Tolerance induction after combined organ and hematopoietic cell transplantation can be achieved using conditioning with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG), in both pre-clinical and clinical studies. In murine studies, granulocytic myeloid derived suppressor cells (MDSCs) were induced by TLI and required for tolerance induction. Here, we studied changes in granulocytic (PMN) MDSCs in blood of patients given combined HLA-matched and -mismatched kidney and hematopoietic cell transplants after TLI and ATG conditioning. We found that in the first 4 months post-transplant, there was profound T cell depletion in the blood of HLA matched and mismatched patients, and a significant increase in the absolute number of Lin^–CD11b^hiDR^loCD15⁺CD14^– (PMN) MDSCs. The ratio of MDSCs-to-T cells significantly changed to favor MDSCs. The ratio returned to pre-transplant values between 6 to 12 months post-transplant. Early following transplantation, the MDSCs had a significantly increased ability to suppress the activation (CD25 expression, IL-2 and IFN-g production) and proliferation of autologous pre-transplant T cells. The suppression was associated with increased surface expression of LOX-1 and the production of arginase-1. The suppressive capacity of the MDSCs returned to pre-transplant values 6 months post-transplant. The gene expression pattern of the pre- and early post-transplant MDSCs determined by RNA seq showed significant changes in certain pathways. Genes in the IL-4/IL-10/FoxP3 immunosuppressive pathway were upregulated whereas genes in the SLAMF6 and NF_kB immune effector pathways were downregulated. In conclusion, PMN MDSCs in the blood developed immune suppressive activity that promote tolerance early after transplantation that are similar to those described in cancer patients.

CITATION INFORMATION: Jensen K., Zheng P., Xuhuai J., Saraswathula A., Scandling J., Busque S., Shizuru J., Lowsky R., Shori A., Maecker H., Engleman E., Meyer E., Strober S. Changes in Phenotype, Immune Suppressive, Function, and Gene Expression of Myeloid Derived Suppressor Cells in Patients Given Combined Kidney and Hematopoietic Cell Transplants in a Tolerance Protocol Am J Transplant. 2017;17 (suppl 3).

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