Summary: Researchers at Johns Hopkins Medicine have developed a method to transplant myelin-producing neural stem cells into mouse brains that avoids lifelong anti-rejection drugs by selectively inducing immune tolerance.
Source: Johns Hopkins Medicine
New method enables neural stem cell transplants without permanent immune suppression
Johns Hopkins Medicine scientists report a promising technique, demonstrated in mice, that allows transplanted glial progenitor cells to survive and function in the brain after only short-term immune modulation. The approach prevents the immune system from rejecting foreign cells without broadly suppressing immunity for life, a major barrier to cell-based therapies for inherited myelin disorders such as Pelizaeus-Merzbacher disease.
These genetic disorders impair formation of myelin—the insulating sheath that enables efficient nerve signaling—leading to severe developmental delays, involuntary muscle spasms, and progressive motor disability. Because the disease stems from malfunction in a single specialized cell type, replacing those defective cells with healthy or genetically corrected donor cells is an attractive therapeutic strategy. However, the recipient’s immune system usually recognizes transplanted cells as “nonself” and mounts a destructive T-cell response, forcing recipients to remain on systemic immunosuppressive drugs that increase infection risk and other side effects.
To overcome that obstacle, the Johns Hopkins team focused on modulating T-cell activation through co-stimulatory pathways—molecular “go” signals T cells need to initiate attacks. By selectively blocking those signals during the critical early period after transplantation, the researchers aimed to teach the immune system to tolerate donor cells long term without continuous immunosuppression.
Investigators used two immune-modulating antibodies, CTLA4-Ig and anti-CD154, which bind to molecules on T cells and interrupt co-stimulatory signaling. This combination had previously prevented organ rejection in animal models but had not been evaluated for cell transplants intended to repair myelin in the central nervous system.
In the core experiments, the team transplanted glial-restricted progenitor (GRP) cells—precursors that generate myelin-producing glia—into mouse brains. The GRPs were genetically labeled to fluoresce so their survival and distribution could be monitored noninvasively. Researchers transplanted these cells into three groups: mice lacking the endogenous myelin-producing glia, normal immunocompetent mice, and immunodeficient mice that cannot mount a T-cell response.
Animals treated with the CTLA4-Ig plus anti-CD154 antibody regimen received only a short course of therapy. The researchers monitored graft survival daily using sensitive imaging to detect fluorescence from the labeled cells. In untreated control animals the transplanted cells began to disappear rapidly and were gone by about three weeks. In contrast, mice receiving the co-stimulation blockade retained substantial grafts for more than 203 days after a brief treatment period, indicating durable survival even after stopping the antibodies.
Lead author Shen Li, M.D., and colleagues interpret this sustained fluorescence as convincing evidence that blocking co-stimulatory signals selectively prevented T-cell–mediated destruction of the grafts, enabling long-term engraftment without continuous immunosuppression.
Next, the team evaluated whether the surviving GRP cells performed their intended function—forming myelin. Using MRI and structural analyses, they observed that in treated animals the donor cells populated appropriate brain regions and contributed to remyelination, confirming functional integration rather than mere survival.
Although these results are preliminary and confined to localized brain regions in mice, they represent an important proof of principle. The researchers emphasize the need for further work to combine immune-tolerance strategies with improved delivery methods that could treat larger brain areas and ultimately support clinical translation for pediatric leukodystrophies and other demyelinating conditions.
Study authors include Piotr Walczak, M.D., Ph.D., Shen Li, M.D., Byoung Chol Oh, Chengyan Chu, Antje Arnold, Anna Jablonska, Georg Furtmüller, Huamin Qin, Miroslaw Janowski (Johns Hopkins University); Shen Li (Dalian Municipal Central Hospital and Johns Hopkins University); Johannes Boltze (University of Warwick); and Tim Magnus and Peter Ludewig (University of Hamburg).
Funding: This research was supported by the National Institute on Neurological Disorders and Stroke (R01NS091110, R01NS091100, R01NS102675, 2017-MSCRFD-3942).
The authors declare no competing interests.
Source:
Johns Hopkins Medicine
Media Contacts:
Rachel Butch – Johns Hopkins Medicine
Image Source:
The image is credited to Johns Hopkins Medicine.
Original Research: Open access
Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts. Piotr Walczak et al. Published in Brain, DOI: 10.1093/brain/awz275.
Abstract
Induction of immunological tolerance to myelinogenic glial-restricted progenitor allografts
The immunological barrier currently limits clinical use of allogeneic stem cells. Glial-restricted progenitors are attractive candidates for treating many neurological diseases, but their survival in immunocompetent recipients is poor. In this study, investigators applied a short-term, systemically delivered co-stimulation blockade strategy using CTLA4-Ig and anti-CD154 antibodies to modulate T-cell activation during allogeneic GRP transplantation. Co-stimulation blockade prevented rejection of GRPs in immunocompetent mouse brains, and long-term engrafted GRPs myelinated dysmyelinated adult mouse brains within one month. The team also identified plasma microRNA signatures that correlate with changes in immune reactivity and could serve as biomarkers for graft rejection or tolerance. This strategy induces alloantigen-specific hyporesponsiveness to stem cells in the central nervous system and may enable more effective clinical application of allogeneic cell therapies.