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Biomedical subjects

D Hamann

Publications and source records attributed to D Hamann.

At least 37 records · Page 2Linked to original sources
PubMed1999

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.

BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.

Adult↗
PubMed1999

Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts.

To assess possible differences in immune status, proportions and absolute numbers of subsets of CD4+ and CD8+ T cells were compared between HIV- healthy Ethiopians (n = 52) and HIV- Dutch (n = 60). Both proportions and absolute numbers of naive CD4+ and CD8+ T cells were found to be significantly reduced in HIV Ethiopians compared with HIV- Dutch subjects. Also, both proportions and absolute numbers of the effector CD8+ T cell population as well as the CD4+CD45RA-CD27- and CD8+CD45RA-CD27- T cell populations were increased in Ethiopians. Finally, both proportions and absolute numbers of CD4+ and CD8+ T cells expressing CD28 were significantly reduced in Ethiopians versus Dutch. In addition, the possible association between the described subsets and HIV status was studied by comparing the above 52 HIV- individuals with 32 HIV+ Ethiopians with CD4 counts > 200/microliter and/or no AIDS-defining conditions and 39 HIV+ Ethiopians with CD4 counts < 200/microliter or with AIDS-defining conditions. There was a gradual increase of activated CD4+ and CD8+ T cells, a decrease of CD8+ T cells expressing CD28 and a decrease of effector CD8+ T cells when moving from HIV- to AIDS. Furthermore, a decrease of naive CD8+ T cells and an increase of memory CD8+ T cells in AIDS patients were observed. These results suggest a generally and persistently activated immune system in HIV- Ethiopians. The potential consequences of this are discussed, in relation to HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults.

Today's antiretroviral combination regimens can induce significant and sustained decreases in human immunodeficiency virus (HIV)-RNA levels, allowing the immune system to recover. To what extent immune reconstitution is possible and what factors determine the outcome have thus far not been resolved. We studied 19 subjects, treated for 2 years with protease inhibitor-containing triple therapy, who had a strong suppression of HIV-RNA levels. CD4+ T-cell numbers increased from medians of 170 to 420x106 cells/L, but in a number of subjects T-cell numbers did not further increase after week 72, without having reached normal values. Long-term CD4+ T-cell change was mainly caused by a slow but continuous increase in naive CD4+ T cells (CD45RA+CD62L+) and was predicted by the baseline number of these cells. Our data indicate that long-term immunological recovery is gradual, even during strong suppression of viral replication, not always complete, and dependent on the preexisting level of naive CD4+ T cells.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Evidence that human CD8+CD45RA+CD27- cells are induced by antigen and evolve through extensive rounds of division.

We recently showed that circulating human CD8(+) effector cells have a CD45RA+CD27(-) membrane phenotype. In itself this phenotype appeared to pose a paradox: CD45RA, a marker expressed by unprimed cells, combined with absence of CD27, characteristic for chronically stimulated T cells. To investigate whether differentiation towards the CD45RA+CD27(-) phenotype is dependent on antigenic stimulation and involves cellular division, TCR Vbeta usage and telomeric restriction fragment (TRF) length were analyzed within distinct peripheral blood CD8(+) subsets. FACS analysis showed that the TCR Vbeta repertoire of CD8(+)CD45RA+CD27(-) cells differed significantly from that of unprimed CD8(+)CD45RA+CD27(+) cells. Moreover, in two out of six individuals large expansions of particular Vbeta families were observed in the CD8(+)CD45RA+CD27(-) subset. CDR3 spectrotyping and single-strand confirmation analysis revealed that within the CD8(+)CD45RA+CD27(-) population most of the 22 tested Vbeta families were dominated by oligoclonal expansions. The mean TRF length was found to be 2.3+/-1.0 kb shorter in the CD8(+)CD45RA+CD27(-) subset compared with the unprimed CD8(+)CD45RA+CD27(+) population, but did not differ substantially from that of memory type, CD8(+)CD45RA-CD27(+) T cells. These findings indicate that the CD8(+)CD45RA+CD27(-) cytotoxic effector population consists of antigen-induced, clonally expanded cells and confirm that the expression of CD45RA is not a strict marker of antigen non-experienced T cells.

CD8-Positive T-Lymphocytes↗
PubMed1999

Longitudinal phenotypic analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes: correlation with disease progression.

Few studies have examined longitudinal changes in human immunodeficiency virus type 1 (HIV)-specific cytotoxic T lymphocytes (CTL). To more closely define the natural history of HIV-specific CTL, we used HLA-peptide tetrameric complexes to study the longitudinal CD8(+) T-cell response evolution in 16 A*0201-positive untreated individuals followed clinically for up to 14 years. As early as 1 to 2 years after seroconversion, we found a significant association between high frequencies of A*0201-restricted p17(Gag/Pol) tetramer-binding cells and slower disease progression (P < 0.01). We observed that responses could remain stable over many months, but any longitudinal changes that occurred were typically accompanied by reciprocal changes in RNA viral load. Phenotypic analysis with markers CD45RO, CD45RA, and CD27 identified distinct subsets of antigen-specific cells and the preferential loss of CD27(+) CD45RO(+) cells during periods of rapid decline in the frequency of tetramer-binding cells. In addition we were unable to confirm previous studies showing a consistent selective loss of HIV-specific cells in the context of sustained Epstein-Barr virus-specific cell frequencies. Overall, these data support a role of HIV-specific CTL in the control of disease progression and suggest that the ultimate loss of such CTL may be preferentially from the CD27(+) CD45RO(+) subset.

Disease Progression↗
PubMed1999

Supportive use of amifostine in patients with head and neck tumors undergoing radio-chemotherapy. Is it possible to limit the duration of the application of amifostine?

BACKGROUND: Amifostine is a new cancer-supporting agent to protect normal tissue in patients receiving radio-chemotherapy. The main question of our study is whether the application of amifostine can be limited on the duration of chemotherapy in patients with advanced head and neck tumors undergoing radio-chemotherapy. PATIENTS AND METHODS: In a randomized study 14 patients were treated with amifostine (500 mg, day 1 to 5 and 29 to 33) during concurrent radio-chemotherapy with carboplatin (70 mg/m2, day 1 to 5 and 29 to 33), 14 patients were treated without amifostine. The analyzed parameters were dermatitis, mucositis, skin temperature, white blood and platelet count, creatinine and scintigram of salivary glands. Median survival of the amifostine group was 19 months, of the control group 10 months. RESULTS: There were no relevant differences in all analyzed parameters between both arms of the study. CONCLUSION: Our form of amifostine application is probably not able to obtain a relevant reduction of the toxicity of radio-chemotherapy.

Adolescent↗
PubMed1998

Restored humoral immune response to influenza vaccination in HIV-infected adults treated with highly active antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy (HAART) effectively suppresses replication of HIV and is accompanied by an increase in CD4+ T lymphocytes. Whether the increase in CD4+ T lymphocytes in the blood is a reflection of a reconstitution of the immune functions is unknown. We investigated the recovery of the humoral immune response during HAART after immunization with T-cell-dependent influenza vaccine. METHODS: Forty-one men and three women infected with HIV and treated with HAART, and 15 healthy hospital staff members were immunized with trivalent influenza subunit vaccine. Antibody titres were determined by haemagglutination inhibiting assay in sera obtained before and 30 days after immunization. Lymphocyte subsets were determined in blood samples taken at the time of vaccination. RESULTS: In all HIV-infected individuals, treatment with HAART caused a median reduction of 2.3 log10 in HIV-1 load. The median increase of CD4+ T lymphocytes after initiation of HAART was 170 x 10(6)/l. The antibody response to influenza antigens was proportional to the number of memory CD4+ T lymphocytes in the blood at the time of vaccination. When a group of patients and healthy controls with approximately similar CD4+ T-lymphocyte counts were considered, the antibody titres after vaccination for influenza strain H1N1 and influenza B did not differ between patients and controls (P=0.12). Vaccination of patients with a CD4+ T-lymphocyte count of < 200 x 10(6)/l (mean 85 x 10(6)/l) before the start of HAART and with a mean of 282 x 10(6)/l CD4+ T lymphocytes at the time of vaccination as a result of HAART, demonstrated a substantial antibody response whereas patients with a CD4+ T lymphocyte count of < 200 x 10(6)/l (mean 56 x 10(6)/l) not treated with HAART (historical controls), and vaccinated with a similar influenza vaccine, failed to induce an antibody response. CONCLUSION: The present findings demonstrate a recovery of the humoral immune response to influenza antigens in HIV-infected individuals treated with HAART. This indicates that functional improvement of antigen specific CD4+ T helper cell reponses occurs.

Adult↗
PubMed1998

Fluconazole prophylaxis in patients with head and neck tumours undergoing radiation and radiochemotherapy.

The aim of the present study was to investigate the incidence of Candida stomatitis and resulting interruptions in radiation and radiochemotherapy in 50 patients suffering from squamous cell carcinomas of the head and neck region receiving fluconazole (100 mg d-1) in comparison with a historical control group (n = 50) without specific prophylaxis. Twenty of the control patients (40%) demonstrated Candida stomatitis, with seven of them (14%) requiring interruptions in anticancer therapy. In contrast, none of the patients with fluconazole had evidence of Candida stomatitis (P = 0.0000051) and subsequent interruption of anti-cancer therapy (P = 0.0061). Laboratory monitoring for the presence of Candida species was performed in 30 patients before and after therapy with fluconazole. Candida albicans was identified less frequently after therapy when compared with the pretreatment status. However, C. glabrata and C. krusei were isolated in some of the patients, probably because of drug resistance of these subspecies. The results demonstrate the clinical usefulness of prophylactic fluconazole applications in patients suffering from head and neck tumours with the aim of reducing Candida stomatitis and the resulting interruptions in radiation and radiochemotherapy.

Adult↗
PubMed1997

Phenotypic and functional separation of memory and effector human CD8+ T cells.

Human CD8+ memory- and effector-type T cells are poorly defined. We show here that, next to a naive compartment, two discrete primed subpopulations can be found within the circulating human CD8+ T cell subset. First, CD45RA-CD45R0(+) cells are reminiscent of memory-type T cells in that they express elevated levels of CD95 (Fas) and the integrin family members CD11a, CD18, CD29, CD49d, and CD49e, compared to naive CD8+ T cells, and are able to secrete not only interleukin (IL) 2 but also interferon gamma, tumor necrosis factor alpha, and IL-4. This subset does not exert cytolytic activity without prior in vitro stimulation but does contain virus-specific cytotoxic T lymphocyte (CTL) precursors. A second primed population is characterized by CD45RA expression with concomitant absence of expression of the costimulatory molecules CD27 and CD28. The CD8+CD45RA+CD27- population contains T cells expressing high levels of CD11a, CD11b, CD18, and CD49d, whereas CD62L (L-selectin) is not expressed. These T cells do not secrete IL-2 or -4 but can produce IFN-gamma and TNF-alpha. In accordance with this finding, cells contained within this subpopulation depend for proliferation on exogenous growth factors such as IL-2 and -15. Interestingly, CD8+CD45RA+CD27- cells parallel effector CTLs, as they abundantly express Fas-ligand mRNA, contain perforin and granzyme B, and have high cytolytic activity without in vitro prestimulation. Based on both phenotypic and functional properties, we conclude that memory- and effector-type T cells can be separated as distinct entities within the human CD8+ T cell subset.

Adult↗
PubMed1997

Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins.

Leukocyte adhesion deficiency (LAD) is characterized by the inability of leukocytes, in particular neutrophilic granulocytes, to emigrate from the bloodstream towards sites of inflammation. Infectious foci are nonpurulent and may eventually become necrotic because of abnormal wound healing. LAD-1 is characterized by the absence of the beta2 integrins (CD11/CD18) on leukocytes. When expression is completely absent, patients often die within the first year. However, low levels of beta2 expression may result in a milder clinical picture of recurrent infection, which offers a better prognosis. In this paper, we describe the in vivo and in vitro findings on a patient with clinical features of a mild LAD-1 disorder, i.e., suffering from bacterial infections without apparent pus formation in the presence of a striking granulocytosis, showing no delayed-type hypersensitivity reaction upon skin testing, no specific antibody generation, but normal in vitro T cell proliferation responses after immunization. Expression levels of CD11/CD18 proteins were completely normal, but leukocyte activation did not result in CD11/ CD18 activation and high-avidity ligand-binding. In vitro chemotaxis and endothelial transmigration of the neutrophils as well as leukocyte aggregation responses were almost absent. On the other hand, beta1 and beta3 integrin-mediated adhesion functions were completely normal. During follow-up, a bleeding tendency related to decreased beta3 activation became clinically apparent, different from previously described cellular adhesion molecule variants. Therefore, this is the first well-documented case of a clinical combined immunodeficiency syndrome that results from nonfunctional CD11/CD18 molecules, and thus designated LAD-1/ variant.

Antigens, CD↗
PubMed1997

[Influence of reduction of radiation dosage on the incidence of radiation-induced pneumonitis, pulmonary fibrosis and pericarditis after mediastinal irradiation in the treatment of lymphogranulomatosis].

BACKGROUND: The amount of radiation dose applied in the treatment of Hodgkin's disease is associated with the incidence of complications including radiation-induced pneumonitis, lung fibrosis and pericarditis. Therefore, from the beginning of 1986, we have started to apply a radiation therapy approach with reduced doses in order to minimize complications while maintaining effective treatment. PATIENTS AND METHOD: From 1983 through 1992 141 patients suffering from Hodgkin's disease were included in the present study. All of them were treated by radiation of mediastinum. In 126 cases polychemotherapy was applied before radiation. From 1986 we used a reduced radiation dose in cases that were treated by radiation alone (affected nodal regions with 40 Gy instead of 45 Gy and unaffected nodal regions with 36 Gy instead of 40 Gy) as well as after application of chemotherapy (affected nodal regions 36 Gy instead of 40 Gy and unaffected nodal regions with 30 Gy instead of 36 Gy). Ninety-five patients were treated according to the new therapy protocol. Forty-six patients had been treated with the higher dosages and served as the historical control group. Radiation therapy included Co-60, 15-MV and 9-MV photons, and 15-MeV and 9-MeV electrons. Serial thoracic X-ray controls were performed. CT scans, echocardiographic and electrocardiographic investigations were added in selected cases. RESULTS: During the period from 1983 to 1992, we diagnosed radiation-induced pneumonitis in 31% of the patients who underwent radiation therapy of the mediastinum. In addition, 16% demonstrated lung fibrosis and 10% pericarditis. After implementation of the reduced radiation dosages, the incidence of pneumonitis decreased from 35% to 24% (nearly significant in the 5% range), lung fibrosis from 24% to 12% (p < 0.05) and pericarditis from 26% to 2% (p < 0.01). The efficacy of treatment remained unaffected by the new therapy approach as has been demonstrated for cumulative survival data and recurrence-free intervals. CONCLUSIONS: Reduction of radiation dose in patients with Hodgkin's disease who undergo mediastinal radiation leads to a decrease in the incidence of radiation-induced complications (pneumonitis, lung fibrosis, pericarditis) whereas treatment efficacy remains unchanged.

Evaluation Studies as Topic↗
PubMed1997

[Use of fluconazole as antimycotic prophylaxis in radiotherapy of patients with head and neck tumors].

The aim of the present study was to investigate the incidence of Candida stomatitis and resulting interruptions in radiation therapy in 50 patients suffering from squamous cell carcinomas of head and neck region receiving fluconazole (100 mg/d) in comparison to a historical control group without specific prophylaxis. 20 of the control patients (40%) demonstrated Candida stomatitis with 7 of them (14%) requiring interruptions of radiation therapy. In contrast, none of the patients with fluconazole had evidence of Candida stomatitis and subsequent interruption of anticancer therapy. Laboratory monitoring for the presence of Candida species was performed in 15 other patients before and after therapy with fluconazole. Candida albicans was identified less frequently after therapy when compared to the pretreatment status. However, C. glabrata and C. krusei were isolated in some of the patients probably due to decreased drug susceptibility of these species. The results demonstrate the clinical usefulness of prophylactic fluconazole applications in patients suffering from head and neck tumors with the aim to reduce Candida stomatitis and resulting interruptions in radiation therapy.

Antifungal Agents↗
PubMed1996

Heterogeneity of the human CD4+ T-cell population: two distinct CD4+ T-cell subsets characterized by coexpression of CD45RA and CD45RO isoforms.

Activation of unprimed CD4+CD45RA+/RO- T cells results in a gradual loss of CD45RA expression concomitant with the acquisition of CD45RO. It has been suggested that this conversion occurs in vivo through a CD45RAbright/RObright stage. Next to this small CD45RAbright/RObright subset (Dbright), a larger subpopulation that expresses both RA and RO isoforms at low levels (Ddull) can be found in the circulating CD4+ T-cell population of all donors. The properties of the latter population are largely undefined. Here, we show that Ddull cells have an intermediate phenotype for antigens such as CD31, CD621, CD58, and CD95 that are differentially expressed on unprimed versus primed T cells. In addition, they are able to provide help for B-cell differentiation and contain substantial numbers of tetanus toxoid (TT)-specific precursor cells. Remarkably, both intracellular cytokine staining and analysis of T-cell clones showed that Ddull cells and CD45RO+ T cells produce comparable high amounts of both interferon (IFN)-gamma and interleukin (IL)-4, which clearly distinguishes them from CD45RA+ and Dbright T cells. Finally, prolonged culture of sorted Ddull cells in a mixture of IL-2, IL-6, and tumor necrosis factor (TNF)-alpha showed that about half of the population retained the Ddull phenotype. Part of the cells upregulated the CD45RA isoform, whereas only a minority switched to single CD45RO expression. Our findings indicate that the Ddull population contains primed T cells, some of which may reacquire an "unprimed" phenotype in the absence of antigenic stimulation.

CD4 Antigens↗
PubMed1996

CD30 expression does not discriminate between human Th1- and Th2-type T cells.

CD30 is a member of the TNF receptor superfamily that is commonly used as a marker for Hodgkin and Reed-Sternberg cells in Hodgkin's disease. More recently, it has been proposed that CD30 is preferentially up-regulated on Th2-type human T cells. We analyzed regulation of CD30 expression on both peripheral blood T cells and T cell clones. In short-term culture, CD30 expression could be induced on T cells by Ags that elicit Th2-type responses (Schistosoma haematobium, adult worm Ag, and Toxocaria canis, excretory/secretory Ag) and Th0-type responses (tetanus toxoid), as well as Th1-type responses (tuberculin purified protein derivative). Moreover, simultaneous measurement of membrane phenotype and cytokine production showed that CD30-expressing cells can produce IFN-gamma. Finally, within panels of randomly generated as well as Ag-specific T cell clones, CD30 expression was found on Th0-, Th2-, and Th1-type clones. We conclude that induction of CD30 on activated T cells is not related to differentiation in Th0-, Th1-, or Th2-type cells.

Cell Differentiation↗
PubMed1996

Conformational changes in CD45 upon monoclonal antibody crosslinking.

The CD45 protein tyrosine phosphatase is expressed in different isoforms that result from alternative splicing of three exons (A, B, and C) encoding regions near the N-terminus of the extracellular part of the molecule. We describe here a novel epitope on the N-terminal end of CD45 that is recognized by the MAb BL-TSub/2. Crossblocking studies showed that BL-TSub/2 and UCHL1 (CD45RO) binding sites are partially overlapping. However, in marked contrast to the CD45RO epitope, protease treatment of cells strongly diminished BL-TSub/2 binding. Similar to the UCHL1 epitope, the BL-TSub/2 binding site involves carbohydrate moieties, since neuraminidase treatment abrogated the reactivity of the MAb. Markedly, preincubation of cells with both CD45 common and CD45RA MAb induced a pronounced increase of BL-TSub/2 binding. This latter finding suggests that crosslinking of the CD45 molecule leads to conformational changes that could influence association of the molecule with putative ligands.

Animals↗
PubMed1995

Expression cloning and chromosomal mapping of the leukocyte activation antigen CD97, a new seven-span transmembrane molecule of the secretion receptor superfamily with an unusual extracellular domain.

CD97 is a monomeric glycoprotein of 75 to 85 kDa that is induced rapidly on the surface of most leukocytes upon activation. We herein report the isolation of a cDNA encoding human CD97 by expression cloning in COS cells. The 3-kb cDNA clone encodes a mature polypeptide chain of 722 amino acids with a predicted molecular mass of 79 kDa. Within the C-terminal part of the protein, a region with seven hydrophobic segments was identified, suggesting that CD97 is a seven-span transmembrane molecule. Sequence comparison indicates that CD97 is the first leukocyte Ag in a recently described superfamily that includes the receptors for secretin, calcitonin, and other mammalian and insect peptide hormones. Different from these receptors, CD97 has an extended extracellular region of 433 amino acids that possesses three N-terminal epidermal growth factor-like domains, two of them with a calcium-binding site, and a single Arg-Gly-Asp (RGD) motif. The existence of structural elements characteristic for extracellular matrix proteins in a seven-span transmembrane molecule makes CD97 a receptor potentially involved in both adhesion and signaling processes early after leukocyte activation. The gene encoding CD97 is localized on chromosome 19 (19p13.12-13.2).

Amino Acid Sequence↗
PubMed1994

Characterization of an early activation-dependent antigen on lymphocytes defined by the monoclonal antibody BL-Ac(F2).

A novel activation-dependent lymphocyte cell-surface antigen which is recognized by a MoAb, BL-Ac(F2), is described. Although not found on resting lymphocytes the antigen is induced rapidly within 2-4 h following stimulation of the cells using mitogens or antibodies against the T-cell CD3 antigen and sIgM on B cells, respectively. Immunoprecipitation and Western Blotting indicated that the MoAb recognizes a molecule in a range of 78-85 kDa. Beyond its activation-dependent expression on lymphocytes the antigen was detected also on myelo-monocytic cells. Expression kinetics and cellular distribution of this molecule suggest that it is distinct from previously described activation-dependent cell-surface antigens such as CD69, CD25 and 4F2.

Animals↗