47 research outputs found
Perforin gene transfer into hematopoietic stem cells improves immune dysregulation in murine models of perforin deficiency
Defects in perforin lead to the failure of T and NK cell cytotoxicity, hypercytokinemia, and the immune dysregulatory condition known as familial hemophagocytic lymphohistiocytosis (FHL). The only curative treatment is allogeneic hematopoietic stem cell transplantation which carries substantial risks. We used lentiviral vectors (LV) expressing the human perforin gene, under the transcriptional control of the ubiquitous phosphoglycerate kinase promoter or a lineage-specific perforin promoter, to correct the defect in different murine models. Following LV-mediated gene transfer into progenitor cells from perforin-deficient mice, we observed perforin expression in mature T and NK cells, and there was no evidence of progenitor cell toxicity when transplanted into irradiated recipients. The resulting perforin-reconstituted NK cells showed partial recovery of cytotoxicity, and we observed full recovery of cytotoxicity in polyclonal CD8 + T cells. Furthermore, reconstituted T cells with defined antigen specificity displayed normal cytotoxic function against peptide-loaded targets. Reconstituted CD8 + lymphoblasts had reduced interferon-γ secretion following stimulation in vitro, suggesting restoration of normal immune regulation. Finally, upon viral challenge, mice with >30% engraftment of gene-modified cells exhibited reduction of cytokine hypersecretion and cytopenias. This study demonstrates the potential of hematopoietic stem cell gene therapy as a curative treatment for perforin-deficient FHL
T cell gene therapy for perforin deficiency corrects cytotoxicity defects and prevents Haemophagocytic Lymphohistiocytosis manifestations
BACKGROUND: Mutations in the PRF1 gene account for up to 58% of familial haemophagocytic lymphohistiocytosis (FHL) syndromes. The resulting defects in effector cell cytotoxicity lead to hypercytokinaemia and hyperactivation with inflammation in various organs. OBJECTIVE: To determine whether autologous gene corrected T cells can restore cytotoxic function, reduce disease activity and prevent haemophagocytic lymphohistiocytosis (HLH) symptoms in in vivo models. METHODS: We developed a gammaretroviral vector to transduce murine CD8-T cells in the prf-/- mouse model. To verify functional correction of prf-/- CD8-T cells in vivo, we used a lymphocytic choriomeningitis virus (LCMV) epitope transfected murine lung carcinoma cell tumour model. Further, we challenged gene corrected and uncorrected mice with LCMV. One patient sample was transduced with a PRF1 encoding lentiviral vector to study restoration of cytotoxicity in human cells. RESULTS: We demonstrated efficient engraftment and functional reconstitution of cytotoxicity after intravenous administration of gene corrected prf-/- CD8-T cells into prf-/- mice. In the tumour model, infusion of prf-/- gene corrected CD8-T cells eliminated the tumour as efficiently as the transplant of wild type CD8-T cells. Similarly, mice reconstituted with gene corrected prf-/- CD8-T cells, displayed complete protection from the HLH phenotype after infection with LCMV. Patient cells showed correction of cytotoxicity in human CD8-T cells after transduction. CONCLUSION: These data demonstrate the potential application of T cell gene therapy in reconstituting cytotoxic function and protection against HLH in perforin deficiency
Figure Text Extraction in Biomedical Literature
Background: Figures are ubiquitous in biomedical full-text articles, and they represent important biomedical knowledge. However, the sheer volume of biomedical publications has made it necessary to develop computational approaches for accessing figures. Therefore, we are developing the Biomedical Figure Search engin
More stories on Th17 cells
For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. the Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4(+) T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4(+) T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. the Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-beta or TGF-beta plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.Crohn's and Colitis Foundation of AmericaNIHLa Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USAUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilNIH: RO1 AI050265-06Web of Scienc