Papel de las células supresoras de estirpe mieloide en la evolución de pacientes con trasplante renal

Abstract

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that expand due to chronic inflammation and participate in the suppression of both innate and adaptive immune responses. Three subsets of MDSC have been described according to phenotypic criteria: polymorphonuclear MDSC (PMN-MDSC), monocytic MDSC (M-MDSC) and early-stage MDSC (eMDSC). MDSC display numerous mechanisms to carry out their immunosuppressive functions such as the production of arginase 1, indoleamine 2,3-dioxygenase, nitric oxide synthase and reactive oxygen species or the expansion of regulatory T cells. This myeloid compartment has been widely studied related to cancer since MDSC have been seen to favour tumor progression, metastasis and have been associated to poor prognosis. In recent years, MDSC were shown to be relevant for tolerance induction after transplantation. However, the analysis of MDSC effects in human kidney transplantation is limited to a few studies including small numbers of patients. In this context, the group Inmunodeficiencias e Inmunologia del Trasplante (GIDIT) from Hospital 12 de Octubre began to study MDSC in patients who underwent a kidney transplant. Their initial results showed that CD33+ CD11b+ CD14+ CD15- HLA-DR-/low cells expanded after transplantation; moreover, a higher number of these cells increased risk for developing cancer in kidney transplant recipients (KTR). Based on these results we aimed to assess MDSC immunosuppression in vitro when cocultured with lymphocytes and to quantify suppressive soluble factors associated with MDSC function. CD33+ CD11b+ CD14+ CD15- HLA-DR-/low were expanded in KTR compared to healthy controls. When co-cultured with lymphocytes, KTR-isolated MDSC were able to suppress both CD4 and CD8 T cells proliferation and production of cytokines. Furthermore, higher M-MDSC counts correlated with higher circulatory arginase 1 activity and interleukin 10 (IL-10), and lower total antioxidant capacity. Taken together, these results suggest that high levels of MDSC and their associated immunosuppressive environment could be promoting de novo malignancy development after kidney transplantation.