Immunosuppressive CD14+HLA-DRlow/neg IDO+ myeloid cells in patients following allogeneic hematopoietic stem cell transplantation

Abstract

Myeloid-derived suppressor cells (MDSCs) have emerged as a heterogeneic immunoregulatory population that can expand in response to inflammatory signals. Predominantly studied in cancer, MDSCs suppress T cells utilizing various mechanisms. In allogeneic hematopoietic stem cell transplantation (allo-HSCT) therapy-related toxicity and alloreactivity increase inflammatory cytokines that might favor an MDSC accumulation. To address this question, circulating CD14 þ HLA-DR low/neg cells were studied retrospectively in 51 allo-HSCT patients. These cells represent one of the few well-described human MDSC subsets under physiological and pathological conditions. The frequency of CD14 þ HLA-DR low/neg cells was significantly increased after allo-HSCT, especially in patients with acute graft-versus-host disease. Compared to healthy donor cells they were pSTAT1 low (phosphorylated signal transducer and activator of transcription) and indoleamine 2,3-dioxygenase (IDO) high. Serum levels of granulocyte colony-stimulating factor and interleukin-6, which both have been linked to MDSC induction, correlated positively with the frequency of CD14 þ HLA-DR low/neg cells. In vitro dysfunction of patient T cells, such as reduced proliferative capacity or CD3z-chain expression, was rescued by blocking the IDO activity of CD14 þ HLA-DR low/neg cells. Overall, we identified a T-cell-suppressive monocytic population that expands after allo-HSCT. The mechanisms responsible for such accumulation remain to be elucidated. It will be of great interest to prospectively investigate the influence of these cells on the graft-versus-tumor and-host reaction.

Increased incidence of chronic GvHD and CMV disease in patients with vitamin D deficiency before allogeneic stem cell transplantation

“…We failed to find an association between IDO activity and vitamin D levels. This might be because IDO activity in serum by circulating monocytes 26 overshadows DC activity in the tissues, but more studies focusing on vitamin D effects in vivo are needed. Previous studies have shown conflicting results; although one study on 53 adult patients suggests an association between vitamin D levels and cGvHD incidence, 6 others have reported better outcomes in established cGvHD after vitamin D supplementation.…”

Cytomegalovirus shapes long-term immune reconstitution after allogeneic stem cell transplantation

“…Future studies are required to incorporate data on myeloid populations in such global profiling of immune reconstitution. 47 In summary, multivariate methods such as correspondence analysis and unsupervized clustering provide useful tools to analyze immune reconstitution and point to the crucial role of CMV serostatus (and CMV replication), and chronic GvHD in shaping long-term immune reconstitution following allogeneic hematopoietic stem cell transplantation. Application of such tools to independent cohorts with different flow cytometry panels may help validate this approach and gain novel insights into immune recovery.…”

Contact-Dependent Depletion of Hydrogen Peroxide by Catalase Is a Novel Mechanism of Myeloid-Derived Suppressor Cell Induction Operating in Human Hepatic Stellate Cells

“…1) and expressed CD163. Of note, CD163 is a marker indicative of M2 polarization that is also present on monocytic IDO + MDSC in patients suffering from graft-versus-host disease after allogenic hematopoetic stem cell transplantation (data not shown) (20). This effect was not observed when CD14 + monocytes were cocultured with the hepatoma cell line HUH7 (data not shown).…”

“…Images were acquired using a Zeiss-Axiovert microscope (Zeiss, Jena, Germany). qPCR qPCR for cytokines/enzymes associated with MDSC immunosuppression (such as arginase and IL-10) and for analysis of oxidative stress (NADPHoxidase subunits) was performed as described previously (20). Total RNA was extracted from purified monocytes and CD14 + HLA-DR low/2 cells ex vivo and after coculture with purified catalase using the RNeasy mini kit (Qiagen, Hilden, Germany) and purity determined spectroscopically.…”

“…The expression of IDO was significantly increased in CD14 + HLA-DR low/2 cells following 5 d in culture with catalase (.1000-fold; p , 0.002). IDO has been shown to deplete tryptophan and produce kynurenine leading to a downregulation of the z chain of the CD3 complex on T cells and is linked with MO-MDSC suppressive capacity (20,23).…”