title: HSCT recipients have specific tolerance to MSC but not to the MSC donor.
abstract: 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 immunogenic in humans and validate the clinical use of MSC from HLA-mismatched donors.
authors: Division of Clinical Immunology and Transfusion Medicine, Department of Laboratory Medicine, Karolinska University Hospital, Stockholm, Sweden. mikael.sundin@ki.se
authors: Mikael
authors: M
authors: Sundin
authors: A John
authors: AJ
authors: Barrett
authors: Olle
authors: O
authors: Ringdén
authors: Mehmet
authors: M
authors: Uzunel
authors: Helena
authors: H
authors: Lönnies
authors: Asa-Lena
authors: AL
authors: Dackland
authors: Birger
authors: B
authors: Christensson
authors: Katarina Le
authors: KL
authors: Blanc
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002648:Child; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007223:Infant; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology; D008875:Middle Aged; D039902:Multipotent Stem Cells / Q000166:cytology / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014019:Tissue Donors; D023001:Transplantation Tolerance / Q000276:immunology*; D055815:Young Adult