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M Breban

Publications and source records attributed to M Breban.

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

[Bone marrow transplantation in the treatment of autoimmune diseases. ISAMAIR Group].

EXPERIMENTAL BASIS AND CLINICAL OBSERVATIONS: Remission of an autoimmune disease has been observed in certain patients after bone marrow allograft from a healthy donor. Autoimmune disease in the donor can also be transmitted to an unaffected recipient. These phenomena would be hematopoietic-dependent. BONE MARROW ALLOGRAFTS: Indications for the treatment of refractory autoimmune diseases are exceptional due to the related mortality even in patients without malignant hematologic disease. A NEW THERAPEUTIC CONCEPT: Therapeutic intensification, followed with autologous peripheral stem cell grafts, a procedure with a mortality below 3% in 1997, constitutes a therapeutic alternative in these difficult indication concerning severe refractory autoimmune diseases including: sclerodermia, vasculitis, lupus, inflammatory myositis, autoimmune cyopenia.

Autoimmune Diseases↗
PubMed1999

Coordinate involvement of invasin and Yop proteins in a Yersinia pseudotuberculosis-specific class I-restricted cytotoxic T cell-mediated response.

Yersinia pseudotuberculosis is a pathogenic enteric bacteria that evades host cellular immune response and resides extracellularly in vivo. Nevertheless, an important contribution of T cells to defense against Yersinia has been previously established. In this study we demonstrate that Lewis rats infected with virulent strains of Y. pseudotuberculosis, mount a Yersinia-specific, RT1-A-restricted, CD8+ T cell-mediated, cytotoxic response. Sensitization of lymphoblast target cells for cytolysis by Yersinia-specific CTLs required their incubation with live Yersinia and was independent of endocytosis. Although fully virulent Yersinia did not invade those cells, they attached to their surface. In contrast, invasin-deficient strain failed to bind to blast targets or to sensitize them for cytolysis. Furthermore, an intact virulence plasmid was an absolute requirement for Yersinia to sensitize blast targets for cytolysis. Using a series of Y. pseudotuberculosis mutants selectively deficient in virulence plasmid-encoded proteins, we found no evidence for a specific role played by YadA, YopH, YpkA, or YopJ in the sensitization process of blast targets. In contrast, mutations suppressing YopB, YopD, or YopE expression abolished the capacity of Yersinia to sensitize blast targets. These results are consistent with a model in which extracellular Yersinia bound to lymphoblast targets via invasin translocate inside eukaryotic cytosol YopE, which is presented in a class I-restricted fashion to CD8+ cytotoxic T cells. This system could represent a more general mechanism by which bacteria harboring a host cell contact-dependent or type III secretion apparatus trigger a class I-restricted CD8+ T cell response.

Adhesins, Bacterial↗
PubMed1999

Intensified-dose (4 gm/m2) cyclophosphamide and granulocyte colony-stimulating factor administration for hematopoietic stem cell mobilization in refractory rheumatoid arthritis.

OBJECTIVE: To evaluate the feasibility, safety, and efficacy of intensified-dose cyclophosphamide (ID-CYC), followed by granulocyte colony-stimulating factor (G-CSF) administration for collection of peripheral blood hematopoietic stem cells (HSC), for patients with severe, refractory rheumatoid arthritis (RA). METHODS: Four patients with severe refractory RA were enrolled in this open study. They received a single infusion of CYC (4 gm/m2) at day 0 followed by G-CSF (5 microg/kg/day) from day 6 until the last day of leukapheresis (performed at the time of hematopoietic recovery) to harvest peripheral blood HSC. Patients were monitored for disease activity, adverse effects, and hematopoietic reconstitution following this procedure. RESULTS: For all patients, administration of ID-CYC induced an early, dramatic improvement of disease activity. Long-term followup indicates that partial disease relapse was observed for all patients. No adverse effect was directly attributable to the treatment procedure. For most patients, HSC collection was sufficient to provide a graft enriched in CD34+ cells by positive selection as well as an unselected rescue graft. CONCLUSION: Patients with severe, refractory RA can benefit from ID-CYC. This procedure, followed by G-CSF administration, appears safe and technically suitable. In addition, it allows immediate improvement of RA activity that can occasionally persist beyond 6 months.

Adult↗
PubMed1999

Concordance between abdominal scintigraphy using technetium-99m hexamethylpropylene amine oxime-labelled leucocytes and ileocolonoscopy in patients with spondyloarthropathies and without clinical evidence of inflammatory bowel disease.

OBJECTIVE: To study the concordance between abdominal scintigraphy using technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO)-labelled leucocytes (ASTLL) and ileocolonoscopy in patients with spondyloarthropathies (SpA) and without clinical evidence of inflammatory bowel disease (IBD). PATIENTS AND METHODS: Fifteen patients with SpA (European Spondylarthropathy Study Group 1991 criteria) without clinical evidence of IBD were studied prospectively with ASTLL and ileocolonoscopy. RESULTS: This cohort consisted of seven men and eight women aged 31.8+/-10.5 yr (18-47) [mean age +/- S.D. (range)] and with a disease duration of 6.0+/-4.4 yr (0.4-15). ASTLL showed abnormal uptake in four patients. Ileocolonoscopy was abnormal in five patients, showing acute inflammatory lesions in one patient with reactive arthritis, undifferentiated chronic inflammatory lesions in two cases, and features indistinguishable from those of Crohn's disease in two cases. ASTLL was negative in two cases in which ileocolonoscopy showed inflammatory lesions and was positive (terminal ileum) in one case with normal ileocolonoscopy. The concordance between the two examinations was statistically significant (kappa = 0.53; P = 0.008). CONCLUSION: ASTLL may be an interesting tool to detect subclinical gut inflammation in patients with SpA.

Abdomen↗
PubMed1999

Cytotoxic T-cell-mediated response against Yersinia pseudotuberculosis in HLA-B27 transgenic rat.

Yersinia-induced reactive arthritis is highly associated with HLA-B27, the role of which in defense against the triggering bacteria remains unclear. The aim of this study was to examine the capacity of rats transgenic for HLA-B27 to mount a cytotoxic T-lymphocyte (CTL) response against Y. pseudotuberculosis and to determine the influence of the HLA-B27 transgene on this response. Rats transgenic for HLA-B*2705 and human beta(2)-microglobulin of the 21-4L line, which do not spontaneously develop disease, and nontransgenic syngeneic Lewis (LEW) rats were infected with Y. pseudotuberculosis. Lymph node cells were restimulated in vitro, and the presence of for Y. pseudotuberculosis-specific CTLs against infected targets was determined. Infection of 21-4L rats triggered a CD8(+) T cell-mediated cytotoxic response specific for Y. pseudotuberculosis. Analysis of this response demonstrated restriction by an endogenous major histocompatibility complex molecule. However, no restriction by HLA-B27 was detected. In addition, kinetics studies revealed a weaker anti-Yersinia CTL response in 21-4L rats than in nontransgenic LEW rats, and the level of cytotoxicity against 21-4L lymphoblast targets sensitized with Y. pseudotuberculosis was lower than that against nontransgenic LEW targets. We conclude that HLA-B27 transgenic rats mount a CTL response against Y. pseudotuberculosis that is not restricted by HLA-B27. Yet, HLA-B27 exerts a negative effect on the level of this response, which could contribute to impaired defense against Yersinia.

Animals↗
PubMed1998

Stable polarization of peripheral blood T cells towards type 1 or type 2 phenotype after polyclonal activation.

Polarization of T lymphocytes towards type 1 (T1) or type 2 (T2) subsets producing a distinct array of cytokines plays a role in several diseases and could be used for therapeutic intervention. Bearing this purpose in mind, we have established suitable in vitro conditions to drive resting polyclonal human T cells towards stable T1 or T2 polarization profiles. Unselected peripheral lymphocytes from normal donors were primed with soluble anti-CD3 monoclonal antibody in the presence of selected sets of recombinant (r) human cytokines. Following this priming process the cytokine secretion profiles of the recovered T cells were assayed after restimulation, both at the population and single-cell levels. A marked shift towards T2 profile, characterized by heightened production of IL-4, IL-5 and IL-13, was obtained after priming in the presence of rIL-4 alone. Addition of rIL-2 partially antagonized this effect. In contrast, priming in the presence of rIL-2 and rIL-12 induced a shift towards a T1 pattern characterized by increased productions of IFN-gamma and IL-2. Strikingly, the T2 profile appeared more stable in culture than the T1 profile. We also observed that the CD4+ helper T cell subset was the major producer of T1 and T2 cytokines after restimulation. These results establish in vitro parameters to deliberately and reproducibly activate resting polyclonal T cells towards a defined and persistent cytokine secretion profile. Autologous T cells polarized under these conditions could be passively transferred as a therapeutic approach in diseases thought to result from imbalance between T1 and T2 responses.

CD4-Positive T-Lymphocytes↗
PubMed1998

Animal models and in vitro models for the study of aetiopathogenesis of spondyloarthropathies.

Among several animal models, HLA-B27 transgenic rodents proved useful for investigating the interplay between genetic factors and the bacterial environment in the aetiopathogenesis of the spondyloarthropathies (SpA). HLA-B27 transgenic rats spontaneously develop a multisystemic inflammatory disease resembling human SpA. This disease is dependent on the presence of a normal bacterial flora and implicates the immune system. The presence of both T cells and antigen-presenting cells expressing high levels of HLA-B27 seems of critical importance in its pathogenesis. HLA-B27 transgenic mice also develop arthritis, under the influence of the bacterial flora. In both types of model, CD8+ T cells seem not to be necessary, arguing against the 'arthritogenic peptide' hypothesis. In vitro models have been used to study the immune response against bacterial agents and the role of HLA-B27 in human SpA. It appears that an impaired immune response against bacteria could be involved in the triggering of human SpA. HLA-B27 could be implicated at the level of interaction between host cells and bacteria in the driving of a specific immune response against bacterial antigens or as a target of an autoimmune response.

Animals↗
PubMed1998

In vitro differentiation of peripheral blood T cells towards a type 2 phenotype is impaired in rheumatoid arthritis (RA).

We have examined the capacity of peripheral blood T cells from RA patients to be polarized in vitro towards a type 1 (T1) or a type 2 (T2) phenotype. Peripheral blood T cells from RA patients and from healthy donors were primed by 1 week of culture with soluble OKT3 in the presence of polarizing cytokines. The recovered T cells were restimulated and their cytokine secretion profile determined. Priming of T cells from RA patients in the presence of recombinant (r)IL-2 plus rIL-12 induced a shift towards a TI pattern, characterized by increased production of interferon-gamma, that was more pronounced than in the case of healthy donors. Conversely, priming of T cells from RA patients in the presence of IL-4 failed to induce a shift towards a T2 profile after 1 week, whereas it induced T cells from healthy donors to acquire such a profile characterized by heightened production of IL-4, IL-5 and IL-13. However, a T2 polarization profile emerged in T cells from RA patients that were primed in the presence of rIL-4 and subsequently maintained in culture in rIL-2 alone for 1 or 2 additional weeks. We conclude that in vitro differentiation of peripheral T cells towards a type 2 phenotype is impaired in RA. Nevertheless, conditions required to drive peripheral T cells towards a type 2 phenotype were established. Administration of autologous polyclonal T cells expressing a type 2 cytokine secretion profile is proposed as a therapeutic strategy in RA.

Adult↗
PubMed1998

HLA-B27 transgenic rats model.

To investigate the role of HLA-B27 in the pathogenesis of spondylarthropathies, rats transgenic for HLA-B27 and human beta 2-microglobulin were produced. Several lines of B27 transgenic rats spontaneously develop a multisystem inflammatory disorder reminiscent of human spondylarthropathies, with gut, joint, skin and male genital lesions. The role of HLA-B27 in this model was studied and it was found that a high expression level of the transgene in cells of hematopoietic origin was critical to induce inflammatory manifestations. Furthermore, a combined implication of CD4+ T cells and antigen presenting cells in this model is suspected, based on passive transfer studies, although a specific influence of HLA-B27 upon T cell education in the thymus is unlikely to be important. Beside the immune system, bacterial flora exerts an important influence in this model, as a triggering agent of gut and joint inflammation. Finally, endogenous rat genetic factors are suspected to be involved in this model.

Animals↗
PubMed1998

Genetic studies of spondylarthropathies. French Spondylarthropathy Genetic Study Group.

Influence of genetic factors in the spondylarthropathies has been clearly established. The goal of familial studies is to determine the respective weight of genetic factors and to discover new genes involved in the pathogenesis of spondylarthropathies. Among these factors, the HLA region appears to be of most importance. We are currently conducting a prospective multicenter French study aimed at collecting multiplex families of spondylarthropathies. We present preliminary results obtained from nearly 300 individuals corresponding to the first 20 collected families. Through the screening procedure, we have identified 57 patients of an average age of 42 and a mean age at onset of 23. The relative risk of spondylarthropathy in males as compared with females is 1.03. HLA typing revealed the presence of HLA-B27 in all affected patients from 19 of the 20 families, whereas in the last family, the two affected individuals shared the HLA-B14 allele. Study of HLA class I allelic transmission confirmed a strong association of spondylarthropathy with HLA-B27 (p < 10(-9)). A weaker association was found with HLA-A28, HLA-C1 and HLA-C2, probably secondary to linkage disequilibrium between these alleles and HLA-B27. Study of HLA class II region indicated a possible protective effect of HLA-DR2 and an influence due to the presence of HLA-DR14. The risk to develop spondylarthropathy in HLA-B27+ relatives of patients decreased very rapidly in respect to the genetic distance, suggesting the genetic contribution of at least one other important gene distinct from the HLA region. These data encourage us to carry on a systematic screening of the whole human genome to discover implicated genes.

Adult↗
PubMed1998

Effects of murine recombinant interleukin-10 on the inflammatory disease of rats transgenic for HLA-B27 and human beta 2-microglobulin.

Rats transgenic for HLA-B27 and human beta 2-microglobulin develop a spontaneous, multisystem, inflammatory disease that resembles human B27-associated disease and that involves the gut mucosa. This model predominantly affects the colon and is characterized by an extensive infiltration of the mucosa by inflammatory cells, largely composed of mononuclear cells. In addition, an increased plasma level of nitric oxide (NO)-derived metabolites was described in this model. Deficiency in the anti-inflammatory cytokine, interleukin-10 (IL-10), leads to the development of colitis in IL-10 knockout mice, suggesting that IL-10 plays a major role in the control of gut inflammation. The objectives of this work were to study the mechanisms of the inflammatory bowel disease (IBD) in HLA-B27 rats and to determine the effects of treatment with IL-10. The 33-3 line of HLA-B27 recombinant rats with established disease was treated in two consecutive experiments with murine recombinant IL-10 for five weeks. Assessment of the effect of this treatment was performed, based on clinical, histological and biological (myeloperoxidase and inducible NO synthase activities; tumor necrosis factor-alpha, interferon-delta, CD3, iNOS and beta-actin mRNA expression. In 33-3 rats with established disease, mesenteric lymph nodes were hyperplastic, and colonic cellularity and MPO and iNOS activities in the colonic mucosa were increased without any detectable effects of IL-10 administration. IFN-gamma and iNOS mRNA were only detected in the colon of transgenic rats. Despite a lack of effect on disease expression, IL-10 strikingly reduced the level of IFN-gamma mRNA in gut mucosa. Up-regulation of IFN-gamma mRNA suggests that the IBD of HLA-B27 rats is mediated by T-helper 1 lymphocytes. Sustained administration of IL-10, in HLA-B27 rats with established disease, efficiently inhibited IFN-gamma mRNA expression but did not influence disease expression: these results indicate that IFN-gamma may exert a critical role at an earlier stage of the disease rather in the maintenance of the lesions.

Animals↗
PubMed1997

[Action of cytokines IL-12 and IL-4 on T helper cells. Cellular immunity or humoral immunity?].

TWO SUBSETS OF T-HELPER CELLS: T-helpers are divided into two subpopulations called Th1 and Th2 depending on the pattern of cytokines they produce. These mutually antagonist subpopulations exert different functions: Th1 cells control cellular immunity whereas Th2 cells control humoral immunity. LYMPHOCYTE DIFFERENTIATION: Several factors are involved, but the presence of certain cytokines in the environment, where cellular interactions driving specific lymphocyte sensitization occur, is the main factor determining differentiation into Th1 or Th2. CRUCIAL ROLE OF IL-12 AND IL-4: IL-12 can polarize lymphocytes towards a Th1 phenotype and IL-4 can direct T lymphocytes towards a Th2 pattern. PRACTICAL IMPLICATIONS: The use of cytokines, or cytokine-inhibiting agents, offers a new strategic approach for intentional modulation of the immune response.

Animals↗
PubMed1996

T cells, but not thymic exposure to HLA-B27, are required for the inflammatory disease of HLA-B27 transgenic rats.

Rats transgenic for the human MHC class I gene HLA-B27 are susceptible to a spontaneous multisystem inflammatory disease that resembles human B27-associated disease. This disease requires a high level of expression of the B27 transgene product in cells of hemopoietic origin and can be adoptively transferred to B27 transgenic or nontransgenic rats by transplantation of bone marrow (BM) or fetal liver (FL) cells. To investigate the role played by T cells and the thymus in the disease process, we produced congenitally athymic rnu/rnu F344 rats carrying the disease-prone B27 transgenic locus of the 33-3 line. Transgenic nude rats were protected from disease manifestations. This protection was abated by reconstitution with T cells from euthymic donors of the 33-3 line, with CD4 T cells being more efficient than CD8 T cells in transferring disease. Lethally irradiated, adult-thymectomized (ATX), nontransgenic recipients reconstituted with intact BM, T cell-depleted BM, FL, or nude BM from syngeneic disease-prone lines all developed disease. Pretreatment of the ATX nontransgenic recipients to deplete T cells enhanced the subsequent transferred disease. The inflammatory disease of B27 transgenic rats is thus T cell-dependent. The relevant T cells do not need to encounter B27 in the thymus, and residual radioresistant and/or extrathymically derived host T cells are sufficient to mediate the adoptively transferred disease. The data are most consistent with a model of B27-mediated disease arising from a failure of tolerance and requiring a population of CD4 T cells.

Animals↗
PubMed1995

High prevalence of colorectal cancer in HLA-B27 transgenic F344 rats with chronic inflammatory bowel disease.

BACKGROUND/AIMS: Transgenic rats expressing the human major histocompatibility class I molecule HLA-B27 develop a spontaneous multisystem disease that includes a chronic colitis resembling ulcerative colitis. The availability of this phenotype in B27 transgenic rats of 2 different inbred strains provided the opportunity to inquire whether colorectal neoplasia, which occurs with increased frequency in humans with inflammatory bowel disease (IBD), would develop in either or both rat genetic backgrounds. METHODS: Clinical and histologic evaluation of B27 transgenic rats with chronic inflammatory bowel disease (IBD) on the F344 and LEW inbred backgrounds. RESULTS: In B27 transgenic rats on an inbred F344 background, hyperplastic lesions evolved in the setting of chronic colitis, with a high frequency of colorectal polyp formation and frequent histologic progression from adenoma to adenocarcinoma. In contrast, no neoplasia occurred in B27 transgenic rats on an inbred LEW background, despite similar colitis. CONCLUSION: A high incidence of spontaneous colorectal neoplasia occurs in a line of B27 F344 rats that shares some features of both sporadic and inflammatory bowel disease-associated human colorectal cancer. This represents a novel example of spontaneous colorectal neoplasia in rodents that is not based on germline modification of one or more already-identified cancer-related genes.

Animals↗