Combined PI3K/Akt and Hsp90 targeting synergistically suppresses essential functions of alloreactive T cells and increases Tregs

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: allogeneic SCT;    acute GvHD;   

DOI  :  10.1189/jlb.5A0814-413R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Acutegraft‐versus‐hostdiseaseisstillamajorcauseoftransplant‐relatedmortalityafterallogeneicstemcelltransplantation.ItrequiresimmunosuppressivetreatmentsthatbroadlyabrogateTcellresponses,includingbeneficialonesdirectedagainsttumorcellsorinfectivepathogens.Inhibitionoftheheatshockproteinof90kDahasbeendemonstratedtoeliminatetumorcells,aswellasalloreactiveTcellswhilepreservingantiviralTcellimmunity.Here,weshowthatthesuppressiveeffectsofheatshockproteinof90kDainhibitiononalloreactiveTcellsweresynergisticallyenhancedbyconcomitantinhibitionofthePI3K/Aktsignalingpathway,whichisalsostronglyactivateduponallogeneicstimulation.Molecularanalysesrevealedthatthisantiproliferativeeffectwasmainlymediatedbyinductionofcell‐cyclearrestandapoptosis.Inaddition,weobservedanincreasedproportionofactivatedregulatoryTcells,whichcriticallycontributetoacutegraft‐versus‐hostdiseasecontrol,uponcombinedheatshockproteinof90kDa/Aktisoforms1and2orheatshockproteinof90kDa/PI3K/p110δisoforminhibition.Moreover,antiviralTcellimmunitywasfunctionallypreservedaftercombinedheatshockproteinof90kDa/Aktisoforms1and2inhibition.Takentogether,ourdatasuggestthatthecombinedheatshockproteinof90kDa/PI3K/AktinhibitionapproachrepresentsareasonabledualstrategytosuppressresidualtumorgrowthandefficientlydepletealloreactiveTcellsandthus,providearationaletopreventandtreatacutegraft‐versus‐hostdiseaseselectivelywithoutimpairingpathogen‐specificTcellimmunity...

【 授权许可】

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