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T.110. Autoantigen Specific Regulatory T Cells Induced in Patients with Type 1 Diabetes Mellitus
Abstracts rabbit model and analyzed the immunogenicity and protective efficacy of lipopeptide vaccine strategy. We found that Lipopeptides immunizations induced in HLA-A2 transgenic rabbits: (1) strong HSV peptide-specific CD4+ and CD8+ immune responses in the spleen, conjunctiva and TGs, (2) high number of HSV peptide-specific CD4+ and CD8+ in the spleen, conjunctiva and TGs, suggesting a better control of acute HSV infection and (3) a protective immunity as demonstrated by the low scores of eye disease and lower virus titration in the tears in comparison with non immunized infected rabbits. In conclusions, this study represent the first report describing that lipopeptides vaccine containing human asymptomatic CD4 and CD8 T cell epitopes protective in humanized HLA-A2 transgenic rabbit which represents the first animal model that simulates the human immune system and mimics the human ocular herpes disease. doi:10.1016/j.clim.2009.03.242
T.110. Autoantigen Specific Regulatory T Cells Induced in Patients with Type 1 Diabetes Mellitus Tihamer Orban1, Klara Farkas1, Heyam Jalahej1, Janos Kis2, Andras Treszl3, Ben Falk4, Helena Reijonen4, Joseph Wolfsdorf5, Alyne Ricker5, Jeffrey Matthews6, Nadia Tchao6, Peter Sayre6, Peter Bianchine7. 1Joslin Diabetes Center, Boston, MA; 2Polyclinic of the Hospitaller Brothers, Budapest, Hungary; 3Semmelweis University, Budapest, Hungary; 4Virginia Mason, Seattle, WA; 5Children's Hospital, Boston, MA; 6UCSF, San Francisco, CA; 7National Institute of Allergy and Infectious Diseases, Bethesda, DC There is a growing body of evidence to suggest that the autoimmunity observed in type 1 diabetes mellitus (T1DM) is the result of an imbalance between autoaggressive and regulatory cell subsets. Therapeutics that supplement or enhance the existing regulatory subset are therefore a much sought after goal in this indication. Here, we report the results of a double blind, placebo controlled phase I clinical trial of a novel antigen-specific therapeutic in 12 subjects with recently diagnosed T1DM. The study drug, human insulin B-chain in incomplete Freund's adjuvant (IFA) was administered as a single intramuscular injection, with subjects followed for 2 years. All subjects completed therapy and all follow-up visits. The therapy was generally safe and well-tolerated. Mixed meal stimulated C-peptide responses, measured every 6 months, showed no statistical differences between arms. All patients vaccinated with the autoantigen, but none who received placebo, developed robust insulin-specific humoral and T cells responses. Up to two years following the single injection, in peripheral blood from subjects in the experimental arm, but not the control arm, insulin B-chain-specific CD4 + T cells could be isolated and cloned that showed phenotypic and functional characteristics of regulatory T cells. The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cell provides strong justification for further testing of this therapy in type 1 diabetes. doi:10.1016/j.clim.2009.03.243
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T.111. Enhanced CD4+ and CD8 + T Cell Responses Followed HIV DNA Lamp/gag Vaccination in Mice During Early Phase of Life Adriana Goldoni1, Milton Maciel3, Paula Rigato1, Orlando Piubelli1, Cyro Brito1, Ana Fusaro1, Noemia Orii1, J. Thomas August2, Ernesto Marques2, Alberto J. Duarte1, Maria Sato1. 1 University of São Paulo School of Medicine, São Paulo, Brazil; 2The Johns Hopkins University School of Medicine, Baltimore, MD; 3University of Maryland School of Medicine, Baltimore, MD This study aimed to evaluate the effect of intranasal (IN) administration in neonatal mice of a chimeric DNA vaccine encoding HIV-GAG and LAMP protein, which directs the traffic of the protein to the MHC II compartments and a DNA vaccine encoding only HIV-GAG. Seven day-old BALB/c mice were immunized with either Lamp/gag or gag vaccines by IN and intradermal (ID) route and boosted twice. The IN immunization with 20μg of the Lamp/gag stimulated synthesis of anti-GAG IgA and IgG in gut mucosa and anti-GAG IgG in serum. Similar profile of splenic and gut CD8 response by Lamp/gag and gag mice was verified by the frequency of IFN-γ spot-forming cells (SFC) to GAG peptides, percentage of CD8+/pentamer+ cells, in vivo CTL response and secretion of cytokines such as TNF-α, IFN-γ and MCP-1. As for the CD4 response, Lamp/gag mice recognized twice the number of pools than gag mice with increased frequency of IFN-γ SFC and IL-4 SFC to GAG peptides. After in vitro stimuli with GAG class II peptide, gag mice produced increased level of TNF-α and IL-10, whereas Lamp/gag mice secreted higher levels of IFN-γ, IL-2 and MCP-1. Mesenteric lymph nodes from Lamp/ gag and gag mice showed augmented percentage of CD4+/ CD25+/FOXP3 + Treg cells, in accordance to the increased level of TGF-β1 observed in intestinal washes. Immunization with gag or Lamp/gag by was immunogenic in the neonatal period and capable of inducing regulatory mechanisms, although only Lamp/gag vaccine induced humoral and cellular immune response. doi:10.1016/j.clim.2009.03.244
T.112. Increased Frequency of Host CD4 + Foxp3 + T Regulatory Cells in Aged Recipients after Immunotherapy and Hematopoietic Stem Cell Transplantation Lisbeth Welniak1, Kory Alderson2, Maite Alvarez1, William Murphy1. 1University of California, Davis, Sacramento, CA; 2 University of Nevada School of Medicine, Reno, NV CD4 + Foxp3 + T regulatory (Treg) cells have a significant impact on the functional status of the global immune response. In aged individuals, the frequency of these cells increases and contributes to reduced immune function. Hematopoietic stem cell transplants (HSCT) and immunostimulatory therapies are two strategies that are used to treat cancer. Recent studies by us and by others have demonstrated increasing frequencies of Treg cells after such treatments. However, the impact of these modalities on Treg cell populations in aged recipients has not been explored. We
T.110. Autoantigen Specific Regulatory T Cells Induced in Patients with Type 1 Diabetes Mellitus Tihamer Orban1, Klara Farkas1, Heyam Jalahej1, Janos Kis2, Andras Treszl3, Ben Falk4, Helena Reijonen4, Joseph Wolfsdorf5, Alyne Ricker5, Jeffrey Matthews6, Nadia Tchao6, Peter Sayre6, Peter Bianchine7. 1Joslin Diabetes Center, Boston, MA; 2Polyclinic of the Hospitaller Brothers, Budapest, Hungary; 3Semmelweis University, Budapest, Hungary; 4Virginia Mason, Seattle, WA; 5Children's Hospital, Boston, MA; 6UCSF, San Francisco, CA; 7National Institute of Allergy and Infectious Diseases, Bethesda, DC There is a growing body of evidence to suggest that the autoimmunity observed in type 1 diabetes mellitus (T1DM) is the result of an imbalance between autoaggressive and regulatory cell subsets. Therapeutics that supplement or enhance the existing regulatory subset are therefore a much sought after goal in this indication. Here, we report the results of a double blind, placebo controlled phase I clinical trial of a novel antigen-specific therapeutic in 12 subjects with recently diagnosed T1DM. The study drug, human insulin B-chain in incomplete Freund's adjuvant (IFA) was administered as a single intramuscular injection, with subjects followed for 2 years. All subjects completed therapy and all follow-up visits. The therapy was generally safe and well-tolerated. Mixed meal stimulated C-peptide responses, measured every 6 months, showed no statistical differences between arms. All patients vaccinated with the autoantigen, but none who received placebo, developed robust insulin-specific humoral and T cells responses. Up to two years following the single injection, in peripheral blood from subjects in the experimental arm, but not the control arm, insulin B-chain-specific CD4 + T cells could be isolated and cloned that showed phenotypic and functional characteristics of regulatory T cells. The induction of a lasting, robust immune response generating autoantigen-specific regulatory T cell provides strong justification for further testing of this therapy in type 1 diabetes. doi:10.1016/j.clim.2009.03.243
S83
T.111. Enhanced CD4+ and CD8 + T Cell Responses Followed HIV DNA Lamp/gag Vaccination in Mice During Early Phase of Life Adriana Goldoni1, Milton Maciel3, Paula Rigato1, Orlando Piubelli1, Cyro Brito1, Ana Fusaro1, Noemia Orii1, J. Thomas August2, Ernesto Marques2, Alberto J. Duarte1, Maria Sato1. 1 University of São Paulo School of Medicine, São Paulo, Brazil; 2The Johns Hopkins University School of Medicine, Baltimore, MD; 3University of Maryland School of Medicine, Baltimore, MD This study aimed to evaluate the effect of intranasal (IN) administration in neonatal mice of a chimeric DNA vaccine encoding HIV-GAG and LAMP protein, which directs the traffic of the protein to the MHC II compartments and a DNA vaccine encoding only HIV-GAG. Seven day-old BALB/c mice were immunized with either Lamp/gag or gag vaccines by IN and intradermal (ID) route and boosted twice. The IN immunization with 20μg of the Lamp/gag stimulated synthesis of anti-GAG IgA and IgG in gut mucosa and anti-GAG IgG in serum. Similar profile of splenic and gut CD8 response by Lamp/gag and gag mice was verified by the frequency of IFN-γ spot-forming cells (SFC) to GAG peptides, percentage of CD8+/pentamer+ cells, in vivo CTL response and secretion of cytokines such as TNF-α, IFN-γ and MCP-1. As for the CD4 response, Lamp/gag mice recognized twice the number of pools than gag mice with increased frequency of IFN-γ SFC and IL-4 SFC to GAG peptides. After in vitro stimuli with GAG class II peptide, gag mice produced increased level of TNF-α and IL-10, whereas Lamp/gag mice secreted higher levels of IFN-γ, IL-2 and MCP-1. Mesenteric lymph nodes from Lamp/ gag and gag mice showed augmented percentage of CD4+/ CD25+/FOXP3 + Treg cells, in accordance to the increased level of TGF-β1 observed in intestinal washes. Immunization with gag or Lamp/gag by was immunogenic in the neonatal period and capable of inducing regulatory mechanisms, although only Lamp/gag vaccine induced humoral and cellular immune response. doi:10.1016/j.clim.2009.03.244
T.112. Increased Frequency of Host CD4 + Foxp3 + T Regulatory Cells in Aged Recipients after Immunotherapy and Hematopoietic Stem Cell Transplantation Lisbeth Welniak1, Kory Alderson2, Maite Alvarez1, William Murphy1. 1University of California, Davis, Sacramento, CA; 2 University of Nevada School of Medicine, Reno, NV CD4 + Foxp3 + T regulatory (Treg) cells have a significant impact on the functional status of the global immune response. In aged individuals, the frequency of these cells increases and contributes to reduced immune function. Hematopoietic stem cell transplants (HSCT) and immunostimulatory therapies are two strategies that are used to treat cancer. Recent studies by us and by others have demonstrated increasing frequencies of Treg cells after such treatments. However, the impact of these modalities on Treg cell populations in aged recipients has not been explored. We