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Immunosuppressive mechanisms of human bone marrow derived mesenchymal stromal cells in BALB/c host graft versus host disease murine models.

Robles JD, Liu YP, Cao J, Xiang Z, Cai Y, Manio M, Tang EH, Chan GC - Exp Hematol Oncol (2015)

Bottom Line: Documentation of suppression of RANTES, CCL3, CXCL9, CCR5 and CXCR3 with simultaneous decrease of donor T cell alloreactivity was demonstrated 6 days after transplantation, along with reduction of levels of inflammatory cytokines, suppression of STAT 5A/B phosphorylation, increased expression of CCR7 and increased production of nitrous oxide by hMSCs.Documentation of homing of hMSCs to lymphoid organs and target tissues was also performed.These mechanisms contribute to the current understanding of MSC mechanisms of immunosuppression and forms a comprehensive picture of how they exert immunosuppression in an in vivo model of immune dysregulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, 102 Pokfulam Rd., HKSAR, PRC.

ABSTRACT

Background: Mesenchymal stromal cells (MSCs) are proven to have immunosuppressive functions via various mechanisms. These mechanisms were demonstrated by administering bone marrow derived human MSCs (hMSCs) to graft versus host disease (GVHD) murine models.

Methods: BALB/c host mice were irradiated prior to receiving C57BL/6 donor T cell depleted bone marrow (TCDBM) cells (negative control) and donor CD4+ T lymphocyte with (treatment group) or without hMSCs (positive control). The presence of hMSCs in target tissues and lymphoid organs was documented by using in vivo imaging and measuring the expression of EphB2 and ephrin-B2 by RTqPCR. Survival rate and GVHD score were also monitored. Tissue sections were obtained for histopathologic analysis. Flow cytometry was used to document donor T cell alloreactivity and expression of CCR5, CXCR3 and CCR7. ELISA was utilized to determine levels of proinflammatory cytokines, RANTES (CCL5) and phosphorylated STAT 5A/B. RTqPCR was performed to quantify expression of CCL3 and CXCL9. Western blotting was performed to qualitatively measure iNOS expression.

Results: Survival rate and GVHD score improved with hMSC treatment. Pathologic changes of GVHD were abrogated. Documentation of suppression of RANTES, CCL3, CXCL9, CCR5 and CXCR3 with simultaneous decrease of donor T cell alloreactivity was demonstrated 6 days after transplantation, along with reduction of levels of inflammatory cytokines, suppression of STAT 5A/B phosphorylation, increased expression of CCR7 and increased production of nitrous oxide by hMSCs. Documentation of homing of hMSCs to lymphoid organs and target tissues was also performed.

Conclusions: These mechanisms contribute to the current understanding of MSC mechanisms of immunosuppression and forms a comprehensive picture of how they exert immunosuppression in an in vivo model of immune dysregulation.

No MeSH data available.


Related in: MedlinePlus

Immunosuppressive mechanisms of hMSCS in GVHD mouse models. (A) In the absence of hMSCs, upregulation of chemokine receptors and ligands causes migration of donor T cells to the target tissues of GVHD causing increased T cell alloreactivity and Th1 response. (B) With hMSC treatment, CCR7 increases migration of hMSCs to lymphoid organs and target tissues, then hMSCs produce soluble mediators (iNOS) causing immunosuppression. These soluble mediators suppress ligands CCL3, RANTES and CXCL9 and corresponding receptors CCR5 and CXCR3 with resultant decresased migration of donor T cells to the target tissues. This subsequently results to decreased TNF-α and IFN- γ. iNOS also suppresses phosphorylation of STAT 5A/B proteins that regulates T cell proliferation. EphB2 and ephrin-B2 which are specifically found in hMSCs also binds with T cells and suppress their proliferation.
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Fig7: Immunosuppressive mechanisms of hMSCS in GVHD mouse models. (A) In the absence of hMSCs, upregulation of chemokine receptors and ligands causes migration of donor T cells to the target tissues of GVHD causing increased T cell alloreactivity and Th1 response. (B) With hMSC treatment, CCR7 increases migration of hMSCs to lymphoid organs and target tissues, then hMSCs produce soluble mediators (iNOS) causing immunosuppression. These soluble mediators suppress ligands CCL3, RANTES and CXCL9 and corresponding receptors CCR5 and CXCR3 with resultant decresased migration of donor T cells to the target tissues. This subsequently results to decreased TNF-α and IFN- γ. iNOS also suppresses phosphorylation of STAT 5A/B proteins that regulates T cell proliferation. EphB2 and ephrin-B2 which are specifically found in hMSCs also binds with T cells and suppress their proliferation.

Mentions: The mechanisms of immunosuppression brought about by MSC treatment in GVHD remains elusive. hMSCs infused to GVHD murine models increase the number of cells expressing CCR7 contributing to homing of hMSCs to lymphoid organs and then to target tissues of GVHD. hMSCs release iNOS to suppress phosphorylation of STAT 5A/B proteins and control T cell replication. The chemokine ligands RANTES, CCL3 and CXCL9 are suppressed along with their corresponding receptors CCR5 and CXCR3 resulting to diminished migration of alloreactive donor T cells to lymphoid organs and target tissues and cytokine response. (Figure 7) Ultimately, these mechanisms result to decreased GVHR which is reflective in the GVHD scores, histopathologic analysis of GVHD target tissues and survival rates.Figure 7


Immunosuppressive mechanisms of human bone marrow derived mesenchymal stromal cells in BALB/c host graft versus host disease murine models.

Robles JD, Liu YP, Cao J, Xiang Z, Cai Y, Manio M, Tang EH, Chan GC - Exp Hematol Oncol (2015)

Immunosuppressive mechanisms of hMSCS in GVHD mouse models. (A) In the absence of hMSCs, upregulation of chemokine receptors and ligands causes migration of donor T cells to the target tissues of GVHD causing increased T cell alloreactivity and Th1 response. (B) With hMSC treatment, CCR7 increases migration of hMSCs to lymphoid organs and target tissues, then hMSCs produce soluble mediators (iNOS) causing immunosuppression. These soluble mediators suppress ligands CCL3, RANTES and CXCL9 and corresponding receptors CCR5 and CXCR3 with resultant decresased migration of donor T cells to the target tissues. This subsequently results to decreased TNF-α and IFN- γ. iNOS also suppresses phosphorylation of STAT 5A/B proteins that regulates T cell proliferation. EphB2 and ephrin-B2 which are specifically found in hMSCs also binds with T cells and suppress their proliferation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4440561&req=5

Fig7: Immunosuppressive mechanisms of hMSCS in GVHD mouse models. (A) In the absence of hMSCs, upregulation of chemokine receptors and ligands causes migration of donor T cells to the target tissues of GVHD causing increased T cell alloreactivity and Th1 response. (B) With hMSC treatment, CCR7 increases migration of hMSCs to lymphoid organs and target tissues, then hMSCs produce soluble mediators (iNOS) causing immunosuppression. These soluble mediators suppress ligands CCL3, RANTES and CXCL9 and corresponding receptors CCR5 and CXCR3 with resultant decresased migration of donor T cells to the target tissues. This subsequently results to decreased TNF-α and IFN- γ. iNOS also suppresses phosphorylation of STAT 5A/B proteins that regulates T cell proliferation. EphB2 and ephrin-B2 which are specifically found in hMSCs also binds with T cells and suppress their proliferation.
Mentions: The mechanisms of immunosuppression brought about by MSC treatment in GVHD remains elusive. hMSCs infused to GVHD murine models increase the number of cells expressing CCR7 contributing to homing of hMSCs to lymphoid organs and then to target tissues of GVHD. hMSCs release iNOS to suppress phosphorylation of STAT 5A/B proteins and control T cell replication. The chemokine ligands RANTES, CCL3 and CXCL9 are suppressed along with their corresponding receptors CCR5 and CXCR3 resulting to diminished migration of alloreactive donor T cells to lymphoid organs and target tissues and cytokine response. (Figure 7) Ultimately, these mechanisms result to decreased GVHR which is reflective in the GVHD scores, histopathologic analysis of GVHD target tissues and survival rates.Figure 7

Bottom Line: Documentation of suppression of RANTES, CCL3, CXCL9, CCR5 and CXCR3 with simultaneous decrease of donor T cell alloreactivity was demonstrated 6 days after transplantation, along with reduction of levels of inflammatory cytokines, suppression of STAT 5A/B phosphorylation, increased expression of CCR7 and increased production of nitrous oxide by hMSCs.Documentation of homing of hMSCs to lymphoid organs and target tissues was also performed.These mechanisms contribute to the current understanding of MSC mechanisms of immunosuppression and forms a comprehensive picture of how they exert immunosuppression in an in vivo model of immune dysregulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong Li Ka Shing Faculty of Medicine, Queen Mary Hospital, 102 Pokfulam Rd., HKSAR, PRC.

ABSTRACT

Background: Mesenchymal stromal cells (MSCs) are proven to have immunosuppressive functions via various mechanisms. These mechanisms were demonstrated by administering bone marrow derived human MSCs (hMSCs) to graft versus host disease (GVHD) murine models.

Methods: BALB/c host mice were irradiated prior to receiving C57BL/6 donor T cell depleted bone marrow (TCDBM) cells (negative control) and donor CD4+ T lymphocyte with (treatment group) or without hMSCs (positive control). The presence of hMSCs in target tissues and lymphoid organs was documented by using in vivo imaging and measuring the expression of EphB2 and ephrin-B2 by RTqPCR. Survival rate and GVHD score were also monitored. Tissue sections were obtained for histopathologic analysis. Flow cytometry was used to document donor T cell alloreactivity and expression of CCR5, CXCR3 and CCR7. ELISA was utilized to determine levels of proinflammatory cytokines, RANTES (CCL5) and phosphorylated STAT 5A/B. RTqPCR was performed to quantify expression of CCL3 and CXCL9. Western blotting was performed to qualitatively measure iNOS expression.

Results: Survival rate and GVHD score improved with hMSC treatment. Pathologic changes of GVHD were abrogated. Documentation of suppression of RANTES, CCL3, CXCL9, CCR5 and CXCR3 with simultaneous decrease of donor T cell alloreactivity was demonstrated 6 days after transplantation, along with reduction of levels of inflammatory cytokines, suppression of STAT 5A/B phosphorylation, increased expression of CCR7 and increased production of nitrous oxide by hMSCs. Documentation of homing of hMSCs to lymphoid organs and target tissues was also performed.

Conclusions: These mechanisms contribute to the current understanding of MSC mechanisms of immunosuppression and forms a comprehensive picture of how they exert immunosuppression in an in vivo model of immune dysregulation.

No MeSH data available.


Related in: MedlinePlus