In:
Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 89, No. 6 ( 2011-03-14), p. 955-964
Abstract:
PI3Kγ is thought to mediate leukocyte migration to injured tissues and may be important in the pathogenesis of various T-lymphocyte-dependent pathologies, including autoimmune and inflammatory diseases. The present study evaluated the relevance of PI3Kγ in donor cells for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PI3Kγ−/− C57BL/6J mice to B6D2F1 mice, and mice that received PI3Kγ−/− cells showed reduced clinical signs of disease, bacterial translocation, tissue injury, and lethality rates. This was associated with reduced production of proinflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL2, CCL3, and CCL5) and reduced infiltration of CD8+, CD4+, and CD11c+ cells in the small intestine. Mechanistically, in addition to decreasing production of proinflammatory mediators, absence or pharmacological blockade of PI3Kγ was associated with decreased rolling and adhesion of leukocytes to the mesenteric microcirculation, as assessed by intravital microscopy. Despite decreased GVHD, there was maintained GVL activity when PI3Kγ−/− leukocytes were transferred into WT mice. In conclusion, PI3Kγ plays a critical role in GVHD by mediating leukocyte influx and activation in tissues. PI3Kγ inhibitors may be useful in the treatment of GVHD in patients undergoing BMT.
Type of Medium:
Online Resource
ISSN:
0741-5400
,
1938-3673
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2011
detail.hit.zdb_id:
2026833-6
SSG:
12
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