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Pathogenesis of transfusion related acute lung injury (TRALI) in an in vivo murine model
S10
Abstracts
1.3 12-OR
INDUCTION OF T REGULATORY CELLS BY STIMULATION WITH IMMATURE AUTOLOGOUS DENDRITIC CELL ENRICHED POPULATION Yide Jin,1 Laphalle Fuller,1 George W. Burke III,1 Violet Esquenazi,1,2 Joshua Miller1,2, 1Surgery, University of Miami, School of Medicine, Miami, FL, USA; 2Miami Veterans Affairs Medical Center, Miami, FL, USA It is now well known that regulatory T cells (Treg) may play a pivotal role in tolerance establishment. In this study, we were able to generate regulatory T cells from peripheral CD3⫹ pool by multiple stimulation with autologous immature DC enriched population either derived from BMC or peripheral blood. Autoreactive T cells generated from different individuals were CD4⫹/CD3⫹ enriched (⬎78%) and were abTCR and CD45RA low, CD45RO high. After activation (with self antigen), their expression of CD25 and intracellular CTLA4 levels were elevated. They were auto-reactive, their proliferative response to self-antigen was 3-fold stronger than to allo-antigen, but exhibited no cytotoxicity to the target bearing self-antigens. Tauto expressed IL-4, IL-10 suppressive cytokine messages and showed immune down-regulation on cellular immunity to allo-antigen as well as viral antigen. Cell-to-cell contact, was required for achieving the better Tauto suppression, and the HLA restriction was not always required for the inhibition. This study demonstrated that self-reactive T cells do not always lead to self-damage; they can also be involved in immune regulation. Their immune suppression on cellular immunity to allo-antigen may be beneficial for graft survival. VA 2514.02 NIH5R01DK25243/23.
2 13-OR
PATHOGENESIS OF TRANSFUSION RELATED ACUTE LUNG INJURY (TRALI) IN AN IN VIVO MURINE MODEL Wyenona Hicks,1 Brian M. Susskind,1 Richard Strait,2 Fred Finkelman3, 1Transplantation Immunology Division, Hoxworth Blood Center, Cincinnati, OH, USA; 2Pediatrics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA; 3Internal Medicine–Immunology, University of Cincinnati Medical School, Cincinnati, OH, USA TRALI, one of the most common noninfectious, life-threatening complications of blood transfusion, is associated with the administration of blood that contains anti-MHC (Major Histocompatibility Complex) antibodies. We developed an in vivo murine model of TRALI by injecting BALB/c (H-2d) mice with 34-1-2s, a murine IgG2a anti-H-2d monoclonal antibody (mAb). Hypothermia (measured by rectal temperatures) and dyspnea (measured by barometric plethysmography) were rapidly induced in BALB/c mice but not in congenic H-2k controls. Pathological changes associated with the lungs include the presence of pulmonary edema after anti-MHC mAb challenge. Lung histology performed 2 and 24 hours after anti-MHC mAb challenge demonstrated significant inflammatory changes. Moderate infiltration of proteinacious materials was present at 2 hours, becoming yet more remarkable at 24 hours. While absent in the control, cellular infiltration of the lungs was predominately polymorphonuclear at 2 hours and mononuclear at 24 hours. Pretreatment with antiFc RII/III mAb, gadolinium, or PAF, histamine or leukotrienes antagonists, inhibited the induction of the hypothermia and dyspnea observed in this model. These results suggest that IgG, Fc RIII, macrophages, PAF, histamine, and leukotrienes are important in anti-MHC antibody induction of hypothermia and pulmonary dysfunction. This animal model may be useful for determining pathogenic mechanisms of TRALI and for identifying potential therapeutic interventions.
Abstracts
1.3 12-OR
INDUCTION OF T REGULATORY CELLS BY STIMULATION WITH IMMATURE AUTOLOGOUS DENDRITIC CELL ENRICHED POPULATION Yide Jin,1 Laphalle Fuller,1 George W. Burke III,1 Violet Esquenazi,1,2 Joshua Miller1,2, 1Surgery, University of Miami, School of Medicine, Miami, FL, USA; 2Miami Veterans Affairs Medical Center, Miami, FL, USA It is now well known that regulatory T cells (Treg) may play a pivotal role in tolerance establishment. In this study, we were able to generate regulatory T cells from peripheral CD3⫹ pool by multiple stimulation with autologous immature DC enriched population either derived from BMC or peripheral blood. Autoreactive T cells generated from different individuals were CD4⫹/CD3⫹ enriched (⬎78%) and were abTCR and CD45RA low, CD45RO high. After activation (with self antigen), their expression of CD25 and intracellular CTLA4 levels were elevated. They were auto-reactive, their proliferative response to self-antigen was 3-fold stronger than to allo-antigen, but exhibited no cytotoxicity to the target bearing self-antigens. Tauto expressed IL-4, IL-10 suppressive cytokine messages and showed immune down-regulation on cellular immunity to allo-antigen as well as viral antigen. Cell-to-cell contact, was required for achieving the better Tauto suppression, and the HLA restriction was not always required for the inhibition. This study demonstrated that self-reactive T cells do not always lead to self-damage; they can also be involved in immune regulation. Their immune suppression on cellular immunity to allo-antigen may be beneficial for graft survival. VA 2514.02 NIH5R01DK25243/23.
2 13-OR
PATHOGENESIS OF TRANSFUSION RELATED ACUTE LUNG INJURY (TRALI) IN AN IN VIVO MURINE MODEL Wyenona Hicks,1 Brian M. Susskind,1 Richard Strait,2 Fred Finkelman3, 1Transplantation Immunology Division, Hoxworth Blood Center, Cincinnati, OH, USA; 2Pediatrics, Cincinnati Childrens Hospital Medical Center, Cincinnati, OH, USA; 3Internal Medicine–Immunology, University of Cincinnati Medical School, Cincinnati, OH, USA TRALI, one of the most common noninfectious, life-threatening complications of blood transfusion, is associated with the administration of blood that contains anti-MHC (Major Histocompatibility Complex) antibodies. We developed an in vivo murine model of TRALI by injecting BALB/c (H-2d) mice with 34-1-2s, a murine IgG2a anti-H-2d monoclonal antibody (mAb). Hypothermia (measured by rectal temperatures) and dyspnea (measured by barometric plethysmography) were rapidly induced in BALB/c mice but not in congenic H-2k controls. Pathological changes associated with the lungs include the presence of pulmonary edema after anti-MHC mAb challenge. Lung histology performed 2 and 24 hours after anti-MHC mAb challenge demonstrated significant inflammatory changes. Moderate infiltration of proteinacious materials was present at 2 hours, becoming yet more remarkable at 24 hours. While absent in the control, cellular infiltration of the lungs was predominately polymorphonuclear at 2 hours and mononuclear at 24 hours. Pretreatment with antiFc RII/III mAb, gadolinium, or PAF, histamine or leukotrienes antagonists, inhibited the induction of the hypothermia and dyspnea observed in this model. These results suggest that IgG, Fc RIII, macrophages, PAF, histamine, and leukotrienes are important in anti-MHC antibody induction of hypothermia and pulmonary dysfunction. This animal model may be useful for determining pathogenic mechanisms of TRALI and for identifying potential therapeutic interventions.