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

Abstract

BackgroundMesenchymal 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.MethodsBALB/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.ResultsSurvival 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40164-015-0007-0) contains supplementary material, which is available to authorized users.

Defibrotide impact on the acute GVHD disease incidence in pediatric hematopoietic stem cell transplant recipients

“…Nomura et al published data, where patients with aGVHD and SOS showed higher levels of this cytokine ( 47 ). These data were also confirmed in vivo experiments in a murine model ( 48 ).…”

IGF-2 Preprograms Maturing Macrophages to Acquire Oxidative Phosphorylation-Dependent Anti-inflammatory Properties

“…A series of studies have demonstrated that the curative effects of MSCs on inflammatory diseases are related to their production of inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase, tumor necrosis factor-inducible gene 6 (TSG-6), or prostaglandin E2 (PGE-2), whose expressions in MSCs are now known to be elicited by inflammatory cytokines, especially interferon gamma (IFN-g) (Galleu et al, 2017;Lee et al, 2009;Né meth et al, 2009;Ren et al, 2008Ren et al, , 2009. Interestingly, it has been reported that human MSCs could effectively ameliorate autoimmune diseases in mice (Galleu et al, 2017;Robles et al, 2015;Yañ ez et al, 2006). It is worth noting that mouse IFN-g does not bind to human receptors, and human cells do not persist in the mouse body (Hemmi et al, 1992;Su et al, 2014).…”

Novel Treatment for Graft-versus-Host Disease

“…Together with another research group, we have found that systemic infusion of human MSCs can alleviate the severity of murine aGvHD manifestation and improve survival 54 . We utilized irradiated BALB/c host mice to receive C57BL/6 donor T-cell-depleted bone marrow with or without donor CD4+ T lymphocytes as controls.…”