Xeno-immunosuppressive properties of human decidual stromal cells in mouse models of alloreactivity in vitro and in vivo.
OBJECTIVE
Human decidual stromal cells (hDSCs) may cure acute graft-versus-host disease (GVHD) in humans. We evaluated immunosuppression by xenogenic hDSCs in mice, both in vitro and in vivo.


METHODS
hDSCs inhibited mouse lymphocyte proliferation in allo- and xeno-stimulation assays in mixed lymphocyte culture (MLC) and after mitogenic stimulation. The immunosuppressive effect of hDSCs was dose-dependent and strain-independent. Trans-well experiments showed that hDSCs needed cell-to-cell contact to be immunosuppressive. In a GVHD model, Balb/c mice were transplanted with bone marrow and splenocytes from C57BL/6 a donor. Varying doses of hDSCs (10(5)-10(6) per mouse) were infused at different time points. Recipient mice showed lower GVHD scores than untreated mice, but they did not have consistently improved survival. Histopathological investigation of liver, gastrointestinal tract and skin of animals with GVHD did not show any significant improvement from hDSC infusion.


RESULTS
hDSCs were transduced with immunosuppressive genes including those encoding interleukin-10, prostaglandin-E2 receptor, indoleamine dioxygenase, interferon-γ and programmed death ligand-1. Transduced and untransduced hDSCs showed similar effects in vitro and in vivo. At a dose of 10(6)hDSCs per mouse, the majority of recipients died of embolism.


CONCLUSIONS
hDSCs inhibit allo-reactivity, xeno-reactivity and mitogen-induced stimulation in mouse lymphocytes. Although the GVHD score was reduced by hDSC infusion, survival and GVHD histopathology were not improved. One reason for failure was fatal embolism.
Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden. Electronic address: behnam.sadeghi@ki.se.
Behnam
B
Sadeghi
Center for Hematology and Regenerative Medicine (HERM), Department of Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
Yaser
Y
Heshmati
Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
Bita
B
Khoein
Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
Helen
H
Kaipe
Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
Mehmet
M
Uzunel
Center for Hematology and Regenerative Medicine (HERM), Department of Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
Julian
J
Walfridsson
Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden; Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet and Karolinska University Hospital Huddinge, Stockholm, Sweden.
Olle
O
Ringdén
D000818:Animals; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D003656:Decidua / Q000166:cytology* / Q000276:immunology; D004195:Disease Models, Animal; D004617:Embolism / Q000401:mortality; D005260:Female; D006086:Graft vs Host Disease / Q000628:therapy*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology / Q000276:immunology; D017154:Stromal Cells / Q000166:cytology / Q000276:immunology*
C508609:IL10 protein, human; D016753:Interleukin-10; D007371:Interferon-gamma
cell therapy; decidual stromal cells; graft-versus-host disease; mesenchymal stromal cells; mouse model