Biomedical subjects

René R Marty

Publications and source records attributed to René R Marty.

6 recordsLinked to original sources

PubMed2006

Dendritic cells and autoimmune heart failure.

Dilated cardiomyopathy is the most common cause of heart failure in young patients and often results from autoimmunity triggered by viral or bacterial infections. Dendritic cells are professional antigen-presenting cells residing in lymphatic tissue and in the heart. They are involved in both, host defense and maintenance of peripheral tolerance. Animal models suggest an important role for dendritic cells in the induction of autoimmune myocarditis. Activated and self-antigen loaded dendritic cells, for example, induce myocarditis and heart failure in susceptible mice. It appears that the combined presence of tissue damage and innate activation exceeding a certain threshold prompts dendritic cells to prime and amplify potentially autoreactive T cells targeting the heart. The concept of dendritic cell induced myocarditis helps us to understand disease pathogenesis and offers a nice approach to develop novel therapeutic strategies against a devastating heart disease.

Animals↗

PubMed2006

T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17.

Experimental autoimmune myocarditis (EAM) appears after infectious heart disease, the most common cause of dilated cardiomyopathy in humans. Here we report that mice lacking T-bet, a T-box transcription factor required for T helper (Th)1 cell differentiation and interferon (IFN)-gamma production, develop severe autoimmune heart disease compared to T-bet+/+ control mice. Experiments in T-bet-/- IL-4-/- and T-bet-/- IL-4Ralpha-/- mice, as well as transfer of heart-specific Th1 and Th2 cell lines, showed that autoimmune heart disease develops independently of Th1 or Th2 polarization. Analysis of T-bet-/- IL-12Rbeta1-/- and T-bet-/- IL-12p35-/- mice then identified interleukin (IL)-23 as critical for EAM pathogenesis. In addition, T-bet-/- mice showed a marked increase in production of the IL-23-dependent cytokine IL-17 by heart-infiltrating lymphocytes, and in vivo IL-17 depletion markedly reduced EAM severity in T-bet-/- mice. Heart-infiltrating T-bet-/- CD8+ but not CD8- T cells secrete IFN-gamma, which inhibits IL-17 production and protects against severe EAM. In contrast, T-bet-/- CD8+ lymphocytes completely lost their capacity to release IFN-gamma within the heart. Collectively, these data show that severe IL-17-mediated EAM can develop in the absence of T-bet, and that T-bet can regulate autoimmunity via the control of nonspecific CD8+ T cell bystander functions in the inflamed target organ.

Animals↗

PubMed2006

Therapeutic protein transduction of mammalian cells and mice by nucleic acid-free lentiviral nanoparticles.

The straightforward production and dose-controlled administration of protein therapeutics remain major challenges for the biopharmaceutical manufacturing and gene therapy communities. Transgenes linked to HIV-1-derived vpr and pol-based protease cleavage (PC) sequences were co-produced as chimeric fusion proteins in a lentivirus production setting, encapsidated and processed to fusion peptide-free native protein in pseudotyped lentivirions for intracellular delivery and therapeutic action in target cells. Devoid of viral genome sequences, protein-transducing nanoparticles (PTNs) enabled transient and dose-dependent delivery of therapeutic proteins at functional quantities into a variety of mammalian cells in the absence of host chromosome modifications. PTNs delivering Manihot esculenta linamarase into rodent or human, tumor cell lines and spheroids mediated hydrolysis of the innocuous natural prodrug linamarin to cyanide and resulted in efficient cell killing. Following linamarin injection into nude mice, linamarase-transducing nanoparticles impacted solid tumor development through the bystander effect of cyanide.

Animals↗

PubMed2006

MyD88 signaling controls autoimmune myocarditis induction.

BACKGROUND: Experimental autoimmune myocarditis (EAM) is a CD4+ T-cell-mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known. METHODS AND RESULTS: In contrast to control littermates, MyD88(-/-) mice were protected from myocarditis after immunization with alpha-myosin heavy chain-derived peptide (MyHC-alpha) and complete Freund's adjuvant. Disease resistance of MyD88(-/-) mice resulted from impaired expansion of heart-specific CD4+ T cells after immunization. Intrinsic defects of MyD88(-/-) CD4+ T cells were excluded. In contrast, MyD88(-/-) but not MyD88(+/+) primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4+ T cells. This defect mainly resulted from the inability of MyD88(-/-) DCs to release tumor necrosis factor-alpha. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-alpha-loaded MyD88(+/+) DCs that fully restored T-cell expansion and myocarditis in MyD88(-/-) mice. CONCLUSIONS: Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy.

Adaptor Proteins, Signal Transducing↗

PubMed2003

Conditional human VEGF-mediated vascularization in chicken embryos using a novel temperature-inducible gene regulation (TIGR) system.

Advanced heterologous transcription control systems for adjusting desired transgene expression are essential for gene function assignments, drug discovery, manufacturing of difficult to produce protein pharmaceuticals and precise dosing of gene-based therapeutic interventions. Conversion of the Streptomyces albus heat shock response regulator (RheA) into an artificial eukaryotic transcription factor resulted in a vertebrate thermosensor (CTA; cold-inducible transactivator), which is able to adjust transcription initiation from chimeric target promoters (P(CTA)) in a low-temperature- inducible manner. Evaluation of the temperature-dependent CTA-P(CTA) interaction using a tailored ELISA-like cell-free assay correlated increased affinity of CTA for P(CTA) with temperature downshift. The temperature-inducible gene regulation (TIGR) system enabled tight repression in the chicken bursal B-cell line DT40 at 41 degrees C as well as precise titration of model product proteins up to maximum expression at or below 37 degrees C. Implantation of microencapsulated DT40 cells engineered for TIGR-controlled expression of the human vascular endothelial growth factor A (hVEGF121) provided low-temperature-induced VEGF-mediated vascularization in chicken embryos.

Animals↗

PubMed2002

Versatile macrolide-responsive mammalian expression vectors for multiregulated multigene metabolic engineering.

The novel macrolide-inducible and -repressible mammalian gene regulation systems (E.REX) have been cloned into a variety of sophisticated expression configurations including (1) multi-purpose expression vectors, (2) pTRIDENT-based artificial operons, (3) dual-regulated expression strategies for independent control of two different transgenes, (4) autoregulated vectors for one-step installation of adjustable multigene expression, and (5) oncoretroviral and lentiviral plasmids for transduction of macrolide-, streptogramin- and tetracycline-dependent transactivators and production of cell lines supporting independent control of three different transgenes. This vector portfolio represents a construction kit-like toolbox for efficient installation of adjustable gene expression responsive to clinically licensed antibiotics and enables the design of multiregulated multigene metabolic engineering strategies required for biopharmaceutical manufacturing, gene therapy, and tissue engineering.

Animals↗