MicroRNA‐181a, a potential diagnosis marker, alleviates acute graft versus host disease by regulating IFN‐γ production

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a valuable therapeutic strategy for a wide variety of diseases. Acute graft-versus-host disease (aGVHD) is a major complication in up to 75% of allo-HSCT. The absence of a reliable predicative marker for aGVHD onset prevents preemptive treatment and impedes widespread and successful application of this therapy. In this study we found that after allo-HSCT, the levels of miR-181a were reduced significantly prior to the onset of aGVHD. More importantly, the degree of its reduction correlated with the severity of aGVHD. Mechanistically, miR-181a affects the function of T lymphocytes by down-regulating IFN-γ in a dose-dependent manner. Meanwhile, we confirmed that miR-181a can effectively preserve the anti-leukemic effect in vitro. Using a murine allo-HSCT model, we demonstrated that murine miR-181b, the human miR-181a homolog, served as an effective predictor of aGVHD. Moreover, expression of this microRNA ameliorated the severity of aGVHD. Collectively, these results show that the level of miR-181a may serve as a reliable marker for the diagnosis and prognosis the onset of aGVHD.

MiR-150 impairs inflammatory cytokine production by targeting ARRB-2 after blocking CD28/B7 costimulatory pathway

“…Our previous study found that patients undergoing acute transplant injury after allo-HSCT showed decreased miR-150 levels in CD4 + T cells at least four days prior to the onset of aGVHD, and the patients without injury showed significantly increased miR-150 expression levels. These results imply not only that miR-150 can be used to predict the occurrence of aGVHD, it may also be involved in the induction of immune tolerance in allo-HSCT (23). …”

“…We have reported that post allogeneic hematopoietic stem cell transplantation (HSCT), miR-150 levels in CD4 + T cells decreased significantly in the patients 4 days before the onset of aGVHD (23). Bioinformatics analyses identified 44 potential miR-150 targets in all three microRNA data bases: miRbase, miRranda and Targetscan (Supplemental Figure 1A).…”

“…Since miR-150 levels started to decline about four days prior the onset of acute graft-versus-host disease (aGVHD), its levels could be used as a predictor of GVHD. More importantly, the miR-150 levels were negatively correlated with the severity of the immune injury (23). However, the role of miR-150 in the suppression of the immune response and inflammatory cytokines is not well understood.…”

MicroRNA-150 negatively regulates the function of CD4+ T cells through AKT3/Bim signaling pathway

“…Shan et al demonstrated that miRNAs participate in the regulation of graft rejection reaction after solid-organ transplantation and induce post-transplantation immune tolerance [22]. We have reported that the level of miR-150 is lower in patients with aGVHD [15] and MiR-150-deficient mice exhibit large numbers of B1 cells. In contrast, in transgenic mice expressing higher levels of miR-150 during early stages of development, B-cells were substantially destroyed and B1 cells were depleted.…”

“…We have reported that through regulation of CD4 + T cell function, miR-150 effectively induces immune tolerance in patients who have undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, the levels of miR-150 have been suggested as a predictive indicator for the occurrence of acute graft-versus-host disease (aGVHD) [15].…”