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Biomedical subjects

P Druet

Publications and source records attributed to P Druet.

At least 55 records · Page 3Linked to original sources
PubMed1996

Th2 and Th1 autoreactive anti-class II cell lines in the rat suppress or induce autoimmunity.

It is now currently thought that Th1 autoreactive cells may induce organ specific autoimmune disease and in these situations Th2 cells are considered as regulatory cells. However, in other situations Th2 cells may be pathogenic. Thus, some chemicals (HgCl2, gold salts or D-penicillamine) may induce Th2-mediated systemic autoimmune disorders in susceptible Brown-Norway (BN) rats. In contrast, HgCl2 induces non antigen specific immunosuppression in Lewis (LEW) rats and protects this strain against organ-specific autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE). Anti-self MHC class II T cells have been detected in both susceptible and resistant strains upon exposure with these chemicals. Autoreactive T cell lines that recognize self MHC class II molecules have been derived from gold salt-injected BN rats (BNAu lines) and from HgCl2-injected LEW rats (LEWHg lines). BNAu T cell lines produced IL-4 and transferred antibody-mediated autoimmunity in BN rats deprived of CD8+ cells. In contrast, HgCl2 protects susceptible rats from Th1-mediated autoimmunity, (autoimmune uveoretinitis). LEWHg lines produced IL-2, IFN-gamma and TGF-beta and were able to protect LEW rats against cell-mediated autoimmunity (EAE) and (LEW x BN)F1 hybrids from antibody-mediated, HgCl2-induced autoimmunity. Several points will be discussed: the specificity of these autoreactive T cells, the mechanisms by which chemicals may induce these cells and the mechanisms by which the immune system maintains or reestablishes self tolerance in rats exposed to these agents.

Animals↗
PubMed1995

Self-reactive anti-class II T helper type 2 cell lines derived from gold salt-injected rats trigger B cell polycolonal activation and transfer autoimmunity in CD8-depleted normal syngeneic recipients.

Brown Norway (BN) rats given gold salts develop an autoimmune syndrome with an immune complex-type glomerulonephritis in the context of a polyclonal B cell activation that was suspected to be due to the emergence of anti-self major histocompatibility complex (MHC) class II T cells. In the present study, six anti-self MHC class II T cell lines have been derived from six gold salt-treated rats by repeated stimulations with normal syngeneic MHC class II-bearing cells. The T cell lines proliferated in the presence of self MHC class II-positive B cell-enriched or B cell-depleted cells and the proliferation was inhibited by preincubating stimulator cells with an anti-IA monoclonal antibody. The T cell lines produced interleukin (IL)-4 only or IL-4 and some interferon (IFN)-gamma and could, therefore, be considered as T helper type 2 (Th2) and Th0 cells, respectively. They triggered normal syngeneic B cells to produce in vitro IgE, anti-DNA, anti-laminin and anti-2,4-6-trinitrophenol antibodies through, at least in part, cognate interactions. More interestingly, these lines when transferred into normal BN rats induced an autoimmune syndrome similar to or even more severe than the one observed in the active gold model, provided the recipients were CD8 depleted. These manifestations included a dramatic increase in serum IgE concentration and the production of anti-DNA and anti-laminin antibodies. In addition, all recipients displayed an autoimmune glomerulonephritis due to anti-laminin antibodies, granular IgG deposits in the interstitium, in the vessel walls and along the tubular basement membranes and a severe tubulointerstitial nephritis with marked mononuclear cell infiltration. An anti-ovalbumin T cell line that produced IL-4 and low amounts of IFN-gamma was used as a control and did not induce autoimmunity. These results demonstrate for the first time the ability of autoreactive Th2 as well as Th0 cell lines to induce antibody-mediated autoimmunity. They also show that CD8+ cells play a crucial role in the control of such autoreactive cells. Finally, this work suggests that Th2 cells could initiate cell-mediated reactions either directly or indirectly.

Animals↗
PubMed1995

Mercuric chloride-induced programmed cell death of a murine T cell hybridoma. I. Effect of the proto-oncogene Bcl-2.

Mercuric chloride (HgCl2) as well as several drugs can induce T cell activation leading to systemic immune-mediated diseases in genetically susceptible individuals or rodents. T cell hybridomas represent a well-characterized model system for in vivo mechanisms of various stimuli-induced cell death. The cellular response to HgCl2 was examined using various T cell lines and particularly the murine T cell hybridoma 2B4.11. Exposure to HgCl2 induced both necrosis and apoptosis in a dose- and time-dependent way as demonstrated by DNA fragmentation analysis, flow cytometry of the whole cells and of isolated nuclei, and morphological examination. HgCl2-induced cell death was partly inhibited by cycloheximide. The expression of human Bcl-2 in 2B4.11 cells after transfection significantly prevented HgCl2-induced cell death but did not affect the susceptibility to apoptosis induced by an anti-CD3 epsilon mAb. Subcytotoxic doses of HgCl2 enhanced metabolic activity of Bcl-2 transfectants in contrast with mock-transfected cell line. Thus, we conclude that apoptosis is part of the cell death process induced by HgCl2 and that the ability of Bcl-2 to prevent the death of one particular cell line is stimulus-dependent suggesting the existence of different pathways leading to cell death.

Animals↗
PubMed1995

Mercuric chloride-induced programmed cell death of a murine T cell hybridoma. II. Opposite effect of interleukin-2 and interleukin-4.

In susceptible animals evidence is accumulating for a primary role for Th2 cells in the course of HgCl2-induced autoimmunity, and for a contribution of Th1 cells in the self-regulated phase of this disease. We have reported that incubation of 2B4.11 T cell hybridoma with HgCl2 induced programmed cell death. This paper shows that recombinant IL-2 significantly diminished HgCl2-induced 2B4.11 cell death. Although no effect was observed upon incubation with exogenous IL-4, we observed a significant protection by adding an anti-IL-4 monoclonal antibody to the culture. Accordingly, by RT-PCR we found the presence of IL-2 receptor-encoding mRNA, and by cytofluorometry, the expression of the protein was detected only after exposure to HgCl2. Moreover, upon HgCl2 treatment, 2B4.11 cells were induced to produce IL-4. Altogether these findings showed that cytokine environment, IL-2, IL-4 otherwise defining the Th1/Th2 dichotomy, in conjunction with a chemical may differentially influence the fate of cell populations, death or survival.

Animals↗
PubMed1995

Genetic study of gold-salt-induced immune disorders in the rat.

BACKGROUND: Rheumatoid arthritis patients treated with gold salts occasionally develop a glomerulonephritis and an increase in serum IgE concentration. Brown-Norway (BN) rats injected with aurothiopropanolsulphonate (ATPS) exhibit an increase in serum IgE concentration, produce antilaminin antibodies (Abs) and develop glomerular linear immunoglobulin (Ig) deposits, occasionally a membranous glomerulopathy and vascular granular Ig deposits. Lewis (LEW) rats are resistant. METHODS: The genetic requirements governing the appearance of these manifestations were studied in congenic rats, and in F1 hybrids injected with ATPS. RESULTS: Non-MHC-linked genes from the BN strain were absolutely required for all the traits to be observed. The RT1n (BN) or RT1(1) (LEW) haplotypes at the MHC were permissive for all the manifestations to appear and two RT1(1) alleles were associated with the highest response. However, granular Ig deposits were only observed in RT1n rats. The high serum IgE concentration and the antilaminin Ab level were associated with the presence of glomerular Ig deposits but were not associated with the presence of vascular Ig deposits. CONCLUSIONS: This study shows that susceptibility to ATPS was mainly dependent upon non-MHC-linked BN genes and that the involvement of MHC-linked genes differed depending upon the character considered. There is an epistatic effect between the various genes.

Analysis of Variance↗
PubMed1995

Mechanism of allergic cross-reactions. V. High incidence of unanticipated cross-stimulation by natural allergens of rat basophilic leukemia cells sensitized with monoclonal IgE antibodies.

The incidence of cross-stimulations by natural allergens was investigated using RBL-2H3 cells sensitized with five different mouse monoclonal anti-DNP IgEs and four mercury-induced rat monoclonal IgEs. Cells sensitized with 3 of the 5 monoclonal anti-DNP IgEs (clones SPE-7, SRT-1, LB4) responded by serotonin release upon stimulation by natural allergens such as Dermatophagoides pteronyssinus, horse dander and mugwort extracts. Serotonin release could be inhibited by monovalent DNP-lysine, indicating the involvement of DNP-binding sites of IgEs. Two of the clones (LO-DNP-30 and LA2) were negative on all tests with allergens. All but one (Hg32) of the mercury-induced rat IgE monoclonal antibodies tested positive with DNP-BSA, and with at least one of the six allergen extracts. IgE clone Hg12 mediated serotonin release with 5 of the 6 allergens tested.

Allergens↗
PubMed1995

Mercuric chloride, a chemical responsible for T helper cell (Th)2-mediated autoimmunity in brown Norway rats, directly triggers T cells to produce interleukin-4.

Mercurials may induce immune manifestations in susceptible individuals. Mercuric chloride (HgCl2) induced autoimmunity in the Brown Norway (BN) strain but an immuno-suppression in the Lewis strain with, however, autoreactive anti-class II T cells present in both strains. In the present study we looked at modifications of cytokine production by PCR and cytofluorometric analyses in normal BN and Lewis rat splenocytes, cultured with or without HgCl2. Unfractionated BN rat splenocytes and purified T cells exposed to HgCl2 expressed high levels of IL-4 mRNA. Increase in class II and CD23 molecule expression on B cells was partly inhibited by anti-IL-4 mAb showing that IL-4 was produced. By contrast, no overexpression of IL-4 mRNA could be seen in Lewis rats. Although an increase in class II molecule expression was observed suggesting that other T helper cell 2 cytokines were produced, there was also a concomitant decrease in CD23 molecule expression that was abrogated after addition of an anti-IFN-gamma mAb to the culture. IFN-gamma mRNA production was induced in unfractionated spleen cells and T cells from both strains after HgCl2 exposure. Altogether these findings demonstrate that HgCl2 has very early direct effects on cytokine production and that these effects differ depending on the strain. The early effect on IL-4 production observed on BN rat spleen cells and T cells may explain that the autoreactive anti-class II T cells that are found in HgCl2-injected BN rats have a Th2 phenotype.

Animals↗
PubMed1995

Hemophagocytic histiocytosis (HH) in renal transplant recipients under ciclosporin therapy: report of the first two cases.

Hematophagocytic histiocytosis is a clinicopathologic syndrome associating fever, liver dysfunction, blood cytopenia and coagulation abnormalities with hematophagocytosis in bone marrow and lymphoïd organs. This syndrome is found in immunocompromized patients and is triggered by infection. We describe herein the first 2 cases of HH in renal transplant recipients treated with ciclosporin. In our 1st case, H.H. was not recognized early and the patient died. In the 2nd case, prompt diagnosis associated to an anti-infectious treatment led to recovery. The clinician must thus be aware of the possibility of such a syndrome in renal transplant patients. Identification and treatment of the underlying infection is mandatory to avoid a fatal outcome.

Adult↗
PubMed1994

[Physiological autoimmunity].

The serum of normal individuals contains antibodies directed against their own antigens (autoantigens). These autoantibodies are the main and the best known component of normal autoimmunity. They mostly involve polyreactive (one antibody recognising several antigens) IgM, but also IgG, usually having low affinity for antigens. The role of natural autoimmunity is becoming better understood. It participates in the equilibrium of the immune system, contributing to controlled production of antibodies, accelerated elimination of external antigens or aged autoantigens, and to triggering of a specific immune response. Some data suggest that the action of autoantibodies in homeostasis can extend beyond the immune system. Many pathological states, of immune nature or not, are associated with an increase or diminution of the titre of natural autoantibodies. The mechanisms and consequences of these changes remain to be elucidated.

Animals↗
PubMed1994

[Autoimmunity and toxic agents].

In certain subjects medicinal drugs or toxic agents may induce organ-specific or systemic diseases. The mechanisms of this induction vary according to the type of toxic agent involved. The modification of autoantigens by a toxic agent might be the cause of autoimmune disorders. Thus, certain drugs metabolized by enzymes are known to bind on these enzymes in a covalent manner, thereby making the enzyme immunogenic. The immune reaction thus induced could be responsible for hepatitis. If the modified autoantigen is a molecule, such as the class II molecules of the major histocompatibility complex, which plays an important role in communication between the immune system cells, the autoimmune reaction could result in polyclonal lymphocyte B activation and in a lupus-like autoimmune disease. It is also possible that a drug interferes with one of the element which control the advent of autoreactive T cells and in this way becomes responsible for autoimmune systemic manifestations.

Animals↗