Plasmacytoid Dendritic Cell microRNAS in Transplantation

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7. Project Summary Liver allografts are generally well tolerated, and other solid organ allografts, such as the small intestine, heart, and kidney, transplanted concurrently with livers show improved graft outcomes. However, the mechanisms underlying “hepatic tolerance” have yet to be elucidated. Hepatic plasmacytoid dendritic cells p(DC) have been shown to have diminished ability to stimulate an immune response as compared with DC in lymphoid tissue. Further, functional differences between DC subsets, including (p)DC and conventional (c)DC, have been defined, with the hypothesis that immature pDC inherently dampen an immune response and are tolerogenic. Indeed, multiple studies show that pDC play a unique and important role in the generation of tolerance. However, the mechanism responsible for the tolerogenic properties of pDC remains elusive. Recently we determined that six members of the miR-181 family of microRNAs were all significantly increased in hepatic pDC as compared to hepatic cDC. Further we show that hepatic pDC significantly prolong solid organ allograft survival and this enhanced survival in abrogated in the absence of miR-181a. The overall goals of our proposal are: 1) to determine the mechanism by which miR-181-expressing pDC alters the immune system to improve the survival of solid organ allografts and 2) exploiting the graft prolonging capacity of miR-181-expressing pDC to generate a therapeutic to prolong allograft survival. In our first specific aim, we will test the hypothesis that miR-181-expressing pDC modifies the immune response towards enhanced graft survival. A complete profiling of the immune response after transplantation with miR-181+ and miR-181-/- pDC, using cutting-edge CyTOF technology, will be performed. The mRNA target of miR-181-expressing pDC, and biological function, will be determined. Further, it will be determined if miR-181-expressing pDC prolongs allograft survival by functioning in cis or trans. In our second specific aim we will test the hypothesis that (over)expression of miR-181a can prolong allograft survival. Since pDC are present in such limited numbers development of hepatic pDC as a cellular therapeutic is limited. In this Aim we will examine whether over-expression of miR-181 in the more plentiful bone marrow derived DC can prolong graft survival. Results from these highly novel studies will result in improved outcomes, and enhance the quality of life for transplant recipients, and their families.