Inhibition of humoral response to allogeneic porcine mesenchymal stem cell with 12 days of tacrolimus.
BACKGROUND
In vivo studies have highlighted allogeneic mesenchymal stem-cell (MSC) immunogenicity. We investigated in vitro MSC-immunosuppressive drugs interaction and further tested in vivo the humoral response to intracardiac allogeneic MSC transplantation in a mini-swine model receiving a short course of immunosuppression.


METHODS
For in vitro experiments, long-term culture MSCs were used. Immunosuppressive drugs tested were mycophenolate mofetil, cyclosporin, tacrolimus (TAC), sirolimus (SIR), and everolimus. Cell proliferation/viability was assessed on day 7. For each drug, the C50 was determined, and the agonistic effect between immunosuppressive drugs and MSCs on alloreactivity was measured in proliferation assay of MSC-peripheral blood mononuclear cell cultures. For in vivo experiments, one-haplotype swine leukocyte antigen class I and II mismatch (n=11) were used. Allogeneic MSCs were transplanted into ischemic myocardium. TAC was administered 12 days. Donor-specific antibody response was assessed by flow cytometry and complement-mediated cytotoxicity assay.


RESULTS
All drugs except TAC significantly decreased cell proliferation (from 17% to 62%). In MSC-peripheral blood mononuclear cell co-culture assay, MSCs' immunomodulatory properties were maintained when TAC or SIR were used. In vivo experiments showed that only 2 of 11 animals under TAC developed donor-specific antibodies. Importantly, sera from those two animals did not elicit a complement-mediated cytotoxic response.


CONCLUSIONS
Immunosuppressive drugs significantly affect proliferation and viability of MSCs, but neither TAC nor SIR had a detrimental impact on MSCs' immunomodulatory properties. In this large-animal model, addition of short course of immunosuppression seems to overcome the immune response to intracardiac allogeneic MSCs, which was recently demonstrated to occur in the absence of immunosuppression.
Poncelet
Alain J
AJ
Laboratory of Experimental Surgery, Faculté de Médecine, Université Catholique de Louvain, Brussels, Belgium. Alain.Poncelet@uclouvain.be
Nizet
Yannick
Y
Vercruysse
Jonathan
J
Hiel
Anne Lise
AL
Saliez
Alain
A
Gianello
Pierre
P
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D018920:Coculture Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D013552:Swine; D016559:Tacrolimus / Q000627:therapeutic use*; D013997:Time Factors; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016559:Tacrolimus