Transferred allogenic S1P3 deficient dendritic cells (DCs) interact with recipient splenocytes to prevent kidney ischemic-reperfusion injury (IRI) (IRC5P.459)

The plasticity of DCs permits phenotypic modulation ex-vivo by gene expression or pharmacological agents. Sphingosine-1-phosphate (S1P), a sphingolipid is the natural ligand for S1Pr1-5s. We tested the ability of S1P3-/-(3KO) DC to suppress kidney IRI. BMDCs from B6 WT (B6DC) or 3KOB6DC were adoptively transferred into (->) Balb/c 1d/7d prior to IRI. Naive Balb (noDC) had higher plasma creatinine (PCr; mg/dl) compared to sham (1.2±0.17;0.2±0.004,p≤0.01). 3KOB6DCs->Balb/c were protected from IRI (PCr:0.3±0.07,p≤0.01). 3KOB6DCs->Balb/c had higher Treg and less CD4 cells compared to naive or B6DC mice in spleen. The protection afforded by 3KOB6DCs->Balb/c mice required the recipient mouse to have a spleen; Tregs, CD11c+ DC and T/B cells; Splnx Balb, use of Rag1-/- mice or depletion of recipient Tregs (PC61) or DCs (CD11c-DTR) rendered adoptively transferred 3KODCs ineffective. PKH-26 labeled DCs from WT or 3KO->Balb/c were located in the marginal zone (MZ) of recipient spleen with close proximity to Tregs. WT and 3KO mice injected with latex beads to demonstrate clearance efficiency showed disruption of MZ in 3KO. Adoptive transfer of 3KOB6DCs prior to IRI attenuates injury through interaction with splenocytes, recipient DCs resulting in induction of Tregs through possible disruption of MZ macs. We conclude that genetically induced deficiency or pharmacological blockade of allogenic S1P3DCs could serve as a useful therapeutic approach to IRI or DGF associated with Transplant.