08.11.22

hUC-EVs-ATO Reduce the Severity of Acute GVHD by Resetting Inflammatory Macrophages Toward the M2 Phenotype

In a recent study published in the Journal of Hematology & Oncology the authors used extracellular vesicles (EVs) derived from the mesenchymal stromal cells (MSCs) of human umbilical cords as a drug carrier of the chemotherapy agent arsenic trioxide (ATO). EVs loaded with ATO (hUC-EVs-ATO) were evaluated in a mouse model of acute graft-versus-host disease (aGVHD), a serious condition that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

The survival of aGVHD mice treated with hUC-EVs-ATO was significantly prolonged compared with that of mice receiving either ATO drug or hUC-EVs vehicle alone. The aGVHD-associated pathological lesions assessed by histological scores of the skin, liver, ileum, and colon of aGVHD mice were lowest in the hUC-EVs-ATO group.

Additionally, using a murine model of graft-versus leukemia (GVL), the authors observed the beneficial therapeutic effect of hUC-EVs-ATO by demonstrating that it not only reduced the severity of aGVHD but also preserved GVL.

At a mechanistic level the authors revealed the immunomodulatory effects of hUC-EVs-ATO on the T cell and macrophage cell populations that were associated with:

  1. Induction of a significantly higher proportion of suppressor Tregs (CD4+,CD25+, and FoxP3+) but significantly lower frequencies of effector T-cells (IFN-γ+, CD4+ and IL-17+,CD4+) in the livers and spleens of aGVHD mice treated with hUC-EVs-ATO. 
  2. Dependence of hUC‑EVs‑ATO therapeutic effects on the macrophage cell populations where   depletion of macrophages blocked the therapeutic effects of hUC-EVs-ATO on aGVHD. 
  3. Decrease in the percentages of M1 pro-inflammatory macrophages (F4/80+ and iNOS+) and increase in the percentages and polarization of M2 anti-inflammatory macrophages (F4/80+ and CD206+). The M1 to M2 polarization and conversion of macrophages was associated with increased number of autophagosomes and inhibition of the mTOR-autophagy pathway.

Overall, this work demonstrates that hUC-EVs-ATO may be a promising therapeutic approach for reducing aGVHD severity while preserving the beneficial GVL effect.

Reference:

Su Y, Sun X, Liu X, Qu Q, et al. hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype Journal of Hematology & Oncology. 15(99):1-17 (2022). https://jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01315-2

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