ABSTRACT
The recently described ICOS-B7RP-1 costimulatory pathway has been implicated in the generation of effector Th2 responses and, hence, has become an attractive therapeutic target for allergic diseases. In the present study, we used B7RP-1-deficient mice to investigate the role of B7RP-1 in the generation and maintenance of Th2 responses in a model of mucosal allergic airway inflammation. We found that exposure of B7RP-1 knockout mice to aerosolized OVA in the context of GM-CSF leads to airway eosinophilic inflammation. This response was long lasting because rechallenge of mice with the same Ag recapitulated airway eosinophilia. Moreover, significant expression of T1/ST2 on T cells and production of Th2-affiliated cytokines (IL-5, IL-4, and IL-13) and Igs (IgE and IgG1) conclusively demonstrate the generation of a Th2 response in the absence of B7RP-1. In addition, expression of two major Th2-associated costimulatory molecules-CD28 and ICOS-indicates T cell activation in the absence of B7RP-1 signaling. Finally, B7RP-1 knockout mice are resistant to the induction of inhalation tolerance as indicated by the sustained eosinophilia in the lung and IL-5 production. In summary, our results demonstrate that in a model of mucosal allergic sensitization, the ICOS-B7RP-1 pathway is redundant for the generation of Th2 responses but essential for the induction of inhalation tolerance.
Subject(s)
Allergens/immunology , B7-1 Antigen/genetics , Immune Tolerance , Lung/pathology , Respiratory Hypersensitivity/immunology , Th2 Cells/immunology , Th2 Cells/metabolism , Administration, Inhalation , Allergens/administration & dosage , Animals , Antigens, Differentiation, T-Lymphocyte/biosynthesis , B7-1 Antigen/physiology , CD28 Antigens/biosynthesis , Disease Models, Animal , Humans , Immune Tolerance/genetics , Immunologic Memory/genetics , Inducible T-Cell Co-Stimulator Ligand , Inducible T-Cell Co-Stimulator Protein , Inflammation/genetics , Inflammation/immunology , Lung/immunology , Lung/metabolism , Mice , Mice, Knockout , Ovalbumin/administration & dosage , Ovalbumin/immunology , Respiratory Hypersensitivity/genetics , Respiratory Hypersensitivity/pathology , Respiratory Mucosa/immunology , Respiratory Mucosa/pathology , Signal Transduction/genetics , Signal Transduction/immunologyABSTRACT
Given its primary role in the execution of T cell, and especially Th2, effector activity, the inducible costimulator (ICOS)/B7-related protein (RP)-1 costimulatory pathway is currently being heralded as a promising therapeutic target for immune-inflammatory disorders such as asthma. This study investigates the merits of ICOS blockade in a murine model of experimental asthma in which mice are sensitized to ovalbumin (OVA) through the respiratory mucosa. Intraperitoneal treatment of mice with anti-ICOS neutralizing antibody during sensitization resulted in a marked reduction in airway eosinophilia and IL-5 in bronchoalveolar lavage, but had no effect on interleukin (IL)-4, IL-13, and eotaxin content in bronchoalveolar lavage or the production of OVA-specific immunoglobulin E in serum. Cultured splenocytes from mice sensitized to OVA in the context of ICOS ablation produced enhanced levels of IL-4 and IL-5 upon stimulation with OVA, and this correlated with elevated inflammation and immunoglobulin E secretion upon long-term in vivo OVA recall; the deleterious effects ICOS blockade, however, were not associated with reduced IL-10 production by splenocytes. Peculiarly, anti-ICOS intervention during OVA rechallenge had no effect on airway inflammation or immunoglobulin production, despite high levels of ICOS expression on infiltrating CD4+ T cells. This study provides in vivo evidence of an exacerbated long-term immune-inflammatory response following acute ICOS blockade, and suggests that ICOS costimulation is functionally redundant in established allergic disease.
Subject(s)
Antigens, Differentiation, T-Lymphocyte/drug effects , Asthma/drug therapy , B7-1 Antigen/drug effects , Inflammation/drug therapy , Animals , Antibodies/pharmacology , Antigens, Differentiation, T-Lymphocyte/immunology , Asthma/chemically induced , Asthma/pathology , B7-1 Antigen/metabolism , Bronchoalveolar Lavage , Cells, Cultured , Chemokine CCL11 , Chemokines, CC/metabolism , Desensitization, Immunologic , Disease Models, Animal , Female , Immunoglobulin E/blood , Inducible T-Cell Co-Stimulator Ligand , Inducible T-Cell Co-Stimulator Protein , Inflammation/chemically induced , Inflammation/pathology , Interleukin-10/metabolism , Interleukin-13/metabolism , Interleukin-4/metabolism , Interleukin-5/metabolism , Lung/drug effects , Lung/immunology , Lung/pathology , Mice , Mice, Inbred BALB C , Ovalbumin , Spleen/cytology , Spleen/metabolism , Th1 Cells/drug effects , Th1 Cells/immunology , Th2 Cells/drug effects , Th2 Cells/immunologyABSTRACT
Most HIV-1 transmission studies use self-reported history to define the source contact. To evaluate the reliability of epidemiologic source partner reporting, heteroduplex mobility assays (HMAs) were performed comparing the different viral strains present in the partners. Partners were typed for human leukocyte antigen (HLA) to evaluate the degree of shared alleles. Of 11 couples evaluated, HMA analysis confirmed nine transmissions (including 1 oral-genital transmission), indicated probable transmission in 1 couple, and suggested an alternative source partner in another. Nine source partners transmitted a major variant. Four source partners knew their HIV status. Previous HIV monitoring was reported by 5 of the 6 confirmed source partners who were unaware of their HIV status at the time of transmission. We also evaluated potential "sharing of HLA alleles" as a risk factor for HIV-1 acquisition; partners were not found to have a higher degree of shared HLA alleles. Lack of awareness about infection status as a consequence of infrequent testing plays a major role in the secondary transmission of HIV. These findings re-emphasize the importance of using safe sex practices at all times.
