CTLA4Ig abrogates allergic airway inflammation through a novel B7-mediated IFNγ/STAT1/NO signaling pathway (63.22)
| Autor: | Christine Deppong, Traci Bricker, Jonathan Boomer, Jonathan Green |
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| Rok vydání: | 2011 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 186:63.22-63.22 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.186.supp.63.22 |
| Popis: | Optimal T cell activation requires both TCR signaling and costimulation through CD28. In vivo use of the drug CTLA4Ig (Abatacept) interrupts B7:CD28 binding and has been an effective therapeutic strategy for chronic inflammatory disease. The presumed mechanism of action of CTLA4Ig is that it prevents the initiation of CD28 signaling. However, previous studies in our laboratory have demonstrated that in a murine model of allergic airway inflammation, CTLA4Ig can function by a novel CD28-independent, NOS2-dependent mechanism. In this study we further dissected this novel mechanism of CTLA4Ig by looking at both in vivo and in vitro models. We now demonstrate through the use of bone marrow chimeras and knockout mice that this in vivo mechanism requires IFNγ and STAT-1 mediated signaling. Furthermore, we used an in vitro coculture system of splenocytes and bone marrow derived macrophages to establish that CTLA4Ig binding to B7 on splenocytes induces IFNγ secretion. This cytokine stimulates the bone marrow derived macrophages to activate STAT-1 dependent NO production, which inhibits T cell proliferation. This data establishes a novel mechanism for immunosuppression by CTLA4Ig. In contrast to accepted dogma, CTLA4Ig inhibits ongoing inflammation not solely by preventing CD28-mediated costimulation, but by a novel mechanism whereby B7 ligation leads to the induction of an IFNγ/STAT1/NO mediated signaling pathway and suppression of T lymphocytes. |
| Databáze: | OpenAIRE |
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