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Immune Response to iPSC-Derivatives Analysed in Non-human Primates

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Recent studies on the host immune response to induced pluripotent stem cells (iPSCs) in mice found that while iPSC-derived teratomas raised a potentially deleterious immune response in genetically identical mice (Zhao et al), their derivatives seem to lack this effect (Araki et al and Guha et al). To better simulate a clinical situation, in a recent study in Stem Cell Reports the group of Jun Takahashi at Kyoto University, Japan have compared immunological responses of dopaminergic (DA) neurons (the cells required for cell replacement therapy in Parkinson's Disease) derived from cynomolgus monkeys in an autologous and allogeneic manner (Morizane et al).

Cells from cynomolgus monkeys (Macaca fascicularis) were used to generate GFP-positive iPSCs: 2 lines derived from oral mucosa using retroviral vectors and 2 from peripheral blood mononuclear cells (PBMCs) with non-integrating episomal vectors. Retroviral iPSCs had some remaining transgene expression in the resulting iPSCs, while episomal-derived iPSCs did not. The researchers next generated dopaminergic (DA) neurons using a protocol based on previously described protocols (Chambers et al, Eiraku et al, and Morizane et al), with resultant differentiated cells expressing midbrain DA neurons markers such as LMX1A, FOXA2, TH, and PITX3.

Immunological analysis started with the investigation of histocompatibility complex class I (MHC-I), finding only a low level of MHC-I on mature neurons on days 35 and 71 (1:100 in comparison to peripheral blood cells) which was enhanced through interferon gamma exposure, which can be induced by an inflammatory process. MHC analysis also allowed for the subsequent allo-transplantation cases to receive mismatched cells. Monkeys received autografts and allografts of DA neurons into the left striatum and were analysed for around 4 months with no immunosuppression. Analysis took the form of investigating microglial activation through positron emission tomography (PET) though an [11C] tagged drug (PK11195) which specifically marks active microglia and inflammation of the brain. Morizane et al found that only one allograft had increased [11C]PK11195 and no increase was observed in the autografts, while immunofluorescence analysis found the presence of MHC-II positive cells more frequently in the allografts rather than the autografts. MHC-II staining did not overlap with GFP (donor cells) and instead was associated with IBA1 expression from host microglia; with the number and density of IBA1+ cells higher in allografts than in autografts. The group also found that CD45+CD3+ T cells and CD45+CD8+ killer T cells accumulated in allografts compared with autografts. The study finished with the analysis of the survival of these grafts with relation to the immune response observed. While cells from auto- and allo-transplantation both survived, larger amounts of TH+/FOXA2+/NURR1+/ dopamine transporter (DAT)+ DA neurons survived in the autografts compared to the allografts.

Excitingly, the results demonstrate that both auto- and allo-grafted DA neurons can survive in the non-human primate brain without the requirement for immunosuppression. However, in comparison to the allografted cells, autografts do not elicit a significant immune response and survive better. The authors do note that while autologous cells are immunologically better suited, their use entails much higher cost and increased labour intensity and suggest that the next step is to compare autografts with HLA-matched allografts and HLA-mismatched allografts with immunosuppression.

References

Araki, R. et al (2013).
Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells.
Nature 494, 100–104

Chambers, S.M. et al. (2012).
Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors.
Nat. Biotechnol.30, 715–720.

Eiraku, M. et al (2008).
Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals.
Cell Stem Cell3, 519–532.

Guha, P. et al (2013).
Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells.
Cell Stem Cell 12, 407–412

Morizane, A. et al (2011).
Small-molecule inhibitors of bone morphogenic protein and activin/nodal signals promote highly efficient neural induction from human pluripotent stem cells. J. Neurosci.
Res. 89, 117–126.

Zhao, T. et al (2011).
Immunogenicity of induced pluripotent stem cells.
Nature 474, 212–215

 

Stem Cell Correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.