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Biomedical subjects

C Desgranges

Publications and source records attributed to C Desgranges.

At least 55 records · Page 3Linked to original sources
PubMed1995

The humanized severe combined immunodeficient mouse as a model for primary human humoral response against HIV1 peptides.

Adequate animal models for the study of human immunodeficiency virus (HIV) infection are important for the analysis of specific cellular and humoral immune responses. Humanized severe combined immunodeficiency (SCID) mice can be constructed either by injecting human peripheral blood lymphocytes (hu-PBL-SCID) or by transplanting human fetal tissues--liver, thymus and bone fragments--(SCID-hu) into these mice. Such animals can produce human immunoglobulins and SCID-hu mice exhibit circulating T and B lymphocytes of human origin. These humanized mice were injected with immunogenic HIV peptides and the specific humoral response was studied. A human antibody response was obtained after de novo contact with HIV1 peptides p583 and p642, from gp41. In SCID-hu mice, a primary, then a secondary response were demonstrated to occur with 225 mg/l of human immunoglobulin (Ig)M and 300-1860 mg/l human IgG. When tested in ELISA, these human antibodies recognized specifically both the immunization peptides and the HIV1 antigens. The antibody response was obviously of a primary nature since the human cells derived from naive fetal cells. When SCID mice received intraperitoneal injections of human peripheral blood lymphocytes pre-incubated in vitro with peptide p583 for 1 week, and when the resulting hu-PBL-SCID mice were injected with the same peptide, only IgM anti-HIV antibodies were produced (372-424 mg/l) and the switch to IgG antibodies did not occur. This model may provide a means to produce human monoclonal antibodies to HIV and to check candidate HIV vaccines.

Amino Acid Sequence↗
PubMed1995

Cell surface phenotypic changes induced in H9 T cells chronically infected with HTLV type I or HIV type 1 or coinfected with the two viruses.

To investigate whether HTLV-I infection, HIV-I infection, or HIV-I infection of HTLV-I-infected cells affect the expression of cellular surface molecules, an HTLV-I-infected T cell line derived from the H9 T cell line was established (H36). H9 cells uninfected or infected with HTLV-I were then infected with HIV-1. We have compared the density of different surface markers on these three infected H9 T cell lines. These markers consist of T cell-specific antigens (CD2, CD3, CD4, and CD8), activated T cell antigens (CD25 and CD71), major histocompatibility complex (MHC) antigens (class I and II), and adhesion molecules (LFA-1 and ICAM-1). The experiments reported in this article show that chronic HTLV-I infection, HIV-1 infection, and HIV-1 infection of HTLV-I-infected T cells modulate the expression of several immunologically important cell surface antigens. The nature and the extent of T lymphoid cell phenotypic modulation depend on the infecting virus. Furthermore, HTLV-I and HIV-1 interact with each other in the phenotypic modulation of coinfected cells.

Antigens, CD↗
PubMed1995

Retroviral infection (HTLV-I) induces cytokine-regulated immunomodulation and cytotoxicity of medulloblastoma cells.

Primitive neuroectodermal tumors are thought to result from disturbed differentiation of neuroepithelial stem cells. These tumor cells retain the capacity to differentiate toward the neuron or glia phenotype under extrinsic stimuli. Previously, we have developed a model for the differentiation of a medulloblastoma cell line (Dev cells) induced by infection with the human retrovirus HTLV-I. This virus delivers signals which trigger the Dev cells to differentiate toward an astrocytic lineage. The aim of this study was to characterize the time course of viral infection, to identify the soluble factors released and to analyze their effects on Dev cells. The early phase of viral replication is followed by latent infection. Viral infection induces glial differentiation in a subpopulation of cells and results in the death of others. The inflammatory cytokines TNF alpha, IL1 alpha and IL6 were detected in medium conditioned by infected Dev cells. TNF alpha was cytotoxic and cytostatic for subpopulations of Dev cells. Furthermore, TNF alpha treatment reproduced the modulation of expression of the major histocompatibility complex antigens (MHC class I) observed in infected Dev cells. These observations support the view that HTLV-I infection, which triggers glial differentiation of medulloblastoma Dev cells, also causes the release of soluble factors capable of downregulating proliferation of dividing tumor cells and of modifying their recognition by cellular immune effectors.

Cell Differentiation↗
PubMed1995

HTLV-I-associated lymphoma presenting as mycosis fungoides in an HTLV-I non-endemic area: a viro-molecular study.

Human T-lymphotropic virus type I (HTLV-I) is endemic in the Caribbean region, south-western Japan and Africa, and is associated with tropical spastic paraparesis and adult T-cell leukaemia/lymphoma (ATLL). Cutaneous forms of ATLL are sometimes indistinguishable from other cutaneous T-cell lymphomas (CTCL). We report a woman living in a non-endemic area for HTLV-I, with no risk factors for viral infection, who developed mycosis fungoides-like ATLL. The findings underline the usefulness of molecular biological techniques in distinguishing between mycosis fungoides and ATLL. We emphasize the need to establish the HTLV-I status of patients with CTCL, even in HTLV-I non-endemic areas, not only to establish a preventive policy in these countries, but also to further our knowledge of the lymphoproliferation spectrum associated with human retroviruses.

Aged↗
PubMed1995

ATP raises [Ca2+]i via different P2-receptor subtypes in freshly isolated and cultured aortic myocytes.

In vascular smooth muscle, extracellular ATP induces an increase in intracellular [Ca2+] ([Ca2+]i). Various agonists have been used to characterize P2-purinoceptor subtypes involved in the ATP-induced [Ca2+]i rise, measured by indo 1 fluorescence, in both freshly isolated and cultured rat aortic smooth muscle cells. alpha, beta-Methylene-ATP increased [Ca2+]i via Ca2+ entry through P2x-receptor channels in freshly isolated but not in cultured cells. 2-Methylthio-ATP and ADP failed to release Ca2+ via P2y-receptor activation in freshly isolated cells, whereas such a response was obtained in cultured cells. UTP, by stimulating P2u receptors, released Ca2+ from intracellular stores in both freshly isolated and cultured cells. These results suggest that, in the course of the culture process, P2x-receptor activation-induced responses were lost, whereas P2y-receptor activation-induced [Ca2+]i rise appeared, these two phenomena being independent. Responses to P2x-receptor agonist were lost in all culture conditions, whereas functional P2y receptors appeared only in cells that were stimulated with serum to induce cell cycle progression. The phenotypic modulation of vascular myocytes was therefore associated with a change in the functional P2-purinoceptor subtypes.

Adenosine Triphosphate↗
PubMed1994

Syngeneic adoptive transfer of anti-human immunodeficiency virus (HIV-1)-primed lymphocytes from a vaccinated HIV-seronegative individual to his HIV-1-infected identical twin.

Immunotherapy by adoptive transfer of lymphocytes was attempted in identical twins, one who was virus-free and the other who was infected with human immunodeficiency virus-1 (HIV-1), at the stage of acquired immunodeficiency syndrome. The noninfected twin was vaccinated by priming with a recombinant vaccinia virus expressing the envelope glycoprotein of one of his brother's viruses and boosting with the same purified gp160 adsorbed on alum. Vaccination elicited major histocompatibility complex class I-restricted CD8+ cytolytic T lymphocytes specific for HIV-1, but no antibody response. The diseased brother, a 38-year-old homosexual who had developed repeated opportunistic infections since 1990 and had a CD4+ count reduced to practically zero, was treated by infusions of lymphocytes collected from the vaccinated brother by lymphopheresis. After a first transfer of the whole lymphocyte population, no changes were observed in the clinical status and biologic or virologic parameters. A second transfer was then applied with activation of the cells with purified envelope glycoprotein before infusion. The outcome of the treatment was an increase in total lymphocytes, in CD4+ and activated CD8+ DR+ cell counts, and in proliferative responses to HIV antigens. A marked but transient 3-log increase in cellular and plasmatic virus loads was also observed after the second adoptive transfer. These observations will be considered with attention to improve the future adoptive transfer protocols, especially in patients with severe CD4+ depletion.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Primary in vitro immunization with multimeric synthetic peptides of HIV-1 envelope glycoproteins: generation of neutralizing human monoclonal antibodies.

Peripheral blood lymphocytes from healthy HIV-1 seronegative donors were immunized in vitro with the following synthetic peptides: (i) an octameric poly-L-lysine conjugated peptide of the HIV-1MN V3 loop and (ii) a resin bound synthetic peptide aa642-665 of HIV-1 gp41. Lymphoblastoid cell lines (LCL) were obtained by immortalization with Epstein-Barr virus (EBV). We produced four LCL secreting human monoclonal antibodies (HuMoAbs) of the IgM isotype: three were directed against the V3 domain (FC10, FC81 and CF41) and one against aa642-665 (CA45C). Two of these HuMoAbs (FC81 and CA45C) reacted to viral surface antigen on HIV-1-infected cells. All the HuMoAbs inhibited 40-53% of cell fusion induced by HIV-1-infected H9 cells at 5 micrograms/ml. They also neutralized, at lower concentrations, cell-free infection with HIV-1MN, HIV-1IIIB and four primary clinical HIV-1 isolates. No enhancing activity of the HuMoAbs in the presence of complement was observed. The results presented here show the feasibility of generating neutralizing human monoclonal antibodies against HIV-1 by primary in vitro immunization with selected synthetic peptides of HIV-1 envelope glycoproteins. This approach has provided tools for further studies of synergistic neutralization assays, and generated potential immunoglobulin candidates for passive immunotherapy.

Amino Acid Sequence↗
PubMed1994

[Vasculitis and neurologic manifestations related to HTLV-1].

OBJECTIVES: The most common neurological picture associated with HTLV-1 infection is a slowly progressive spastic paraplegia often involving nerve and muscle inflammation. We report here six cases of inflammatory vasculitis of the nervous system observed among HTLV-1 infected patients. METHODS: HTLV-1 infection was diagnosed in 6 female patients, mean age 58 years (range 40-77 years) using ELISA, Western blot or polymerase chain reaction. RESULTS: All 6 patients presented a pyramidal syndrome which was associated with peripheral neuropathy in 3, myositis in 1 and a sicca syndrome in 3. Two groups of patients could be identified. In 3 patients, the neurological picture was typical of HTLV infection; pathology examination of biopsy material revealed necrozing vasculitis. In 3 other patients, the clinical course was particularly rapid, highly suggestive of anterior spinal artery infarction, associated, in 2, with a major inflammatory syndrome. CONCLUSION: These 6 cases demonstrate that vasculitis can be associated with HTLV-1 infection as has been observed in HIV-infected patients. In certain cases, clinical signs of vasculitis may be lacking while in others they may dominate the clinical manifestations.

Adult↗
PubMed1994

IL-2-dependent HTLV-I-infected T cells escape from non-specific, MHC-unrestricted cellular cytotoxicity.

The susceptibility of NK cell-mediated cytolysis was compared between 5 human HTLV-I-transformed T cell lines and 10 newly established IL-2-dependent HTLV-I-infected lines. None of the cell lines were killed after 4 hr incubation with normal PBMC. However, after 20 hr, 3 HTLV-I-transformed lines were significantly lysed. All the HTLV-I-infected lines, except 2, weakly inhibited the NK cell-mediated lysis of K562 targets. They showed a reduced ability to bind normal PBMC as compared with control NK-sensitive T cell lines. The IL-2-dependent lines remained unaffected by PBMC from HTLV-I-infected individuals, including the autologous donors. In contrast to the HTLV-I-transformed lines, they were weakly lysed or not lysed at all by LAK cells and only 5 were killed by ADCC with HTLV-I+ sera and normal PBMC. Taken together, the results show that IL-2-dependent HTLV-I-infected T cells strongly resist NK cell-mediated cytolysis at a post-binding level and suggest that such cells may escape in vivo from non-specific, MHC-unrestricted cellular cytotoxicity.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1994

Detection of HIV-specific DNA sequences in epidermal Langerhans cells infected in vitro by means of a cell-free system.

As dendritic antigen-presenting cells in skin and mucous membranes, Langerhans cells (LC) are found in areas at risk of inoculation by the human immunodeficiency virus (HIV). LC have been reported as targets for HIV-1. The aim of the present study was to investigate whether LC can be experimentally infected by HIV provided by a cell-free infection system. A cell-free suspensions was prepared from viral particles provided by chronically infected cell lines (U937 or H9 cells) by low-speed centrifugation followed by 0.45-microns filtration. LC-enriched epidermal cell (EC) suspensions with no CD3+ cells (assessed by flow cytometry and electron microscopy) and uninfected U937 cells (cell-free infection system control) were infected with two isolates (HTL VIII-B and RF). The infectiousness of the cell-free virus fluids was controlled on U937 cells where proviral DNA was amplified (gag, pol, and env gene sequences by the polymerase chain reaction, PCR) and release of virus particles into the supernatant was controlled either by measure of the reverse transcriptase (RT) activity or detection of viral RNA amplified by RT-PCR for the gag gene sequences). Proviral DNA (gag gene sequences) was found in LC-enriched epidermal cellular DNA from day 4 post-infection with isolate HTL VIII-B and from day 7 with isolate RF. Although the RT activity did not reach a significantly high level, viral RNA was found in the supernatant of LC-enriched EC cultures at the same time as proviral DNA was detected in LC.(ABSTRACT TRUNCATED AT 250 WORDS)

Base Sequence↗
PubMed1994

Identification of novel neutralization-inducing regions of the human T cell lymphotropic virus type I envelope glycoproteins with human HTLV-I-seropositive sera.

The humoral immune response in sera from 30 human T cell lymphotropic virus type I (HTLV-I)-positive individuals from Martinique in the French West Indies was studied. The subjects were subdivided into those suffering from TSP/HAM and those being asymptomatic. In general, TSP/HAM patient sera seemed to contain more virus-specific antibodies than did the sera from the asymptomatic subjects. Three of the 13 TSP/HAM sera and 1 of the 17 asymptomatic sera contained HTLV-I-specific IgM antibodies, whereas 6 and 5 sera, respectively, contained IgA antibodies. By correlating the ability of patient sera to inhibit HTLV-I-induced syncytia with their antibody reactivity in ELISA to 42 synthetic peptides, together corresponding to the entire envelope glycoprotein of HTLV-I, a number of putative neutralizing domains were identified. Eight synthetic peptides representing the regions with the highest coefficient of correlation between neutralizing titer and ELISA reactivity were employed to specifically adsorb potentially neutralizing antibodies, and were also used directly, without sera, in the syncytium-neutralizing test. By those techniques, three novel and two previously described domains that seemed to contain neutralizing epitopes were identified. Two of the novel neutralizing sites resided in the external glycoprotein (gp46) and were contained within amino acids 53-75 and 287-311, respectively, and one was located in the transmembrane glycoprotein (gp21) within amino acids 346-368. Our findings may have implications for the rational design of subunit vaccines for prevention of and/or alteration of the clinical outcome of HTLV-I-related diseases.

Adult↗
PubMed1994

Transient adult T-cell leukemia/lymphoma picture during varicella infection in an HTLV-1 carrier.

HTLV-1 (human T-lymphotropic virus type 1) is associated with tropical spastic paraparesis, adult T-cell lymphoma (ATL), and also with opportunistic infections. The risk for developing ATL in HTLV-1 healthy carriers is low, between 1 and 4%. Nothing is known about the events promoting the evolution from the healthy carrier state to symptomatic ATL. We describe the case of a 44-year-old French Caribbean man with a chronic and recurrent strongyloidiasis in which the occurrence of a hemorrhagic and necrotic varicella led to the discovery of an infection by HTLV-1 and an acute form of ATL. All hematological data were normal before the onset of varicella. ATL completely disappeared at the same time as the varicella healed. This leads us to hypothesize that acute infections such as the reactivation of varicella-zoster may act as a promoting factor for the development of ATL in healthy HTLV-1 carriers.

Adult↗