whereas vascular cell adhesion molecule (VCAM)-1 was increased in HUVEC but decreased in HIMEC. Furthermore, HCMV-infection enhanced the expression of intercellular adhesion molecule (ICAM)-1 in both cell types. In conclusion, the enhanced susceptibility to HCMV infection observed in HIMEC and the elevated expression of E-selectin and ICAM-1 observed in these cells may provide an indication to the liability of developing gastrointestinal HCMV disease and may have a possible relevance to the survival of intestinal transplants.

Cell Adhesion Molecules↗
PubMed1999

CD4+ and CD8+ lymphocytes and HIV RNA in HIV infection: high baseline counts and in particular rapid decrease of CD8+ lymphocytes predict AIDS.

OBJECTIVE: To study the progression of HIV infection in relation to immunological and virological variables with emphasis on the role of CD8+ lymphocytes. DESIGN: Prospective follow-up from October 1991 of patients observed for at least 18 months allowing nucleoside analogue monotherapy. Peripheral CD4+ and CD8+ lymphocyte counts, HIV RNA, and soluble CD8 were analysed by statistics allowing the evaluation of serial data, avoiding time points with concurrent infections. SETTING: Tertiary university clinic. PATIENTS: Forty-nine patients were followed for 52.6 months, baseline CD4+ count of 300 x 10(6)/l, sample interval of 5.9 months (medians). MAIN OUTCOME MEASURES: AIDS, death, and CDC groups B- or C-related events. RESULTS: AIDS developed in 28% of patients. Baseline CD8+ counts above the median were significantly associated with AIDS development; the best Cox model included CD8+ cells and the log10RNA/CD4 ratio. A decline in CD8+ counts relative to baseline most significantly predicted AIDS, along with higher baseline RNA and actual CD4+ counts of less than 200 x 10(6)/l. Levels of soluble CD8 in the blood relative to total CD8+ cells significantly increased in patients developing AIDS. Death occurred in 16% of the patients, and was only predicted by high CD8+ cell counts at baseline. CDC B- and C-related events occurred in 35% of the patients and were best predicted by high baseline CD8+ counts and high RNA levels. CONCLUSIONS: The serial quantitation of CD8+ lymphocytes gave highly significant predictive information on the natural progression of HIV infection in patients with moderate to severe immune deficiency. Our data suggest that the hyperactivation of CD8+ lymphocytes is an important factor leading to a numerical decrease of CD8+ lymphocytes in progressive HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Different regulatory pathways employed in cytokine-enhanced expression of secretory component and epithelial HLA class I genes.

The transmembrane secretory component (SC, or pIg receptor) plays a crucial role in mucosal immunity by translocating dimeric IgA and pentameric IgM through exocrine epithelia. This receptor is up-regulated by cytokines in parallel with increased epithelial HLA expression. By use of the human epithelial cell line HT-29m3, we show that IFN-gamma, TNF-alpha and IL-4 activate transcription of the SC gene. This activation was slow, suggesting mediation via newly synthesized protein factors. IFN-gamma and TNF-alpha, but not IL-4, also up-regulated expression of HLA class I genes. However, this gene induction was rapid and did not depend on new protein synthesis. Nuclear run-on experiments showed that the transcription rate of HLA class I genes nearly peaked after only 30 min of IFN-gamma or TNF-alpha stimulation, whereas the SC transcription rate did not peak until after 20-36 h of IFN-gamma, TNF-alpha or IL-4 stimulation. Gel electrophoresis mobility shift assays demonstrated binding of nuclear proteins from cytokine-stimulated HT-29 cells to consensus elements in the promoter of the SC gene, involving the binding site for the nuclear factor-kappaB p50 subunit after TNF-alpha stimulation, and IFN-stimulated response element after IFN-gamma stimulation (and weakly after TNF-alpha. Our observations in vitro likely parallel events in vivo by which activated mucosal T cells and macrophages enhance pIg receptor-mediated external transport of secretory IgA and IgM and up-regulate epithelial HLA expression.

Base Sequence↗
PubMed1999

IL-10 in HIV infection: increasing serum IL-10 levels with disease progression--down-regulatory effect of potent anti-retroviral therapy.

To examine the potential pathogenic role of IL-10 in HIV infection, we measured serum IL-10 levels in 51 HIV-infected patients and 23 healthy controls both on cross-sectional and longitudinal testing. All clinical groups (Centers for Disease Control (CDC) categories) of HIV-infected patients had significantly higher circulating IL-10 levels than controls, with the highest levels among the AIDS patients, particularly in patients with ongoing Mycobacterium avium complex (MAC) infection. Among 32 HIV-infected patients followed with longitudinal testing (median observation time 39 months), patients with disease progression had increasing IL-10 levels in serum, in contrast to non-progressing patients where levels were stable. While both IL-10 and tumour necrosis factor-alpha (TNF-alpha) increased in patients with disease progression, the IL-10/TNF-alpha ratio decreased in these patients, suggesting imbalance between these two cytokines. Finally, we found that highly active anti-retroviral therapy (HAART) induced a significant, gradual decrease in IL-10 levels but without normalization. These findings suggest a pathogenic role for IL-10 in HIV infection, and may suggest a possible role for immunomodulating therapy which down-regulates IL-10 activity in addition to concomitant potent anti-retroviral therapy in HIV-infected patients.

AIDS-Related Opportunistic Infections↗
PubMed1999

Tumor necrosis factor (TNF) system levels in human immunodeficiency virus-infected patients during highly active antiretroviral therapy: persistent TNF activation is associated with virologic and immunologic treatment failure.

Because persistent tumor necrosis factor (TNF)-alpha activation may play a pathogenic role in human immunodeficiency virus infection, TNF component levels were assessed over 78 weeks in plasma and peripheral blood mononuclear cells (PBMC) during highly active antiretroviral therapy (HAART) in 40 HIV-infected patients. HAART induced a significant decline in plasma levels of TNF-alpha and soluble TNF receptors and was associated with a fall in the abnormally increased unstimulated and a rise in the abnormally low Mycobacterium avium complex-purified-protein derivative-stimulated TNF-alpha released from PBMC. However, concentrations of these TNF components were not normalized. Patients with virologic and immunologic treatment failure after 52 weeks had higher levels of several TNF components than other patients early after initiation of therapy, also during periods with adequate virologic response. Although TNF components significantly decreased during HAART, these results support data indicating that full immunologic normalization is not achieved during such therapy. The persistent activation of the TNF system in a subgroup of persons may be involved in treatment failure.

Adolescent↗
PubMed1998

Major histocompatibility complex class II-dependent antigen presentation by human intestinal endothelial cells.

BACKGROUND & AIMS: In the normal gut, human intestinal microvascular endothelial cells (HIMECs) express major histocompatibility complex (MHC) class II molecules. Enhanced expression is found in chronic inflammation. We examined the cytokine regulation of MHC class II molecules and the associated invariant chain (Ii) in HIMECs and investigated whether such cells can process and present a complex protein antigen to T cells. METHODS: Enzyme-linked immunosorbent assay, flow cytometry, immunoelectron microscopy, as well as T-cell activation assay with HIMECs and HLA-DR-restricted T-cell clones were employed. RESULTS: In unstimulated HIMEC monolayers, HLA-DR, -DP, and -DQ and Ii were undetectable at the protein level, but interferon gamma (IFN-gamma) (100 U/mL) induced expression that peaked for DR after 2-3 days, for DP after 4-6 days, for DQ after 10-12 days, and for Ii after 2-3 days. Tumor necrosis factor alpha had no effect alone but enhanced class II expression in combination with IFN-gamma, most notably for DQ and DP. HLA-DR3-restricted and Mycobacterium tuberculosis heat shock 65-kilodalton-specific T-cell clones were activated to produce IFN-gamma in response to relevant antigen presented by IFN-gamma-treated HIMECs. This response was inhibited by blocking monoclonal antibody to HLA-DR and by chloroquine when compared to professional antigen-presenting cells, HIMECs activated T-cell clones quite efficiently. CONCLUSIONS: These data suggest that microvascular endothelial cells can present complex protein antigens in the human gut.

Antigen Presentation↗
PubMed1997

[Q-fever imported into Norway].

Q fever is an important zoonosis that occurs throughout the world. In contrast to most other European countries, there has been no evidence of endemic Q fever in Norway up to now. The disease is caused by Coxiella burnetii, a rickettsia-like bacterium. Humans are infected mainly by inhalation of contaminated aerosols from cattle, sheep and goats. Clinical manifestations are protean, ranging from asymptomatic infection to life-threatening endocarditis. In this article we present the first four cases of serological proven acute Q fever imported into Norway. The patients were Norwegian tourists who had visited Bhutan, the Canary Islands, and Morocco. Two patients had fever with maculopapular exanthema, one had pneumonia, and one had biopsy-proven granulomatous hepatitis. Three were treated with tetracyclines. All four patients recovered well.

Aged↗
PubMed1997

Topographic distribution of homing receptors on B and T cells in human gut-associated lymphoid tissue: relation of L-selectin and integrin alpha 4 beta 7 to naive and memory phenotypes.

In mice, integrin alpha 4 beta 7 is the main receptor used by lymphocytes that home to the Peyer's patches, although L-selectin contributes to the initial interaction with high endothelial venules. Less is known about the expression and function of these adhesion molecules in humans. The distribution of L-selectin and alpha 4 beta 7 on various B- and T-cell subsets was examined in human Peyer's patches (n = 8) and appendix (n = 4), collectively called gut-associated lymphoid tissue. Multicolor immunophenotyping was performed on cryosections, and dispersed cells were examined by flow cytometry. In cryosections, CD45RA+ T cells around and within interfollicular high endothelial venules, as well as surface (s)IgD+ B lymphocytes in the follicle mantles, often expressed abundant L-selectin but only intermediate levels of alpha 4 beta 7. CD45RO+ T cells and sIgD- B cells expressed higher levels of alpha 4 beta 7 and were often located near putative efferent lymphatics; only a small fraction (< 20%) of such memory cells expressed L-selectin. By flow cytometry, considerably more T than B lymphocytes co-expressed L-selectin and alpha 4 beta 7 (40% versus 25% and 67% versus 39%, respectively). In samples with many L-selectin+ cells (> 30%), more of these lymphocytes co-expressed alpha 4 beta 7 than in samples with few L-selectin+ cells. Because L-selectin and alpha 4 beta 7 were co-expressed on lymphocytes located near high endothelial venules, and because such co-expression was relatively common when many L-selectin+ cells were present, both of these molecules might participate in homing to human gut-associated lymphoid tissue. Such homing is probably most pronounced for T lymphocytes that were found to express L-selectin and alpha 4 beta 7 more often than B lymphocytes. The selective and relatively high expression of alpha 4 beta 7 on memory cells located near efferent lymphatics indicated a different migratory capacity; after exit from gut-associated lymphoid tissue, such stimulated cells might home mainly to mucosal effector sites.

Adolescent↗
PubMed1996

Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells.

Endothelial cells (EC) recruit circulating leukocytes to sites of inflammation, partly by expression of endothelial-leukocyte adhesion molecules. Whereas the regulation of some adhesion molecules is well characterized in cultured HUVEC, similar data for microvascular human test systems are limited. We studied the cytokine-regulated expression of vascular cell adhesion molecules E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) in cultured human intestinal microvascular endothelial cells (HIMEC). E-selectin and VCAM-1 were induced, and ICAM-1 was enhanced, in a dose-dependent fashion after stimulation with IL-1beta, TNF-alpha, and LPS. Each adhesion molecule displayed characteristic time-related responses comparable to those obtained with HUVEC, and each molecule supported adhesion of leukocytes. Notable disparities between the two endothelial test systems were that 1) expression of total cellular E-selectin (but not surface membrane expression) was sustained after 72 h of IL-1beta stimulation in HIMEC, contrasting a rapid biphasic response in HUVEC; 2) LPS did not maintain prolonged expression of ICAM-1 and VCAM-1 in HIMEC; and 3) VCAM-1 protein was dose-dependently up-regulated by IL-4 in HUVEC, peaking after 8 h, while IL-4 had only a negligible effect on the expression of this protein in HIMEC. In conclusion, the regulation of these adhesion molecules appears to be somewhat different in HIMEC compared with HUVEC, and the differences from available data on skin-derived microvascular endothelial cell cultures are to some extent substantial. Our findings document the importance of using relevant endothelial cell culture systems for studies of leukocyte-endothelial cell interactions.

Base Sequence↗
PubMed1996

Intercellular adhesion molecule-1 (ICAM-1; CD54) expression in human hepatocytic cells depends on protein kinase C.

BACKGROUND/AIMS: Intracellular regulation of intercellular adhesion molecule-1 has mainly been studied in lymphoid, endothelial, and epithelial cells. Intercellular adhesion molecule-1 plays a central role in many immune responses, and we have previously studied its regulation in hepatocytes. Here we report how manipulation of intracellular signal systems influenced its expression. METHODS: The constitutive and cytokine-induced expression of intercellular adhesion molecule-1 mRNA and protein was studied in the human hepatocytic cell lines Hep G2 and SK-Hep-1. RESULTS: When agonists and antagonists of protein kinase C, calmodulin, and protein kinase A were introduced in addition to prostaglandin E2 and a cyclooxygenase inhibitor, only the protein kinase C activator phorbol 12-myristate 13-acetate resulted in a rapid and dose-dependent increase in intercellular adhesion molecule-1 protein and mRNA. Phorbol 12-myristate 13-acetate stimulated sustained high levels of intercellular adhesion molecule-1 protein, whereas the corresponding mRNA response was biphasic, peaking at 3 h. Actinomycin D blocked the stimulatory mRNA phase, suggesting that de novo transcription was induced. Coincubation with phorbol 12-myristate 13-acetate and the protein synthesis inhibitor cycloheximide gave considerably higher mRNA levels than with phorbol 12-myristate 13-acetate alone. Protein kinase C may therefore even stimulate synthesis of proteins that speed up the turnover of intercellular adhesion molecule-1 mRNA. The protein kinase C inhibitor staurosporine abrogated the induction of intercellular adhesion molecule-1 by phorbol 12-myristate 13-acetate, indicating that this effect was indeed exerted by protein kinase C. More original was our observation that staurosporine also completely blocked the stimulatory effects of interferon-gamma, tumour necrosis factor-alpha, and interleukin-1. Recent reports have noted that these cytokines apparently use receptors which activate different intracellular pathways. We also noted that the glucocorticoid dexamethasone partially inhibited the stimulation of intercellular adhesion molecule-1 by these cytokines. This phenomenon could be important for the immunosuppressive effects of corticosteroids in patients with liver disease. CONCLUSIONS: Our data suggest that a certain level of protein kinase C activity is mandatory for liver cells in cytokine-mediated upregulation of intercellular adhesion molecule-1.

Cell Line↗
PubMed1995

Butyrate differentially affects constitutive and cytokine-induced expression of HLA molecules, secretory component (SC), and ICAM-1 in a colonic epithelial cell line (HT-29, clone m3).

In conclusion, we have found that physiological concentrations of butyrate increase the constitutive levels of HLA class I and SC molecules in HT-29m3 cells. Moreover, butyrate at high concentrations induces de novo synthesis of HLA-DR but not ICAM-1 molecules. Our data further showed that butyrate generally facilitates the cytokine-induced expression of immunological molecules in these cells but, interestingly, it specifically reduces the stimulatory effects of TNF and IL-4 on HLA class I and SC, respectively. We are currently studying how butyrate affects transcriptional regulation of the genes encoding these molecules. Further knowledge about the effects of butyrate in relation to gene regulation is required. It is possible that butyrate might interfere with specific, cytokine-dependent regulatory elements in certain genes which, in turn, could have implications for immune regulation of colonic epithelial cells in vivo.

Adenocarcinoma↗
PubMed1995

Constitutive and cytokine induced expression of HLA molecules, secretory component, and intercellular adhesion molecule-1 is modulated by butyrate in the colonic epithelial cell line HT-29.

Normal colonic epithelial cells play an important part in the mucosal immune system and use butyrate, a bacterial fermentation product, as an important energy source. Butyrate deficiency has been associated with inflammatory bowel disease, diversion colitis, and pseudomembranous colitis. Butyrate effects on important molecules for epithelial immune functions were studied in a colonic epithelial cell line (HT-29): the constitutive and cytokine regulated expression of secretory component (poly-Ig receptor), HLA class I and II molecules, and intercellular adhesion molecule-1 (ICAM-1). Butyrate facilitated the constitutive expression of secretory component and HLA class I. Butyrate furthermore tended to enhance cytokine mediated stimulation of protein expression, although tumour necrosis factor alpha (TNF) and interleukin 4 (IL 4) responses on HLA class I and secretory component, respectively, were relatively inhibited by butyrate. Cytokine mediated accumulation in the various mRNAs usually increased even more in the presence of butyrate, with the exception of TNF response on HLA class I and secretory component mRNA concentrations. In conclusion, butyrate may substantially influence constitutive and cytokine mediated expression of molecules with immune functions in a complex and differentiated manner, and butyrate deficiencies, as seen in various clinical conditions, might influence mucosal immune responses.

Base Sequence↗
PubMed1995

Isolation and longterm culture of human intestinal microvascular endothelial cells.

Microvascular endothelial cells play an important part in inflammation as well as in organ specific leucocyte traffic, and may be functionally different from large vessel endothelium in this respect. This study therefore established a method for isolation and longterm culture of human intestinal microvascular endothelial cells (HIMEC). After dissociation by collagenase/dispase/DNase of mucosal and submucosal tissue obtained from normal adult jejunum, cells were plated and cultured to subconfluence in endothelial serum free medium containing 2.5% fetal calf serum, hydrocortisone, and N6, O2-dibutyryladenosine cyclic monophosphate. Primary cultures were trypsinised and endothelial cells were isolated by paramagnetic beads armed with monoclonal antibody to CD31. Optimal growth conditions for HIMEC cultures were established, allowing up to nine passages (three months in vitro). The cells contained Weibel-Palade bodies, expressed von Willebrand factor, CD31, and VE-cadherin; and bound Ulex Europaeus lectin I. A method to establish longterm cell cultures of HIMEC will facilitate further investigation of the function of intestinal endothelial cells and their participation in physiological and pathological events in the gut.

Adult↗
PubMed1993

Immune modulation of adhesion molecules ICAM-1 (CD54) and LFA-3 (CD58) in human hepatocytic cell lines.

Interactions between leukocytes such as T cells and accessory or target cells are promoted by adhesion molecules, in particular intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-3 (LFA-3). Hepatocytes are usually negative for these surface membrane proteins which, however, may be up-regulated in inflammatory processes within the liver. Because the regulatory signals for, and tissue distribution of, these adhesion molecules vary among different tissues, expression of ICAM-1 and LFA-3 was studied in the Hep-G2 and SK-Hep-1 human hepatocytic cell lines in vitro. Low, constitutive membrane expression of the two molecules was detected in both cell lines. ICAM-1, but not LFA-3, was rapidly up-regulated by interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF), and to some extent by interferon-gamma (IFN) and IL-6, whereas IL-4 had variable low effects, if any. Considerable synergism on ICAM-1 protein levels was observed after stimulation with TNF, IL-1, and IFN, whereas co-incubation with actinomycin D abolished these effects. ICAM-1 mRNA levels increased 16-20 times after cytokine incubation. Our data indicated that hepatocytes share the regulatory pathways for ICAM-1 described for several other cell types. Absence of these molecules in vivo may reflect a dominance of negative modulation signals in the normal liver, which might also explain the low levels of HLA class I molecules.

Antigens, CD↗