Inhibition of T cell costimulation abrogates airway hyperresponsiveness in a murine model.

Activation of naive T cells requires at least two signals. In addition to the well characterized interaction of the T cell antigen receptor with the antigen/MHC expressed on an antigen-presenting cell, T cell activation also requires costimulation by a second set of signals. The best characterized costimulatory receptor is CD28, which binds to a family of B7 ligands expressed on antigen-presenting cells. In asthma, although activated T cells play a role in the initiation and maintenance of airway inflammation, the importance of T cell costimulation in bronchial hyperresponsiveness had not been characterized. Therefore, we tested the hypothesis that inhibition of the CD28:B7 costimulatory pathway would abrogate airway hyperresponsiveness. Our results show that blockade of costimulation with CTLA4-Ig, a fusion protein known to prevent costimulation by blocking CD28:B7 interactions, inhibits airway hyperresponsiveness, inflammatory infiltration, expansion of thoracic lymphocytes, and allergen-specific responsiveness of thoracic T cells in this murine model of allergic asthma.

[1]  D. Christiani,et al.  T cell activation in a murine model of asthma. , 1996, The American journal of physiology.

[2]  J. Bluestone,et al.  Regulation of CTLA-4 expression during T cell activation. , 1996, Journal of immunology.

[3]  J. Allison,et al.  Enhancement of Antitumor Immunity by CTLA-4 Blockade , 1996, Science.

[4]  J. Bluestone,et al.  CD28 expression is not essential for positive and negative selection of thymocytes or peripheral T cell tolerance. , 1996, Journal of immunology.

[5]  P. Finn,et al.  Plasticity of the T cell receptor repertoire in TCR beta-chain transgenic mice. , 1996, Cellular immunology.

[6]  H. Griesser,et al.  Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4 , 1995, Science.

[7]  J. Bluestone,et al.  Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. , 1995, Immunity.

[8]  E. Lander,et al.  Quantitative locus analysis of airway hyperresponsiveness in A/J and C57BL/6J mice , 1995, Nature Genetics.

[9]  J. Allison,et al.  CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation , 1995, The Journal of experimental medicine.

[10]  L. Kobzik,et al.  Increased airway responsiveness to inhaled methacholine in a rat model of chronic bronchitis. , 1995, American journal of respiratory and critical care medicine.

[11]  E Claassen,et al.  Requirement of CTLA-4 counter receptors for IL-4 but not IL-10 elevations during a primary systemic in vivo immune response. , 1995, Journal of immunology.

[12]  P. Linsley,et al.  Treatment of murine lupus with CTLA4Ig. , 1994, Science.

[13]  P. Linsley,et al.  CTLA-4 can function as a negative regulator of T cell activation. , 1994, Immunity.

[14]  P. Linsley,et al.  CTLA-4 ligands are required to induce an in vivo interleukin 4 response to a gastrointestinal nematode parasite , 1994, The Journal of experimental medicine.

[15]  P. Finn,et al.  Differential expression of activation markers during tolerance induction by superantigens in T-cell receptor (beta-chain) transgenic mice. , 1994, Cellular immunology.

[16]  P. Linsley,et al.  T-cell activation by the CD28 ligand B7 is required for cardiac allograft rejection in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[17]  P. Linsley,et al.  Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. , 1992, Science.

[18]  P. Linsley,et al.  Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. , 1992, Science.

[19]  H. P. Fell,et al.  Chimeric L6 anti-tumor antibody. Genomic construction, expression, and characterization of the antigen binding site. , 1992, The Journal of biological chemistry.

[20]  J. Virchow,et al.  Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. , 1992, The American review of respiratory disease.

[21]  J. Allison,et al.  CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones , 1992, Nature.

[22]  P. Linsley,et al.  CTLA-4 is a second receptor for the B cell activation antigen B7 , 1991, The Journal of experimental medicine.

[23]  P. Venge,et al.  Current understanding of the role of the eosinophil granulocyte in asthma , 1991, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[24]  S. Durham,et al.  Identification of activated T lymphocytes and eosinophils in bronchial biopsies in stable atopic asthma. , 1990, The American review of respiratory disease.

[25]  J. Bousquet,et al.  Eosinophilic inflammation in asthma. , 1990, The New England journal of medicine.

[26]  M. Gefter,et al.  Identical peptides recognized by MHC class I- and II-restricted T cells , 1989, The Journal of experimental medicine.

[27]  A. Wardlaw,et al.  Eosinophils and mast cells in bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial hyperreactivity. , 1988, The American review of respiratory disease.

[28]  C. Snapper,et al.  Polyclonal activation of the murine immune system by a goat antibody to mouse IgD. IX. Induction of a polyclonal IgE response. , 1987, Journal of immunology.

[29]  G. Hunninghake,et al.  Bronchoalveolar lavage of allergic asthmatic patients following allergen bronchoprovocation. , 1986, Chest.

[30]  H. Kauffman,et al.  Plasma histamine concentrations and complement activation during house dust mite‐provoked bronchia] obstructive reactions , 1983, Clinical allergy.

[31]  Robert A. Lewis,et al.  Bronchoconstrictor effects of leukotriene C in humans. , 1982, Science.

[32]  N. Thomson,et al.  Bronchial responsiveness to histamine or methacholine in asthma: measurement and clinical significance. , 1981, The Journal of allergy and clinical immunology.

[33]  M. Dunnill.  THE PATHOLOGY OF ASTHMA, WITH SPECIAL REFERENCE TO CHANGES IN THE BRONCHIAL MUCOSA , 1960, Journal of clinical pathology.