Alterations of Bone Marrow Microenvironment in Acute Graft-Versus-Host Disease

Severe acute graft-versus-host disease (aGVHD) indicates a poor prognosis after allogeneic hematopoietic stem cell transplantation. In our previous study, we found that hematopoiesis was progressively suppressed during aGVHD, while the hematopoietic regenerative potential of donor-derived hematopoietic stem cells remains intact. It prompts us to investigate whether bone marrow niche is a major target of GVHD. We addressed this issue by studying the critical components in bone marrow microenvironment, including mesenchymal stem cell (MSC), osteoblasts and adipocytes in haplo-MHC-matched murine bone marrow transplantation model. By comparing confocal images of femurs from control and aGVHD SCF-GFP mice or Col2.3-GFP mice, we found that both MSCs and osteoblasts were significantly reduced during aGVHD development. In addition, anti-perilipin staining showed that adipocytes were also decreased in aGVHD mice. We found a defect in the differentiation potential of MSCs from aGVHD niche by in vitro culture of both murine and human bone marrow niche cells. qRT-PCR showed decreased gene expressions of PPAR-gamma, Adipoq, Runx1 and Col2a1, suggesting the potential of MSCs differentiation into adipocytes and osteoblasts was blocked. These data provide new insights into the pathogenesis of aGVHD and may improve the clinical management of aGVHD. Disclosures No relevant conflicts of interest to declare.

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Effect of Early Post-Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Cancers ◽

10.3390/cancers13040613 ◽

2021 ◽

Vol 13 (4) ◽

pp. 613

Author(s):

Nidhi Sharma ◽

Qiuhong Zhao ◽

Bin Ni ◽

Patrick Elder ◽

Marcin Puto ◽

...

Keyword(s):

Stem Cell ◽

Graft Versus Host Disease ◽

Tacrolimus Concentration ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

The Impact ◽

Risk Of Relapse ◽

Acute Graft

Acute graft versus host disease (aGVHD) remains a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant (allo-HSCT). Tacrolimus (TAC), a calcineurin inhibitor that prevents T-cell activation, is commonly used as a GVHD prophylaxis. However, there is variability in the serum concentrations of TAC, and little is known on the impact of early TAC levels on aGVHD. We retrospectively analyzed 673 consecutive patients undergoing allo-HSCT at the Ohio State University between 2002 and 2016. Week 1 TAC was associated with a lower risk of aGVHD II–IV at TAC level ≥10.15 ng/mL (p = 0.03) compared to the lowest quartile. The cumulative incidence of relapse at 1, 3 and 5 years was 33%, 38% and 41%, respectively. TAC levels at week 2, ≥11.55 ng/mL, were associated with an increased risk of relapse (p = 0.01) compared to the lowest quartile. Subset analysis with acute myeloid leukemia and myelodysplastic syndrome patients showed significantly reduced aGVHD with TAC level ≥10.15 ng/mL at week 1 and a higher risk of relapse associated with week 2 TAC level ≥11.55 ng/mL (p = 0.02). Hence, achieving ≥10 ng/mL during the first week of HCT may mitigate the risk of aGVHD. However, levels (>11 ng/mL) beyond the first week may be associated with suppressed graft versus tumor effect and higher relapse.

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