Kidney-derived mesenchymal stromal cells modulate dendritic cell function to suppress alloimmune responses and delay allograft rejection.
BACKGROUND
Mesenchymal stromal cells (MSCs) are multipotent cells with immunoregulatory capacity that are present in most adult organs. We previously demonstrated that co-culture of C57BL/6 kidney-derived MSCs (KSCs) in syngeneic bone marrow-derived dendritic cell (DC) culture induced a DC phenotype (KSC-DC) with reduced major histocompatibility complex (MHC) class II/increased CD80 expression and ability to suppress T-cell responses.


METHODS
To study their effects on allogeneic DCs, C57BL/6 KSCs were added to incipient BALB/c DC culture, with surface expression of MHC class II/CD80 measured by fluorescence-activated cell sorting. The ability to stimulate T-cell responses was then assessed in an allogeneic mixed leukocyte response. Next, we isolated either BALB/c (donor) or C57BL/6 (recipient) KSC-DCs from co-culture and measured the tempo of rejection after cotransplantation with islet grafts in a mouse model of islet transplantation. Finally, we measured the effects of KSC-DC stimulation on B-cell proliferation and IgM/IgG production in allogeneic cultures.


RESULTS
C57BL/6 KSCs induced a BALB/c DC phenotype with significantly decreased MHC class II, increased CD80 expression, and decreased T-cell stimulatory capacity in the mixed leukocyte response (P<0.01 vs. control). Cotransplantation of donor (BALB/c) but not recipient (C57BL/6) KSC-DCs resulted in significant delay of rejection after islet transplantation (P<0.01 vs. control). Finally, stimulation by KSC-DCs resulted in significantly reduced B-cell proliferation and antibody production in allogeneic culture (P<0.01 vs. control).


CONCLUSIONS
Our results highlight an important mechanism of MSC-based immunotherapy and its potential for use in clinical transplantation as prevention of rejection and possibly sensitization.
Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Yanfei
Y
Huang
Ping
P
Chen
Cassie B
CB
Zhang
Gang Jee
GJ
Ko
Miriam
M
Ruiz
Paolo
P
Fiorina
Mehboob A
MA
Hussain
Barbara A
BA
Wasowska
Hamid
H
Rabb
Karl L
KL
Womer
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology; D018929:Cell Culture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry / Q000379:methods; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008213:Lymphocyte Activation; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology*
D018122:B7-1 Antigen; D000949:Histocompatibility Antigens Class II