Overexpression of S100A9 in donor T cells is associated with reconstitution of gut microbiota and outcome of allogeneic hematopoietic stem cell transplantation

Kim, Se-Na; Lim, Sora; Razmkhah, Farnaz; Choi, Jaebok

doi:10.5045/br.2023.2022238

Cited by 1 publication

(2 citation statements)

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“…Furthermore, inhibition of JAK1/JAK2 using BARI promotes gastrointestinal repair by upregulating EGFR signaling, thereby treating established GvHD after allo-HCT [15]. More recently, we demonstrated that a blockade of IFNGR signaling upregulates S100A9 expression in donor T cells, not only altering donor T cell trafficking but also modulating intestinal microbiota reconstitution after allo-HCT [25][26][27]. Surprisingly, targeting IFNGR signaling preserved or enhanced GvL effects in our preclinical mouse model of allo-HCT [12,13,27].…”

Section: Discussionmentioning

confidence: 63%

“…Allo-HCT was performed as previously described [12,13,15,[25][26][27]32]. Briefly, BALB/c mice were used as recipients and received 9 Gy total body irradiation on day −1, then were transplanted with 5 × 10 6 T cell-depleted bone marrow (TCD-BM) cells from B6 (CD45.1+) mice along with 0.5 × 10 6 splenic T cells from B6 (CD45.2+) mice on day 0.…”

Section: Preclinical Mouse Model Of Allo-hctmentioning

confidence: 99%

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Novel JAK Inhibitors to Reduce Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in a Preclinical Mouse Model

Kim,

Ruminski,

Singh

et al. 2024

Molecules

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Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced inhibition of JAK1/JAK2 while sparing JAK3 is important for the optimal prevention of GvHD. Thus, we have generated novel JAK1/JAK2 inhibitors, termed WU derivatives, by modifying baricitinib. Our results show that WU derivatives have the potential to mitigate GvHD by upregulating regulatory T cells and immune reconstitution while reducing the frequencies of antigen-presenting cells (APCs) and CD80 expression on these APCs in our preclinical mouse model of allo-HCT. In addition, WU derivatives effectively downregulated CXCR3 and T-bet in primary murine T cells. In summary, we have generated novel JAK inhibitors that could serve as alternatives to baricitinib or ruxolitinib.

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