Human Mesenchymal Stromal Cells Attenuate Graft-Versus-Host Disease and Maintain Graft-Versus-Leukemia Activity Following Experimental Allogeneic Bone Marrow Transplantation

Abstract

We sought to define the effects and underlying mechanisms of human, marrow-derived mesenchymal stromal cells (hMSCs) on graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) activity. Irradiated B6D2F1 mice given C57BL/6 BM and splenic T-cells and treated with hMSCs had reduced systemic GvHD, donor T-cell expansion, and serum TNFα and IFNγ levels. Bioluminescence imaging demonstrated that hMSCs redistributed from lungs to abdominal organs within 72h; and target tissues harvested from hMSC-treated alloBMT mice had less GvHD than untreated controls. Cryo-imaging more precisely revealed that hMSCs preferentially distributed to splenic marginal zones and regulated T-cell expansion in the white pulp. Importantly, hMSCs had no effect on in vitro cytotoxic T-cell activity and preserved potent GvL effects in vivo. Mixed leukocyte cultures containing hMSCs exhibited decreased T-cell proliferation, reduced TNFα, IFNγ, and IL-10, but increased PGE2 levels. Indomethacin and E-prostanoid 2 (EP2) receptor antagonisms both reversed while EP2 agonism restored hMSC-mediated in vitro T-cell suppression, confirming the role for PGE2. Furthermore, cyclo-oxygenase inhibition following alloBMT abrogated the protective effects of hMSCs. Together, our data show that hMSCs preserve GvL activity and attenuate GvHD and reveal that hMSC biodistribute to secondary lymphoid organs wherein they attenuate alloreactive T-cell proliferation likely through PGE2 induction.

Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

“…Female C57BL/6J (B6; H-2 b ) and B6D2F1 (F1; H-2 bxd ) mice aged 8 to 12 weeks were purchased from The Jackson Laboratory (Bar Harbor, ME). Detailed methods for the generation of Cdk5-null hematopoietic chimeras, 13 immunoprecipitation and Cdk5 kinase activity assay, 25 T-cell isolation and BM transplant (BMT) procedures, 33 mixed lymphocyte reactions, T-cell proliferation and cytolytic activity, 33,34 assessment of clinical 35 and target organ GVHD, 33 in vivo graft-versus-leukemia (GVL) models, 33,34 bioluminescent imaging techniques, 34,36 and statistical analysis have been previously described and are outlined in supplemental Methods (available on the Blood Web site).…”

“…Functional characterization of Cdk5 2/2C T cells in response to alloantigen stimulation showed only modest reductions in T-cell proliferation to higher concentrations of splenic dendritic cells (DCs) collected from B6D2F1 mice ( Figure 1E), and no differences in cytolytic T lymphocyte (CTL) activity ( Figure 1F) or cytokine production (data not shown) were noted between groups. 33,34,37,38 We first assessed whether enhanced Cdk5 activity could be detected during early stages of GVHD as described in supplemental Methods. 13 Cdk5 activity was notably increased by day 10 after allo-HCT in the spleen and small intestine, established sites of activation, and initial recruitment of donor T cells (Figure 2A HCT (Figure 2B-C; P , .01).…”

Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials

“…A number of mouse GVHD models—including humanized mouse models—have been developed, and the infusion of mouse and human BMMSCs have generally demonstrated efficacy against the disease by suppressing donor leukocyte inflammatory responses [66–68]. MSC factors involved include PGE 2 [69] and nitric oxide (NO) [70]; and effects can be enhanced with pretreatment of IFN-γ to the MSCs [68]. Animal model studies also demonstrate that sources of MSCs other than BMMSCs may also ameliorate GVHD, and may involve vascular endothelial growth factor (VEGF), PGE 2 , and TGF-β [71–74].…”

Regulatory B cells promote graft-versus-host disease prevention and maintain graft-versus-leukemia activity following allogeneic bone marrow transplantation

“…The role of human MSCs in attenuating GVHD and maintaining GVL effects was also demonstrated following experimental allogeneic BMT. 8 Therefore, our results provide novel evidence and indicate that except for Tregs and MSCs, Bregs can prevent GVHD and maintain GVL activity.…”

“…C regulatory T cells (Tregs), myeloid-derived suppressor cells, 5 and mesenchymal stromal cells (MSCs), [6][7][8] have been investigated to elucidate whether these cells could be used for prevention or therapy of GVHD. Although several studies using a mouse bone marrow transplant (BMT) model 9 have identified Tregs, myeloid-derived suppressor cells, and MSCs as available strategies for GVHD alleviation, none of them can be routinely applied in clinic.…”