Rapamycin Combined with Anti-CD45RB mAb and IL-10 or with G-CSF Induces Tolerance in a Stringent Mouse Model of Islet Transplantation 英文参考文献.docVIP

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Rapamycin Combined with Anti-CD45RB mAb and IL-10 or with G-CSF Induces Tolerance in a Stringent Mouse Model of Islet Transplantation 英文参考文献.doc

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Rapamycin Combined with Anti-CD45RB mAb and IL-10 or with G-CSF Induces Tolerance in a Stringent Mouse Model of Islet Transplantation 英文参考文献

RapamycinCombinedwithAnti-CD45RBmAbandIL-10 orwithG-CSFInducesToleranceinaStringentMouse ModelofIsletTransplantation NicolaGagliani1,2,3,SilviaGregori2,TatianaJofra1,AndreaValle1,3,AngelaStabilini1,DavidM. Rothstein4,MarkAtkinson5,MariaGraziaRoncarolo2,3,ManuelaBattaglia1* 1SanRaffaeleDiabetesResearchInstitute,SanRaffaeleScientificInstitute,Milan,Italy,2SanRaffaeleTelethonInstituteforGeneTherapy,SanRaffaeleScientificInstitute, Milan,Italy,3Vita-SaluteSanRaffaeleUniversity,Milan,Italy,4StarzlTransplantationInstitute,UniversityofPittsburghMedicalCenter,Pittsburgh,Pennsylvania,United StatesofAmerica,5DepartmentofPathology,TheUniversityofFlorida,Gainesville,Florida,UnitedStatesofAmerica Abstract Background: A large pool of preexisting alloreactive effector T cells can cause allogeneic graft rejection following transplantation. However, it is possible to induce transplant tolerance by altering the balance between effector and regulatoryT(Treg)cells.AmongthevariousTreg-celltypes,Foxp3+TregandIL-10–producingTregulatorytype1(Tr1)cells have frequently been associated with tolerance following transplantation in both mice and humans. Previously, we demonstrated that rapamycin+IL-10 promotes Tr1-cell–associated tolerance in Balb/c mice transplanted with C57BL/6 pancreaticislets.However,thissametreatmentwasunsuccessfulinC57BL/6micetransplantedwithBalb/cislets(classified asastringenttransplantmodel).Weaccordinglydesignedaprotocolthatwouldbeeffectiveinthelattertransplantmodel bysimultaneouslydepletingeffectorTcellsandfosteringproductionofTregcells.Weadditionallydevelopedandtesteda clinicallytranslatableprotocolthatusednodepletingagent. Methodology/Principal Findings: Diabetic C57BL/6 mice were transplanted with Balb/c pancreatic islets. Recipient mice transiently treated with anti-CD45RB mAb+rapamycin+IL-10 developed antigen-specific tolerance. During treatment, Foxp3+Tregcellsweremomentarilyenrichedintheblood,followedbyaccumulationinthegraftanddraininglymphnode, + + + + whereas