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Biomedical subjects

Michel Goldman

Publications and source records attributed to Michel Goldman.

At least 55 records · Page 3Linked to original sources
PubMed2004

Distinct mechanisms are involved in tumoristatic and tumoricidal activities of monocyte-derived dendritic cells.

Monocyte-derived dendritic cells (DC) were found to inhibit proliferation of different tumor cell lines. LPS-induced maturation of DC strongly increased their capacity to inhibit tumor cell growth. We observed that tumoristatic activity of LPS-activated DC was independent of their cytotoxic potential. Indeed, LPS-activated DC were able to inhibit growth of caspase-8-deficient or Bcl-2-overexpressing Jurkat cells whereas they were not cytotoxic towards the same targets. On the other hand, we found that supernatant derived from LPS-activated DC exerted a significant anti-proliferative activity against Jurkat cells while it did not induce any cytotoxic effect. Tumor necrosis factor (TNF) was shown to critically contribute to tumor growth inhibition in this system.

Cell Division↗
PubMed2004

Induction of FOXP3-expressing regulatory CD4pos T cells by human mature autologous dendritic cells.

Current literature suggests that T cells recognizing antigen on mature dendritic cells (DC) differentiate into effector T cells whereas tolerance is induced when antigen is presented by immature DC. We investigated the consequences of the interactions between immature or lipopolysaccharide-matured DC and CD4(pos) T lymphocytes in absence of foreign antigen. While immature DC did not induce significant CD4(pos) T cell activation, we observed that a significant fraction of CD4(pos) T cells cultured with mature autologous DC displayed phenotypic features of activation and produced IL-2, IFN-gamma, IL-10 and TGF-beta. Furthermore, CD4(pos) T lymphocytes primed by mature, but not immature, autologous DC acquired regulatory properties. Indeed, when added to an allogeneic mixed leukocyte reaction, they suppressed the response of alloreactive T lymphocytes to the priming DC while responses to third-party stimulators were spared. The generation of CD4(pos) T cells with regulatory function by autologous stimulation did not require the presence of natural CD4(pos)CD25(pos) regulatory T cells. In addition, the acquisition of regulatory function by CD4(pos)CD25(neg) T cells stimulated by autologous mature DC was accompanied by the induction of FOXP3 expression. Our data suggest that during inflammatory conditions, presentation of self antigens by mature DC to autologous T lymphocytes could contribute to the generation of regulatory mechanisms.

Antigen Presentation↗
PubMed2004

Trapidil inhibits monocyte CD40 expression by preventing IFN-gamma-induced STAT1 S727 phosphorylation.

Trapidil is a triazolopyrimidine that has been found to prevent restenosis after vascular injury. Although its precise mode of action is still unclear, several biological effects have been described including inhibition of IFN-gamma-induced CD40 expression on monocytes. Herein, we investigated the molecular mechanisms by which Trapidil exerts this inhibitory action. First, we observed that the inhibition of CD40 expression is associated with the suppression of CD40 gene transcription, as demonstrated by a clear decrease of CD40 nuclear RNA (nRNA) levels and unchanged CD40 mRNA half-life. IFN-gamma-induced CD40 transcription has been shown to be mediated by STAT1alpha dimers (p91/p84) which, after nuclear translocation, bind to GAS elements present in the promoter of IFN-gamma responsive genes. Electrophoresis mobility shift assay (EMSA) with both STAT1 consensus and CD40 mGAS probes showed that Trapidil did not affect the DNA binding ability of STAT1 dimers. STAT1 dimerization and activation are conferred by upstream phosphorylation of two amino acid residues of the STAT1 protein. The subsequent studies on these two potential STAT1 phosphorylation sites (Tyr701, Ser727) revealed that Trapidil attenuated IFN-gamma-induced Ser727 but not Tyr701 phosphorylation. The inhibition of CD40 transcription by Trapidil could at least partially owing to the impaired Ser727 phosphorylation of STAT1, since IFN-gamma failed to trigger CD40 expression in U3A S727A cells, a cell line displaying a point mutation at the Ser727 site. Collectively, our results indicate that phosphorylation of STAT1 at the Ser727 site enhances CD40 transcription and that Trapidil might be used as a selective inhibitor that could differentially modulate STAT1 target genes.

CD40 Antigens↗
PubMed2004

Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders.

Recent advances in understanding the molecular basis for mammalian host immune responses to microbial invasion suggest that the first line of defense against microbes is the recognition of pathogen-associated molecular patterns by a set of germline-encoded receptors: the Toll-like receptors (TLRs). TLRs have been identified as being part of a large family of pathogen-recognition receptors that play a decisive role in the induction of both innate and adaptive immunity. Indeed, activation of T lymphocytes depends on their interaction with dendritic cells previously stimulated by TLR agonists such as bacterial lipopolysaccharide (LPS), a TLR-4 ligand. A novel PKC epsilon (epsilon) was recently found to be a critical component of TLR-4 signaling pathway and thereby to play a key role in macrophage and dendritic cell (DC) activation in response to LPS. Thus, controlling the kinase activity of PKC epsilon might represent an efficient strategy to prevent or treat certain inflammatory disorders of microbial origin.

Animals↗
PubMed2003

Vaccination and autoimmune disease: what is the evidence?

As many as one in 20 people in Europe and North America have some form of autoimmune disease. These diseases arise in genetically predisposed individuals but require an environmental trigger. Of the many potential environmental factors, infections are the most likely cause. Microbial antigens can induce cross-reactive immune responses against self-antigens, whereas infections can non-specifically enhance their presentation to the immune system. The immune system uses fail-safe mechanisms to suppress infection-associated tissue damage and thus limits autoimmune responses. The association between infection and autoimmune disease has, however, stimulated a debate as to whether such diseases might also be triggered by vaccines. Indeed there are numerous claims and counter claims relating to such a risk. Here we review the mechanisms involved in the induction of autoimmunity and assess the implications for vaccination in human beings.

Autoimmune Diseases↗
PubMed2003

CD8+ T lymphocytes regulating Th2 pathology escape neonatal tolerization.

Transplantation tolerance induced by neonatal injection of semiallogeneic spleen cells is associated in several strain combinations with a pathological syndrome caused by Th2 differentiation of donor-specific CD4(+) T lymphocytes. We investigated the role of host CD8(+) T cells in the regulation of this Th2 pathology. IgE serum levels and eosinophilia significantly increased in BALB/c mice neonatally injected with (A/J x BALB/c)F(1) spleen cells when CD8(+) T cells were depleted by administration of anti-CD8 mAb or when beta(2)-microglobulin-deficient mice were used as recipients. In parallel, increased serum levels of IL-5 and IL-13 were measured in blood of tolerant CD8(+) T cell-deficient mice. Whereas neonatally injected mice were unable to generate anti-donor cytotoxic effectors, their CD8(+) T cells were as efficient as control CD8(+) T cells in reducing the severity of Th2 pathology and in restoring donor-specific cytotoxicity in vitro after in vivo transfer in beta(2)-microglobulin-deficient mice. Likewise, CD8(+) T cells from control and tolerant mice equally down-regulated the production of Th2 cytokines by donor-specific CD4(+) T cells in vitro. The regulatory activity of CD8(+) T cells depended on their secretion of IFN-gamma for the control of IL-5 production but not for IL-4 or IL-13. Finally, we found that CD8(+) T cells from 3-day-old mice were already able to down-regulate IL-4, IL-5, and IL-13 production by CD4(+) T cells. We conclude that regulatory CD8(+) T cells controlling Th2 responses are functional in early life and escape neonatal tolerization.

Aging↗
PubMed2003

CD4+CD25+ and CD4+CD25- T cells act respectively as inducer and effector T suppressor cells in superantigen-induced tolerance.

The repeated injection of low doses of bacterial superantigens (SAg) is known to induce specific T cell unresponsiveness. We show in this study that the spleen of BALB/c mice receiving chronically, staphylococcal enterotoxin B (SEB) contains SEB-specific CD4(+) TCRBV8(+) T cells exerting an immune regulatory function on SEB-specific primary T cell responses. Suppression affects IL-2 and IFN-gamma secretion as well as proliferation of T cells. However, the suppressor cells differ from the natural CD4(+) T regulatory cells, described recently in human and mouse, because they do not express cell surface CD25. They are CD152 (CTLA-4)-negative and their regulatory activity is not associated with expression of the NF Foxp3. By contrast, after repeated SEB injection, CD4(+)CD25(+) splenocytes were heterogenous and contained both effector as well as regulatory cells. In vivo, CD4(+)CD25(-) T regulatory cells prevented SEB-induced death independently of CD4(+)CD25(+) T cells. Nevertheless, SEB-induced tolerance could not be achieved in thymectomized CD25(+) cell-depleted mice because repeated injection of SEB did not avert lethal toxic shock in these animals. Collectively, these data demonstrate that, whereas CD4(+)CD25(+) T regulatory cells are required for the induction of SAg-induced tolerance, CD4(+)CD25(-) T cells exert their regulatory activity at the maintenance stage of SAg-specific unresponsiveness.

Animals↗
PubMed2003

Blood plasmacytoid dendritic cell responses to CpG oligodeoxynucleotides are impaired in human newborns.

Plasmacytoid dendritic cells (pDCs) respond to unmethylated cytosine-phosphate-guanosine (CpG) motifs present in bacterial DNA or unmethylated synthetic oligodeoxynucleotides (CpG). In order to assess the function of pDCs in human newborns, interferon-alpha (IFN-alpha) production induced by CpG 2216 and phenotypic maturation of pDCs in response to CpG 2006 were compared in cord blood and adult blood. We first observed that neonatal pDCs displayed decreased up-regulation of CD80, CD83, CD86, and CD40, whereas HLA-DR and CD54 up-regulation did not differ significantly between adults and neonates. We then found that the production of IFN-alpha in response to CpG was dramatically impaired in cord blood. This neonatal defect was detected both at protein and mRNA levels and was still present in blood of 4-day-old babies. Further experiments on enriched pDCs confirmed that these cells are intrinsically deficient in CpG-induced IFN-alpha production at birth. These findings might be relevant to the increased susceptibility of human newborns to infections as well as to the use of CpG oligodeoxynucleotides as vaccine adjuvants in the neonatal period.

Base Sequence↗
PubMed2003

Interleukin-9 promotes eosinophilic rejection of mouse heart allografts.

BACKGROUND: Eosinophils participate in allograft rejection when donor-reactive helper T lymphocytes are T-helper type 2 (Th2)-biased. Whereas the involvement of interleukin (IL)-4 and IL-5 in these forms of rejection is well established, the role of IL-9, another Th2-type cytokine promoting eosinophilia, has not been determined. METHODS: We first used real-time polymerase chain reaction to quantify IL-9 mRNA in rejected allografts in a mouse model of fully mismatched heart transplantation in which recipients were devoid of CD8 T cells and developed a Th2 alloimmune response. We then compared allograft survival in wild-type versus IL-9-deficient mice depleted of CD8 T cells. Finally, we compared the fate of major histocompatibility complex class II-mismatched cardiac transplants from wild-type versus IL-9 transgenic donors to determine the influence of IL-9 overexpression within the graft. RESULTS: The Th2 alloimmune response in CD8-deficient mice was associated with the accumulation of IL-9 mRNA in the rejected graft. In IL-9-deficient recipients depleted of CD8 T cells, eosinophil infiltration of heart allografts did not develop, but rejection still occurred. In the major histocompatibility complex class II disparate model, heart allografts from IL-9 transgenic donors were acutely rejected, whereas grafts from wild-type donors did not develop rejection. Acute rejection of IL-9 transgenic hearts was associated with massive eosinophil infiltration and prevented by neutralization of either IL-4 or IL-5. CONCLUSION: IL-9 is critically involved in heart transplant eosinophilia in conjunction with IL-4 and IL-5.

Animals↗
PubMed2003

Anaphylactic shock caused by immunoglobulin E sensitization after retreatment with the chimeric anti-interleukin-2 receptor monoclonal antibody basiliximab.

BACKGROUND: Repeated administration of chimeric or humanized monoclonal antibodies is generally well tolerated. Anti-idiotypic sensitization is rare and is considered to be of no clinical significance. We observed a child who experienced anaphylactic shock when he received a second course of basiliximab at the time of his second renal transplantation. We therefore searched for the presence of anti-basiliximab immunoglobulin (Ig) E in this patient. METHODS: Serum levels of anti-basiliximab IgE, assay of the anti-murine reactivity of circulating anti-basiliximab IgE, and assays for serum anti-mouse antibodies and global anti-basiliximab anti-idiotypic antibodies were carried out by enzyme-linked immunosorbent assay. Anti-basiliximab IgE antibodies on circulating basophils were evaluated by the ability of the patient's blood to produce leukotrienes in vitro after exposure to basiliximab. RESULTS: Sequential assays of serum samples by enzyme-linked immunosorbent assay indicated that anti-basiliximab IgE antibodies appeared after the second basiliximab course. There was no IgE reactivity toward a control murine IgG2a monoclonal antibody (mAb), indicating that the IgE response was directed exclusively against basiliximab idiotypes. There was no IgE reactivity against the humanized anti-interleukin-2 receptor mAb daclizumab, which was derived from a distinct parental murine mAb. Patient basophils harvested months after the anaphylactic shock produced leukotrienes in vitro on exposure to basiliximab. CONCLUSIONS: Patients exposed to chimeric antibodies may develop an anti-idiotypic IgE response that can trigger anaphylactic shock on further exposure. Specific anti-idiotypic IgE may be bound to basophils even in the absence of circulating IgE.

Anaphylaxis↗
PubMed2003

The impact of maternal infection or immunization on early-onset autoimmune diabetes.

Maternal immune responses exert short and long-term influences on the newborn immune system. The transfer of maternal antibodies helps the newborn controlling infectious agents that are prevalent in the population. Furthermore, recent studies indicate that the fetus is able to mount inflammatory and cytotoxic T lymphocyte responses in the course of maternal infections. Herein, we discuss the relevance of these observations to the possible relation between maternal infection or immunization and childhood-onset autoimmune diabetes.

Child, Preschool↗
PubMed2003

Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data.

Many strategies for tolerance induction have been developed, because this is the major goal of clinical transplantation. One of the most effective and best-studied approaches has been based on the injection of hematopoietic cells derived from the donor bone marrow, to establish a state of microchimerism in the recipient. A subset of hematopoietic stem cells might be responsible for the tolerogenic properties. These CD34+ bone marrow stem cells can be isolated and safely injected into kidney transplant recipients. In the authors' clinical trial, no adverse effects were observed, and the infusion of donor CD34+ cells was well tolerated.

Antigens, CD34↗
PubMed2003

Tolerance induction in clinical transplantation: the pending questions.

Despite the dramatic improvement of early graft survival due to the introduction of cyclosporin, late graft loss caused by chronic rejection and the lethal consequences of long-term immunosuppression, such as infection and cancer, remain major concerns for the transplantation community. Tolerance induction would avoid these complications. The ways to go are controversial, reflecting the redundancy of rejection pathways. They include the induction of central tolerance by establishment of mixed chimerism through hematopoietic stem cell transplantation and the induction of "operational tolerance" through immunodeviation involving dendritic or regulatory T cells. Major advances have been made in animal models exploring these strategies and, some preliminary data are even now available in humans, allowing the initiation of pilot clinical trials. In this article, we discuss the key questions that these trials will have to address.

Dendritic Cells↗
PubMed2003

Immune monitoring in whole blood using real-time PCR.

There is a need for simple and sensitive assays to assess innate and adaptive immune responses to microbial agents and vaccines. Herein, we describe a whole blood method allowing to measure the induction of cytokine synthesis at the mRNA level. The originality of this method consists in the combination of PAXgene tubes containing an mRNA stabilizer for blood collection, the MagNA Pure instrument as an automated system for mRNA extraction and RT-PCR reagent mix preparation, and the real-time PCR methodology on the Lightcycler for accurate and reproducible quantification of transcript levels. We first demonstrated that this method is adequate to measure the induction of interleukin (IL)-1beta and IL-1 receptor antagonist (IL-1 RA) mRNA upon the addition of bacterial lipopolysaccharide (LPS) to whole blood. We then showed that this approach is also suitable to detect the production of mRNA encoding T cell-derived cytokines in whole blood incubated with tetanus toxoid as a model of in vitro immune response to a recall antigen. Finally, we demonstrated that this methodology can be used successfully to assess inflammatory as well as T cell responses in vivo, as it allowed to detect the induction of IL-1beta and IL-1 RA after injection of LPS in healthy volunteers, and also the induction of IL-2 upon recall immunisation with tetanus vaccine.

Adult↗
PubMed2003

Preconditioning of donors with interleukin-10 reduces hepatic ischemia-reperfusion injury after liver transplantation in pigs.

BACKGROUND: Graft ischemia-reperfusion injury (IRI) resulting from postreperfusion inflammatory reaction remains a major cause of complications after liver transplantation. In this article, the authors investigated the effect of anti-inflammatory cytokine interleukin (IL)-10 on IRI, in a preclinical model of liver transplantation in pigs. METHODS: Donor pigs received IL-10 or saline at the start of liver graft harvesting. After 5 hr of cold ischemia, liver grafts were transplanted into untreated recipient pigs. IRI severity was measured in recipients by transaminase release and by cellular infiltration and necrosis on liver biopsy specimens. RESULTS: Donor IL-10 administration attenuated IRI, as indicated by significant reduction of mean peak of transaminase in recipients of grafts from IL-10-treated donors. In contrast, no significant differences in cell infiltration or amount of necrosis were observed on liver biopsy specimens between groups. CONCLUSIONS: Donor preconditioning with IL-10 may constitute an interesting pharmacologic approach to reduce IRI severity after liver transplantation.

Alanine Transaminase↗
PubMed2003

Dendritic cells exposed to nacystelyn are refractory to maturation and promote the emergence of alloreactive regulatory t cells.

BACKGROUND: Drugs blocking dendritic cell (DC) maturation might be useful in transplantation by inhibiting the induction of primary alloimmune responses and promoting the emergence of regulatory T lymphocytes (Treg). We investigated the effects of Nacystelyn (NAL), an N-acetyl-L-cysteine derivative, on human DCs, paying attention to the T-cell responses elicited by NAL-treated DCs in vitro. METHODS: Lipopolysaccharide (LPS) was used to induce the maturation of DCs naturally present in blood or generated from human monocytes cultured in interleukin-4 and granulocyte-macrophage colony-stimulating activity. We first analyzed the consequences of NAL on cytokine production and expression of major histocompatibility complex class II and costimulatory molecules. Monocyte-derived DCs were then used as stimulators in mixed leukocyte cultures with naive CD4 T cells. Cytokine levels were measured in culture supernatants; the phenotype of T cells and their capacity to inhibit the proliferation of third-party T-cell responders was determined at the end of the culture. RESULTS: NAL proved to be a potent inhibitor of DC maturation in whole blood experiments and on monocyte-derived DCs. Alloreactive T cells stimulated with DCs pretreated with LPS in the presence of NAL produced much less interferon-gamma but similar levels of interleukin-13 compared with DCs treated with LPS alone. Immature DCs induced Treg, which was not observed with mature DCs. DCs cultured with LPS in the presence of NAL were as efficient as immature DCs to generate alloreactive T cells with regulatory activity. CONCLUSIONS: NAL is a potent inhibitor of DC maturation, which might be useful to promote allograft acceptance by inducing the differentiation of allospecific Treg.

Acetylcysteine↗
PubMed2003

Bone marrow-derived immature dendritic cells prime in vivo alloreactive T cells for interleukin-4-dependent rejection of major histocompatibility complex class II antigen-disparate cardiac allograft.

BACKGROUND: Dendritic cells (DC) at the immature state express low levels of major histocompatibility complex and costimulatory molecules and are poor stimulators of primary T-cell response in vitro. Injection of immature bone marrow-derived DC, however, was shown to prime in vivo alloreactive CD4 T lymphocytes toward type 2 cytokine-producing cells in the absence of CD8 T-cell activation. METHODS: We undertook the present study to determine whether Th2-immunization by immature DC could lead to allograft rejection. We first analyzed, in the major histocompatibility complex class II antigen-disparate B6-anti-bm12 combination, the capacity of immature DC to regulate the activity of alloreactive CD4 T cells. We then determined, in this model of weak antigenicity, whether injection of bm12 DC in B6 recipients before transplantation could modify the survival of vascularized bm12 cardiac allografts. RESULTS: We confirmed that in vitro immature DC are poor stimulators of T-cell alloresponse. However, when given in vivo, immature bm12 DC primed anti-bm12 T cells for the production of interleukin (IL)-4. Moreover, they induced the acute rejection of bm12 cardiac allograft. The process of rejection was dependent on IL-4 because immunization of IL-4-deficient mice did not trigger rejection. CONCLUSIONS: Allogeneic immature DC generated with granulocyte-macrophage colony-stimulating factor are potent stimulators of primary alloreactive response in vivo and prime for transplant rejection. Our results indicate that strategies based on immature DC for the induction of transplantation tolerance should be considered with caution.

Animals↗