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Presenter: Shinji, Okano, Cleveland, United States
Authors: Shinji Okano, Kareem Abu-Elmagd, Robert Fairchild, Masato Fujiki, Ajai Khanna, Mohammed Osman, Guilherme Costa, Charles Miller, Koji Hashimoto
Shinji Okano1, Kareem Abu-Elmagd1, Robert L. Fairchild2, Masato Fujiki1, Ajai Khanna1, Mohammed Osman1, Guilherme Costa1, Charles Miller1, Koji Hashimoto1.
1Transplant Center, Dept. General Surgery, Digestive Disease & Surgery Institute, Cleveland Clinic, Cleveland, OH, United States; 2Dept. immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States
Background and aims: Recent advances in immunosuppressive regimens have decreased rejection rates and improved intestinal transplant (ITx) recipient survival. The potential mechanisms underlying these improvements remain to be elucidated. Myeloid-derived suppressor cells (MDSCs) are potent immature myeloid cells capable of suppressing T cell responses. The impact of MDSCs on clinical transplant outcomes remains unknown.
Methods: Thirty-eight ITx recipients were enrolled from January 2015 to December 2016. Thirty-four ITx recipients received induction therapy and all received maintenance steroids and FK506. Peripheral blood mononuclear cells (PBMCs) and mononuclear cells in the intraepithelial and lamina propria compartments were isolated. MDSCs were identified by antibody-staining and flow cytometry as: CD33+CD11b+lineage-HLA-DR-/low cells with 3 subsets, CD14-CD15- (I-MDSC), CD14+CD15- (M-MDSC), and CD14-CD15+ (G-MDSC) and used to perform functional studies of the MDSCs.
Results: The total numbers of MDSCs and each subset of MDSCs significantly increased in PBMCs after ITx when compared with pre-transplant levels. All MDSC subsets suppressed CD4 and CD8 T-cell responses to anti-CD3 or allogenic B cell stimulation. Total numbers of MDSCs in PBMCs from ITx recipients with acute cellular rejection (ACR) were significantly lower than those without ACR. The number of MDSCs positively correlated with serum IL-6 levels and the glucocorticoid administration index based on the relative potency, but not with serum TNF-a levels and trough levels of FK506. IL-6 and methylprednisolone dramatically enhanced the differentiation of bone marrow cells to MDSC in vitro, suggesting steroid administration and IL-6 could induce accumulation of MDSCs after ITx. M-MDSCs and I-MDSCs expressed CCR1-3 but G-MDSCs expressed low/absent CCR1-3, and I-MDSCs and G-MDSCs but not M-MDSCs expressed CXCR2, suggesting MDSC have the potential to traffic to the intestinal grafts expressing the corresponding chemokine ligands. In support of this, the percentages of total MDSC and each subset among CD45+ cells in graft lamina propria mucosa significantly increased after ITx when compared with pre-reperfusion grafts. Finally, recipient MDSCs suppressed donor-reactive T cell-mediated destruction of ex vivo donor intestinal epithelial stem cell formation of organoids.
Conclusion: These results indicate MDSC accumulation in ITx recipients and support their important role in controlling ACR.
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