Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts.
Given their self-renewing and pluripotent capabilities, human embryonic stem cells (hESCs) are well poised as a cellular source for tissue regeneration therapy. However, the host immune response against transplanted hESCs is not well characterized. In fact, controversy remains as to whether hESCs have immune-privileged properties. To address this issue, we used in vivo bioluminescent imaging to track the fate of transplanted hESCs stably transduced with a double-fusion reporter gene consisting of firefly luciferase and enhanced GFP. We show that survival after transplant is significantly limited in immunocompetent as opposed to immunodeficient mice. Repeated transplantation of hESCs into immunocompetent hosts results in accelerated hESC death, suggesting an adaptive donor-specific immune response. Our data demonstrate that transplanted hESCs trigger robust cellular and humoral immune responses, resulting in intragraft infiltration of inflammatory cells and subsequent hESC rejection. Moreover, we have found CD4(+) T cells to be an important modulator of hESC immune-mediated rejection. Finally, we show that immunosuppressive drug regimens can mitigate the anti-hESC immune response and that a regimen of combined tacrolimus and sirolimus therapies significantly prolongs survival of hESCs for up to 28 days. Taken together, these data suggest that hESCs are immunogenic, trigger both cellular and humoral-mediated pathways, and, as a result, are rapidly rejected in xenogeneic hosts. This process can be mitigated by a combined immunosuppressive regimen as assessed by molecular imaging approaches.
Swijnenburg
Rutger-Jan
RJ
Department of Cardiothoracic Surgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA.
Schrepfer
Sonja
S
Govaert
Johannes A
JA
Cao
Feng
F
Ransohoff
Katie
K
Sheikh
Ahmad Y
AY
Haddad
Munif
M
Connolly
Andrew J
AJ
Davis
Mark M
MM
Robbins
Robert C
RC
Wu
Joseph C
JC
D000818:Animals; D000917:Antibody Formation / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000276:immunology*; D017930:Genes, Reporter; D006084:Graft Rejection / Q000276:immunology* / Q000628:therapy*; D006085:Graft Survival / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007121:Immunocompetence / Q000187:drug effects; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007167:Immunotherapy; D051379:Mice; D033581:Stem Cell Transplantation; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
D007166:Immunosuppressive Agents; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins