Study On Allogeneic Tolerance Induced By Donor-Specific Immature Dendritic Cells Treated With MMF

Allograft rejection remains to be the rnain obStacle of tranSlanation medicine. Whhthe development of twungenetics, we have deepened our Anowledge on immnologicalmecbosms Underlying toplanation rejection. The aPplicatiOn of CsA to clinical usegreatly reduced the morbidity of rejections and toroved the outcome oftraxisplanation.But the systedric bounosuppressive agents, Which are obviously a double-bladed sword,have a lot of side effects and toxicities, which have formed haPetus to seek methods andStrategies fOr induction of donor-specilic tolerance.Dendritic cel1s (DCs) are highly potent anigenpresenting cells of bone marrow originthat can stbolate both primary and secondary T- and B-cell resPonses. These cells haVeevery necessny comPonent for POtent antigen-presenting funtiOns, including theProduction of a variety of twrtant beunostdrilatory cytokines and the erpression ofcritical ce1l-surface molecules. Depending on their level of mauriy, DCs exPressproIninnt 1evels of MHC class l and class II molecules, as well as costdrilatory moleculessuch as CD40, CD80, and CD86. Wl studies show them to be responsible prAnarily fOrsensitto naive T cells in their firSt empsure to anigen. Steinman and Cohn identthedmouse spleen DC in 1973 and ndiated a series of erperfornts tha eStab1ished lymPhoidtissuedrived DC as potent sthaulators ofprbo drine resPonses. The obserVaion thasbolar cells were present in the nonlymPhOid tissues of both rodents and humans,combined with early evidence tha they played an irnPortant role in heart and kidneytranSlan rejeCtio4 generated Wr intereSt in DC. On the other hand, there is subStanialevidences tha DCs mediate tolerane. The GM-CSF-Stbolated mouse bonemwderived MHC class II + DC progendors tha are deficient in cell surfaceerpressiOn of the coStbolatory molecules B7-l and B7-2 can induce alloanginspecific Tceil anergy in vbo. SyStendc adchStraiOn of these donor-derived DC progendors toreciPients intravenously 7 days before tranSplantatiOn prolonged the median graft survivaltAne from 9.5 days to 22 days wbout additiOnal twnosuppressions in a mouse cardinctwlanatiOn model. The auhOrs also noticed tha follOwing injectiOn of these Iabe DCProgendors, Iabe cells tha alsO exPressed B7-l or B7-2 could be deteCted in T-dependentareas of C3H (H2k) reciPient spleens within 7 days. Tha rnay reflect the uP-regUlation ofthe costdrilatory molecu1es on these injected DC progeultors, which then shifted from'tolerogenic" to "inunnogenic", Under the comPlex cytokine ndlieu in vivo. Indeed,although GM-CSF-Stirnulated B7-deficient DC progenitors induced only low levels of Tcell priIning and prolonged allograft survival, they failed to induce indefmite cardiacallogr8ft sed.Mycophenolate mofetil (MMF) has been successfullyintroduced to allogeneictranSPlanatiOn medicine and, recently in the treatInnt of autoforne disorders. MMF isthe morphOlinoethyl eSter prodrug of its active metabolite Inycophenolic acid (MPA. MPAis a noncomPetitive, reversible inhibitor of the enZyme inOsine 5'-monophosphatedehydrogenase (IMPDH), Which plays a maor role in the de novo spohesis of guansinenucleotides. Unlilie other cells that also use the salvage pathway for purine biosynhesis,prolfferating B and T cells are solely dependent on the de novo pathWay for the generatiOnof Wsine. By blocking IMPDH, B and T cells cannot Synthesise the necessary levels ofANA and DNA to moLm a proliferathe resPonse to Ags and ndogens.Moreover, recent data have SUggested a possible role of inOsine 5'-monoPhosphaedehydrogenase in the rnatUratiOn of DCs. They indicated tha in addition to thecting TlymPhOcytes, MMF directly affected DCs, resulting in an impairment of haune resPonses.In the present Study we wer to examine the characteristics of DC progendors cuitured in amedium suPPlemented with MMF, to find otit if such DC progenitors of donor origin wouldWr promote the outcome ofallOgeneic tranSPlanatiOn.M L The...