HSCT Recipients Have Specific Tolerance to MSC but not to the MSC Donor

作者：Mikael Sundin, A. John Barrett, Olle T.H. Ringdén, Mehmet Uzunel, Helena Lönnies, Åsa-Lena Dackland, Birger Christensson, Katarina Le Blanc · 发表于：Journal of Immunotherapy · 年份：2009 · DOI：10.1097/cji.0b013e3181ab1807 · 被引用次数：50 · 研究领域：Mesenchymal stem cell research、Hematopoietic Stem Cell Transplantation、Immunotherapy and Immune Responses

Multipotent mesenchymal stromal cells (MSC) are increasingly used to treat refractory graft-versus-host-disease and other complications after hematopoietic stem cell transplantation (HSCT). We evaluated immunogenicity of HLA-mismatched MSC infused posttransplant to HSCT recipients. Recipient lymphocyte response to MSC and peripheral blood lymphocytes (PBL) from the MSC or third party donors was measured before and after infusion. In vitro primary and rechallenge lymphocyte responses of healthy individuals to MSC and to PBL from the MSC donor were similarly studied. HSCT recipients given MSC responded to third party allostimuli, but showed no response to infused MSC before and upto 6 months after infusion, whereas maintaining an alloresponse to the MSC donor. This indicates immune unresponsiveness restricted to MSC, as the HSCT recipient was not tolerized to the MSC donor. In vitro, we confirmed that MSC failed to prime responder lymphocytes to rechallenge with PBL from the MSC donor, and lymphocytes primed with MSC donor and rechallenged with MSC only showed weak responses at high stimulator-responder ratios. Although MSC up-regulated lymphocyte gene expression of CD25, IFN-gamma, FoxP3, CTLA-4, and IL-10, they failed in both unprimed and primed responders to induce CD25+ (activated) or CD57+ (effector) CD4+ or CD8+ T-lymphocyte subsets and only inconsistently induced FoxP3+ regulatory T-lymphocytes. These results show for the first time that infused MSC are only weakly immun...