Introduction Dendritic Cells (DC)

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1 mirna-181 Promotes Graft Prolongation by Plasmacytoid Dendritic Cells by increasing T Regulatory cells and Decreasing B cells as Revealed by Mass Cytometry (CyTOF) Audrey H. Lau, MD, PhD UCSF Department of Pediatrics, Division of Gastroenterology Department of Surgery, Division of Abdominal Transplantation 1 Audrey H. Lau, MD, PhD Instructor Lucile Packard Children s Hospital/Stanford University I have no financial relationships with commercial interests to disclose AND My presentation does not include discussion of off-label or investigational use. Introduction Dendritic Cells (DC) Major subsets are the conventional (c)dc and plasmacytoid (p)dc Adapted from KX Wang et al, Cytokine & Growth Factor Reviews 19 (2008)

2 Plasmacytoid (p)dc Important in innate and adaptive T cell responses to viral infections Type 1 IFN-producing cells Regulate immune reactivity shown to be involved in Treg generation Hepatic pdc express lower MHCII and CD86 as well as have poor allostimulatory capacity compared to splenic pdc Methods Freshly-Isolated DC Liver Digestion Density gradient T cells B cells M 10 days of Flt3L treatment DC PDCA-1 Flow Sort CD11c magnetic bead purification ~95% purity + Bulk CD11c + cells CD11c Title Adoptive & Content Transfer and Transplant Main point number one Day -7: Bead-purified Bullets to support your points CD11c + DC or Flow Sorted Each pdcsublevel gets indented using the (C57BL/6) promote/demote buttons on the Home ribbon Layout available in all four background colors The last pre-formatted level Main point number two i.v. injection (allogeneic BALB/c recipient) Day 0: Allogeneic heterotopic cardiac allograft transplant (C57BL/6J graft)

3 Hepatic pdc prolong cardiac allograft survival (n=4) 7 Liver transplant patients are more likely to attain tolerance to their graft What properties are inherent to hepatic pdc which promote tolerance? ~22 nucleotides long single-stranded RNA microrna Regulate one or more target genes by binding and degrading mrna A Harris et al, American J Transplant 10 (2010)

4 Bulk cdc pdc Differential microrna profile of pdc Affymetrix version 4 microrna gene chip Profiles all known microrna 113 differentially regulated microrna (FDR 10%) Differential mrna expression in mir- 181a1b1 -/- KO pdc KO pdc WT pdc Affymetrix Mu430-2 gene chip SAM analysis with FDR<10% mir-181a1b1 modulates ~380 genes in pdc Genes involved in immune regulation and associated processes mir-181a1b1 targets activation of pathways GSEA of >3000 gene sets identified 14 immune sets with FDR<30% and p<0.06 mir181a KO Wild Type Majority represented DC immune processes 4

5 CD86 and MHCII are more highly upregulated on mir-181a1b1 -/- KO pdc Geomean KO Geomean WT x 100 = * p<0.05 by Wilcoxon sign rank test n = 5 9 Loss of mir-181a1b1 abrogates the tolerogenic properties of WT pdc (n=4) Analysis of Alloactivation by Cytometry Time-of-Flight (CyTOF, mass cytometry) Bendall C et al. Trends Immunol

6 Examining the Alloimmune Response injection of pdc C57BL/6J Heart transplant C57BL/6J Spleen BALB/cJ Day -7 Day 0 Day +7 Analysis of Mass Cytometry Data: Citrus a method for unsupervised identification of significant cellular populations, clustered on the basis of the expression of markers studied Each node is a specific cell population Color scale Node size CyTOF: Differing alloimmune response in mice pre-treated with mir-181a1b1 -/- pdc 18 6

7 Increased CD3 + CD4 + CD127 - / lo T cells are detected in graft recipients that receive hepatic pdc Node A background cluster Increased B cells are detected in graft recipients that receive mir-181a1b1 -/- pdc Node B background cluster FACS: Marginal Zone B cells and Plasmablasts are decreased in mir- 181a1b1-expressing pdc treated mice p < 0.05 WT n=5 KO n=3 7

8 CONCLUSIONS mir-181a1b1 is a critical regulator of the tolerogenic properties of plasmacytoid dendritic cells mirna-181 promotes graft prolongation by pdc by increasing Treg cells and decreasing B cells mir-181a Treg B cells? cdc mir-181a pdc Promotes graft survival Acknowledgements Co-authors: Matthew Vitalone, Xiumei Qu, Todd Shawler, Olivia M. Martinez, Carlos O. Esquivel, and Sheri M. Krams Grant Support NIDDK F32 DK94548 ALF Postdoctoral Research Fellowship Award American Heart Association (to SMK) CHRI Pilot Early Career Award 8

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