title: PI3Kγ controls leukocyte recruitment, tissue injury, and lethality in a model of graft-versus-host disease in mice.
abstract: PI(3)Kγ 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 PI(3)Kγ in donor cells for the pathogenesis of acute GVHD using a model of adoptive transfer of splenocytes from WT or PI(3)Kγ(-/-) C57BL/6J mice to B6D2F1 mice, and mice that received PI(3)Kγ(-/-) 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 PI(3)Kγ 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 PI(3)Kγ(-/-) leukocytes were transferred into WT mice. In conclusion, PI(3)Kγ plays a critical role in GVHD by mediating leukocyte influx and activation in tissues. PI(3)Kγ inhibitors may be useful in the treatment of GVHD in patients undergoing BMT.
authors.affiliation: Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Av. Antonio Carlos, 6627, Pampulha 31270-901, Belo Horizonte, MG, Brazil.
authors.forename: Marina G M
authors.initials: MG
authors.lastname: Castor
authors.forename: Bárbara M
authors.initials: BM
authors.lastname: Rezende
authors.forename: Priscila T T
authors.initials: PT
authors.lastname: Bernardes
authors.forename: Angélica T
authors.initials: AT
authors.lastname: Vieira
authors.forename: Erica L M
authors.initials: EL
authors.lastname: Vieira
authors.forename: Rosa M E
authors.initials: RM
authors.lastname: Arantes
authors.forename: Danielle G
authors.initials: DG
authors.lastname: Souza
authors.forename: Tarcília A
authors.initials: TA
authors.lastname: Silva
authors.forename: Mauro M
authors.initials: MM
authors.lastname: Teixeira
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pinho
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism / Q000401:mortality*; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D007124:Immunoenzyme Techniques; D007421:Intestine, Small / Q000276:immunology* / Q000293:injuries / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000276:immunology* / Q000293:injuries / Q000378:metabolism; D008297:Male; D034801:Mastocytoma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D015996:Survival Rate
chemical_list: D018925:Chemokines; D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases