The histone deacetylase HDAC11 regulates the expression of interleukin 10 and immune tolerance
Alejandro Villagra1, Fengdong Cheng1, Hong-Wei Wang1, Ildelfonso Suarez1,2, Michelle Glozak3,4, Michelle Maurin1, Danny Nguyen1, Kenneth L Wright1,4, Peter W Atadja5, Kapil Bhalla6, Javier Pinilla-Ibarz1,4, Edward Seto3,4 & Eduardo M Sotomayor1,3,4
Antigen-presenting cells (APCs) induce T cell activation as well as T cell tolerance. The molecular basis of the regulation of this critical ‘decision’ is not well understood. Here we show that HDAC11, a member of the HDAC histone deacetylase family with no prior defined physiological function, negatively regulated expression of the gene encoding interleukin 10 (IL-10) in APCs. Overexpression of HDAC11 inhibited IL-10 expression and induced inflammatory APCs that were able to prime naive T cells and restore the responsiveness of tolerant CD4+ T cells. Conversely, disruption of HDAC11 in APCs led to upregulation of expression of the gene encoding IL-10 and impairment of antigen-specific T cell responses. Thus, HDAC11 represents a molecular target that influences immune activation versus immune tolerance, a critical ‘decision’ with substantial implications in autoimmunity, transplantation and cancer immunotherapy.
Wednesday, January 21, 2009
Thursday, January 15, 2009
Humoral Immunity
Slides have been intentionally made 'wordy' to enable better understanding of the topic.
Wednesday, January 14, 2009
Journal Club- 14th January 2009 (CIMR)
Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease
Maria Florencia Delgado1, Silvina Coviello1, A Clara Monsalvo1, Guillermina A Melendi1,2, Johanna Zea Hernandez1,2, Juan P Batalle1, Leandro Diaz1, Alfonsina Trento3, Herng-Yu Chang4, Wayne Mitzner4, Jeffrey Ravetch5, Jose ́ A Melero3, Pablo M Irusta1,6 & Fernando P Polack1,2,7,8
Abstract:
Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.
Maria Florencia Delgado1, Silvina Coviello1, A Clara Monsalvo1, Guillermina A Melendi1,2, Johanna Zea Hernandez1,2, Juan P Batalle1, Leandro Diaz1, Alfonsina Trento3, Herng-Yu Chang4, Wayne Mitzner4, Jeffrey Ravetch5, Jose ́ A Melero3, Pablo M Irusta1,6 & Fernando P Polack1,2,7,8
Abstract:
Respiratory syncytial virus (RSV) is a leading cause of hospitalization in infants. A formalin-inactivated RSV vaccine was used to immunize children and elicited nonprotective, pathogenic antibody. Immunized infants experienced increased morbidity after subsequent RSV exposure. No vaccine has been licensed since that time. A widely accepted hypothesis attributed the vaccine failure to formalin disruption of protective antigens. Here we show that the lack of protection was not due to alterations caused by formalin but instead to low antibody avidity for protective epitopes. Lack of antibody affinity maturation followed poor Toll-like receptor (TLR) stimulation. This study explains why the inactivated RSV vaccine did not protect the children and consequently led to severe disease, hampering vaccine development for 42 years. It also suggests that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation, and it identifies affinity maturation as a key factor for the safe immunization of infants.
Monday, January 12, 2009
Thursday, January 8, 2009
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