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Biomedical subjects

G Penne

Publications and source records attributed to G Penne.

13 recordsLinked to original sources
PubMed1998

Altered receptor expression and decreased sensitivity of T-cells to the stimulatory cytokines IL-2, IL-7 and IL-12 in HIV infection.

A dysregulated production of regulatory cytokines has been proposed as a determinant in the progression of HIV infection. The sensitivity of T-cells to these cytokines has, however, not fully been investigated. Therefore, the responses of PBMC and T-cell subsets to the stimulatory cytokines IL-2, IL-7 and IL-12 in HIV-infected patients and HIV-negative controls were compared by examining their effect on the production of secondary cytokines (IFNgamma, IL-4 and IL-10), by simultaneous determination of T-cell activation and apoptosis and by measuring cytokine receptor expression. Production of IFNgamma was decreased in PBMC from the patients after stimulation with several combinations of stimulatory cytokines. IL-10 was only induced upon stimulation with IL-2 and IL-12 and tended to be produced more in patients. Expression of the different cytokine receptor chains showed complex alterations in HIV+ patients as compared to controls. The most pronounced changes were decreased expression of both IL-2Ralpha and IL-7Ralpha chain on CD8+ T-cells and an increase of IL-12Rbeta on both T-cell subsets from the patients. Evaluation of CD25 upregulation and blast formation revealed a deficient response to all three stimulatory cytokines in CD8+ but not in CD4+ T-cells from patients as compared to controls. Both CD4+ and CD8+ T-cells from the patients were less sensitive to the anti-apoptotic effect of IL-7 whereas only CD8+ T-cells were less sensitive to the anti-apoptotic effect of IL-2. The present data show that CD8+ T-cells, and to a lesser extent CD4+ T-cells, become less sensitive to IL-2, IL-7 and IL-12 during HIV infection. The decreased capacity of T-cells to respond to these cytokines could contribute to the HIV-related immune dysfunction.

Adult↗
PubMed1998

Superantigen activation of CD4+ and CD8+T cells from HIV-infected subjects: role of costimulatory molecules and antigen-presenting cells (APC)

T cell receptor (TCR) triggering via superantigens induces decreased proliferative responses and increased apoptosis in T cells from HIV-infected patients compared with controls. Our aim was to delineate the role of intrinsic T cell defects, of APC dysfunction and of cytokines and costimulatory signal dysregulation in the deficient responses of CD4+ and CD8+ T cells from HIV+ subjects to the superantigen Staphylococcus enterotoxin A (SEA). Proliferation and IL-2R alpha up-regulation on SEA-stimulated CD4+ and CD8+ T cells in whole blood were reduced in HIV+ subjects with CD4 counts < 500, compared with controls. Neither addition of IL-2, IL-12 or phorbol myristate acetate (PMA) nor neutralization of endogenous IL-10, tumour necrosis factor-alpha (TNF-alpha), TNF-beta or transforming growth factor-beta (TGF-beta) could restore the decreased activation by SEA. Possible intrinsic T cell defects were studied by presenting SEA on HLA-DR-transfected Chinese hamster ovary (CHO) cells, co-expressing LFA3 and/or CD80, to purified T cells. In this system CD8+ T cells from most HIV+ patients were hyporesponsive with regard to IL-2 production, IL-2R alpha up-regulation and proliferation, whereas clearly reduced responses were only shown in CD4+ T cells from AIDS patients. Similarly, apoptosis was increased in CD8+ T cells from all patients, but only in CD4+ T cells from AIDS patients. During HIV infection, the responses to TCR triggering through SEA are deficient in both T cell subsets. The intrinsic defect appears earlier during disease progression in purified CD8+ T than in CD4+ T cells, it occurs in conjunction with both CD2 and CD28 costimulation, and it is correlated with increased levels of apoptosis.

Animals↗
PubMed1997

CD8+ cells and not CD4+ T cells are hyporesponsive to CD28- and CD40L-mediated activation in HIV-infected subjects.

T cell dysfunction in HIV-infected subjects could be the consequence of altered sensitivity of CD4+ or CD8+ T cells to various costimulatory signals. Therefore, we studied proliferation and cytokine production in highly purified CD8+ and CD4+ T cells from HIV-infected and HIV- subjects, induced by co-activation via cell-bound CD80, CD86 and CD40 or by allo-activation. Regardless of the nature of the first and the costimulatory signal, CD8+ T cells from patients proliferated consistently less than controls, while responses from CD4+ T cells were similar in patients and controls. This phenomenon was observed after ligation of CD28 combined with anti-CD3 or phorbol myristate acetate (PMA), but also after allogeneic stimulation and after activation by CD40 and anti-CD3. Anti-CD3 combined with CD80 or CD86 induced a mixed Th1/Th2-type cytokine profile in both CD4+ and CD8+ T cells from controls, whereas anti-CD3 plus CD40 induced only low levels of Th2-type cytokines and no interferon-gamma (IFN-gamma) in CD4+ T cells. Compared with controls, CD4+ T cells from patients produced slightly lower levels of IL-10 but equal amounts of IFN-gamma, IL-4 and IL-5, while CD8+ T cells from patients produced less of all cytokines tested. In conclusion, responses of purified CD4+ T cells from HIV+ subjects to various costimulatory pathways are relatively intact, whereas CD8+ T cells are hyporesponsive at the level of proliferation and cytokine production. A generalized intrinsic CD8+ T cell failure might contribute to viral and neoplastic complications of HIV infection.

Adult↗
PubMed1995

Phenotypic and functional parameters of cellular immunity in a chimpanzee with a naturally acquired simian immunodeficiency virus infection.

The cellular immunologic and virologic status of a chimpanzee, naturally infected with a human immunodeficiency virus type 1 (HIV-1)-like lentivirus (SIVcpz-ant), was compared longitudinally with those of 3 HIV-1-infected and 5 uninfected chimpanzees for a period of 49 months. Evidence of immune deficiency was not observed in the HIV-1-infected chimpanzees, nor could virus be isolated from plasma. Virus could be isolated from plasma of the SIVcpz-ant-infected chimpanzee, but clinical signs of immune deficiency were never observed. Absolute CD4+ cell counts remained relatively stable, but NK cells fluctuated significantly over time and tended to correlate inversely with the virus titer in peripheral blood. Although only CD8+ T cells were directly demonstrated to exert a suppressive effect on viral replication in vitro, the observed fluctuation of NK cells suggests that these cells may also be involved in the interaction with lentivirus infection in this species.

Animals↗
PubMed1994

The interleukin-2 receptor subunit expression and function on peripheral blood lymphocytes from HIV-infected and control persons.

The expression of interleukin-2 receptor (IL2R) was studied on circulating lymphocytes from HIV-infected (HIV+) and control subjects, using chain-specific monoclonal antibodies and indirect immunofluorescence flow cytometry. The IL2R alpha chain expression was decreased on CD4 and CD8 T cells from HIV+ persons compared to controls. Conversely, beta chain expression was enhanced on both T cell subsets from the patients. IL2R-subunit levels were similar on natural killer cells from patients and controls. To evaluate the function of IL2R, we investigated to what extent IL2 could induce CD69, an early activation marker of lymphocytes. A dose-dependent increase of CD69 expression was observed on T and NK cells from all subjects. The upregulation of CD69 was similar on CD4 T and NK cells from patients and controls, but was more pronounced on CD8 T cells from HIV+ compared to HIV- subjects. Based on inhibition studies, both the alpha and the beta chain contributed to the IL-2-induced CD69 expression on CD4 T cells, pointing to involvement of the high-affinity receptor. The early activation of CD8 T cells and NK cells was mainly dependent on the intermediate-affinity receptor. We conclude that significant changes in IL2R alpha and beta chain expression on circulating T cells occur after HIV infection, but that early activation through IL2 is preserved or enhanced, even in advanced stages.

Adult↗
PubMed1994

Deficient T-cell responses in non-responders to hepatitis B vaccination: absence of TH1 cytokine production.

The inability to mount a protective level (> or = 10 IU/l) of hepatitis B surface antigen (HBsAg)-specific antibodies after vaccination is presumably the consequence of a defect in the cellular immune regulation. We compared the in vitro immune responses of peripheral blood mononuclear cells (PBMC) from high, intermediate and non-responders, after stimulation with recombinant HBsAg. The absence of a proliferative response in non-responders was not reversed by removal of CD8+ T cells, indicating that HBsAg-specific CD8+ T-cell-induced suppression was not the underlying cause of non-responsiveness. Non-responders did not produce cytokines after HBsAg stimulation. High responders displayed a typical Th1-like profile since their PBMC produced interleukin-2 (IL-2) and gamma-interferon (IFN gamma) and no detectable IL-4 or IL-5 upon stimulation with HBsAg.

Adult↗
PubMed1993

Immunological parameters during treatment with ditiocarb (Imuthiol).

OBJECTIVES: To examine the effect of ditiocarb (DTC) treatment on immunological parameters of HIV infection. Immunophenotyping included CD4+ T-cell counting and the analysis of activation markers on CD8+ T cells. Anti-CD3-induced proliferation and anti-CD3-mediated cytotoxicity were monitored as indexes of T-cell function. In addition to the clinical evolution, HIV antigen and anti-p24 levels were monitored during treatment. DESIGN: In this double-blind, placebo-controlled study, 50 HIV-seropositive patients belonging to all clinical disease stages were randomized to treatment with DTC or placebo and followed for 4 months. METHODS: Immunophenotyping on whole blood was performed by flow cytometry, using combinations of anti-CD8 with anti-CD4, anti-HLA-DR, anti-CD38, anti-CD45RO and anti-CD57. Patient lymphocytes were freshly assayed for cytolytic capacity against OKT3-coated targets. T-cell proliferation was measured after 3 days of OKT3-stimulation. RESULTS: No effect was observed on CD4 and CD8+ T-cell counts or on CD8+ T-cell activation markers, except for a selective increase in HLA-DR expressing CD8 cells in the DTC-treated group. Decline in anti-CD3-induced T-cell proliferation and rise in anti-CD3-mediated T-cell cytotoxicity were observed in the DTC and placebo groups. No effect on HIV antigen and anti-p24 antibody titres was observed. The incidence of clinical complications was similar in each group. CONCLUSION: No beneficial immunomodulatory effect of DTC was demonstrated.

Adult↗
PubMed1993

Decreased expression of the memory marker CD26 on both CD4+ and CD8+ T lymphocytes of HIV-infected subjects.

Using a novel anti-CD26 (or anti-dipeptidyl peptidase IV) monoclonal antibody, we showed that the absolute numbers and the proportions of T4 and T8 cells expressing CD26 were significantly lower in HIV-infected persons than in controls. The absolute number of CD26+ T4 cells decreased according to disease progression, whereas the number of CD26+ T8 cells was low throughout all clinical stages. These trends were similar in CD26 dim and bright positive T-cell subsets. In both controls and HIV-positive subjects, the CD26 bright positive T cells were restricted to the CD45RO+ subset and preferentially co-expressed CD25 but largely lacked HLA-DR and CD38. Recall antigen-responsive cells from seronegative individuals were shown to co-express CD26 and CD45RO. The deficient CD26 expression on T8 cells from HIV-infected subjects could be normally upregulated after in vitro stimulation. In contrast to decreased T-cell-bound CD26, the enzymatic activity of plasma CD26/dipeptidyl peptidase IV was unchanged in HIV-infected patients compared with controls. We conclude that HIV infection leads to a deficient in vivo co-expression of CD26 bright and CD45RO on T cells. We speculate that this deficiency might play a part in the decrease of immunological memory during HIV infection.

ADP-ribosyl Cyclase↗
PubMed1991

Subset markers of CD8(+) cells and their relation to enhanced cytotoxic T-cell activity during human immunodeficiency virus infection.

Using fresh whole blood or isolated lymphocytes, the activity of in vivo generated cytotoxic T-lymphocytes (CTL) was measured as the OKT3-specific lysis of HL-60 targets, in a cross-sectional study of 53 HIV (+) patients. CTL activity in the entire HIV(+) group was two to three times higher than in HIV(-) controls, with WHO stage 3 (=pre-AIDS) patients showing the highest cytolytic function. The whole-blood CTL assay was validated and its practical and theoretical advantages are discussed. Within the CD8(+) cells, the number and proportion of the CD45RO(+) "memory" subset were significantly increased in HIV(+) subjects. The HLA-DR(+) subset rose most spectacularly in the asymptomatic stage of the infection, while the CD38(+) subset was the only one still significantly rising between the pre-AIDS and the AIDS stage. CTL activity was most closely correlated with T8 cells expressing the CD38 marker. In the context of CTL, CD38 thus seems to reflect activation rather than immaturity. Lymphocytes from HIV(+) subjects with a high OKT3-specific lytic capacity also destroyed normal lymphoblasts to a significant extent, pointing to their possible involvement in an autodestructive process. Our data thus suggest the importance of T8 cytolytic function and/or T8 subtyping in the immunopathogenesis and the prognosis of HIV infection.

ADP-ribosyl Cyclase↗