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Few Immune Issues with Dopamine Stem Cell Transplants in Primates

Samson, Kurt

doi: 10.1097/01.NT.0000438147.45559.90
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In a direct comparison of the growth, survival, and immunoreactivity of autologous versus allogeneic transplants of induced pluripotent stem cells (iPSCs) in nonhuman primates, investigators reported that while autologous cells survived better and produced more robust dopamine activation than those from matched donors (allogeneic), many cells proliferated without any major immune response in both groups of primates.

Transplantation of dopamine-producing pluripotent stem cells in the brains of nonhuman primates did not cause significant immune reactions without the use of immunosuppressive drugs, regardless of whether cells from the same animal or a compatible donor were used, according to a new study by Japanese researchers.

While autologous cells survived better and produced more robust dopamine activation than those from matched donors (allogeneic), and despite the fact that donor cells triggered minor signs of immunoreactivity at three to four months, many cells proliferated without any major immune response in both groups of primates.

It is the first study to directly compare the growth, survival, and immunoreactivity of autologous versus allogeneic transplants of induced pluripotent stem cells (iPSCs).

Harvested pluripotent stem cells can be coaxed into becoming nascent or active dopaminergic neurons in the laboratory before being transplanted into the brain, where still more begin to grow. It is hoped that the technique might one day help patients with Parkinson's disease (PD) and other disorders where dopamine levels are compromised.

Earlier this year researchers at the RIKEN Center for Molecular Imaging Science in Kobe, Japan, successfully used autologous stem cells collected from bone marrow to restore significant motor function in adult monkeys with induced PD. Cells were treated in the laboratory to become dopaminergic neurons before being transplanted.

The latest findings were reported in the Oct. 15 issue of the International Society for Stem Cell Research publication, Stem Cell Reports, published by Cell Press.



The study was led by principal investigator Jun Takahashi, MD, PhD, a researcher at the Center for iPS Cell Research and Application (CiRA) at Kyoto University in Kyoto, Japan, together with scientists at the RIKEN Center for Life Science Technologies and several other Japanese research groups.

“Our results indicate that autologous transplantation is beneficial in terms of the immune response and cell survival, however this strategy is associated with higher costs and labor,” Dr. Takahashi told Neurology Today. “An alternative method is allogeneic transplantation using HLA-matched iPSC stocks. The next step is to perform a critical analysis to determine whether autografts have advantages over HLA-matched allografts and human leukocyte antigen (HLA)-mismatched allografts with immunosuppression.”

In 2011, Dr. Takahashi and his team were the first to successfully use iPSCs to transplant cells composed of dopamine-producing neurons in monkeys.

Unlike autologous transplants, allogeneic grafts from matched donors (allografts) caused an acquired immune response, but only after two or three months, with activation of microglia and the infiltration of leukocytes into the graft area. Activated astrocytes and other signs of neuroinflammation were present in allogenic but not in autologous grafts.

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In the new study, the researchers compared the two approaches using cloned iPSCs harvested from four monkeys that were differentiated in their laboratory before being transplanted. The criteria for selecting which cells to clone included the stability of their stem-cell-like morphology in lab colonies, their ability to express pluripotent markers, having few or no integrated transgenes, which can cause cancers, and their potential to differentiate into stable neurons.





Magnetic resonance imaging and histological analysis were performed to evaluate the grafted cells three to four months after transplantation. Histopathological testing showed that the cells survived well in both groups of animals, and there were no significant differences in cell volume, however additional testing showed a larger number of cells from autografts while their density were lower in allograft animals.

Almost twice as many dopaminergic neurons (average 4,428) survived in animals that received autografts than in monkeys treated with allografts (2,247). Moreover, these surviving neurons coexpressed markers of a mesencephalic phenotype, such as FOXA2, NURR1, and the dopamine transporter (DAT). Even in allografts without immunosuppression, the TH+ neurons survived well, but their number and density were lower, the researchers said.

“Our results suggest that the autologous transplantation of iPSC-derived neural cells is advantageous for minimizing the immune response in the brain compared with allogeneic grafts,” Dr. Takahashi said. “My guess is that a laboratory somewhere will start a clinical trial for Parkinson disease in a couple of years.”

CiRA may begin human studies as early as fiscal year 2014, which in Japan starts April 1.

Dr. Takahashi told Neurology Today that the main obstacles facing the human research are safety, especially the potential tumorigenicity of donor cells, and proper preparation of clinical grade donated cells.

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“This study is very important because it highlights the important issue of immunological matching,” said Xianmin Zeng, PhD, associate professor in the Laboratory for Stem Cells and Aging at the Buck Institute for Age Research in Novato, CA. “Some people believe this is very important with research involving stem cell transplants in the brain, but we are finding out that the brain is not so immunoreactive and this study confirms this.”

She told Neurology Today that the key is whether HLA matching in allografts is a significant immunoreactive issue or not. If it is not a significant risk then it will prove to be very advantageous, but there appears to have been some risk in the study, however small.

A major advance is that the study was conducted in nonhuman primates rather than in mice, as many similar studies have been.

“These findings can serve as an important guide for designing phase 1 human trials of iPSC techniques for dopamine. We are already developing cell lines that could be used, but we need this information about whether or not immunosuppression is necessary, and in this study it appears that not much is going wrong and most cells seem to have survived.”

Nonetheless there are still many minor issues that need to be addressed, Dr. Zeng noted.

“While this research shows that transplanted autologous stem cells survive better than donor cells, the risk of immune reaction is not very high. The next question will be whether or not the differences between the two types of cells are that important in terms of treating patients.”

In addition, while cell survival was only around 2,000 with allogeneic cells compared to more than 4,000 with autografts, 2,000 cells may be enough to treat patients, she said.

“Another big question is whether the use of immunosuppression is necessary in human trials. These results should help guide decisions about this.”

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•. Morizane A, Doi D, Takahashi J, et al. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a nonhuman primate. Stem Cell Reports 2013; 1:1–10; E-pub 2013 Sept. 26.
    •. Ikuchi K, Morizane A, Takahashi J, et al. Transplantation of human induced pluripotent stem cell-derived midbrain dopaminergic neurons into the brain of a primate model in Parkinson's disease., J Park Dis 2011;1:395–412.
      •. Swistowski A, Peng J, Zeng X. Efficient generation of functional dopaminergic neurons from human induced pluripotent stem cells under defined conditions. Stem Cells 2010;28:1893–1904.
        •. Hayashi T, Wakao S, Kitada M, et al. Autologous mesenchymal stem cell–derived dopaminergic neurons function in parkinsonian macaques. Clin Invest 2013;123:272–284.
          © 2013 American Academy of Neurology