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Engineering Cells to Avoid Immune Detection in Transplants

This technique is designed to remove the risk of rejection.

InvisibilityInvisibility
 

Gene editing can make stem cells invisible to the immune system, making it possible to carry out cell therapy transplants without suppressing the patients’ immune response [1].

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Cellular therapies involve transplanting cells into a patient to replace the activity of malfunctioning or damaged cells. For example, cardiomycetes could be transplanted to repair or restore heart function, and endothelial cell transplants could be used to treat vascular diseases. While these therapies hold exciting potential, rejection of the transplanted cells is a significant hurdle to their widespread use. Rejection can be overcome by immunosuppression or by growing custom cells using a sample from the patient, but both approaches have drawbacks.

Instead, scientists in the US and Germany are using immune engineering to develop universal cell products that could be used in all patients. The idea is to create stem cells that evade the immune system; these hypoimmune stem cells are then used to generate cells of the desired type that can be transplanted into any patient without the need for immunosuppression, since the cells won’t elicit an immune response.

Hidden helpers

To accomplish this, the researchers used CRISPR-Cas9 to knock out two genes involved in the major histocompatibility complex, which is used for self/non-self discrimination. They also increased the expression of a protein that acts as a “don’t eat me” signal to protect cells from macrophages. Together, these changes made the stem cells look less foreign and avoid clearance by macrophages.

The team then differentiated endothelial cells and cardiomycetes from the engineered stem cells, and they used these to treat three different diseases in mice. Cell therapy treatments using the hypoimmune cells were effective in rescuing hindlimbs from vascular blockage, preventing lung damage in an engineered mouse model, and maintaining heart function following a myocardial infarction. In all three cases, transplanted cells derived from ordinary stem cells, which hadn’t been engineered to evade the immune system, were not effective.

“We showed that immune-engineered hypoimmune cells reliably evade immune rejection in mice with different tissue types, a situation similar to the transplantation between unrelated human individuals,” said Tobias Deuse of the University of California, San Francisco, in a press release.

Abstract

The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.

Conclusion

This technology is still far from clinical application, but this is nevertheless an exciting first step. Immunosuppression poses obvious risks to a patient, and generating custom cells for transplant therapy is expensive, often prohibitively so. The development of universal donor cells that can be used as therapeutics could bring the cost down significantly, making cellular therapeutics available to many more patients in a much safer way.

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Literature

[1] Deuse, T. Hypoimmune induced pluripotent stem cell–derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice. PNAS (2021), doi: 10.1073/pnas.2022091118

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About the author
Sedeer el-Showk

Sedeer el-Showk

Sedeer became a professional science writer after finishing a degree in biology. He also writes poetry and sff, and somehow juggles an ever-growing list of hobbies from programming to knitting to gardening. Eternal curiosity and good fortune have taken him to many parts of the world, but he’s settled in Helsinki, Finland for the moment. He hopes he’ll never stop learning new things.
  1. jimofoz
    July 15, 2021

    Repair Biotechnologies is using the same technology when creating their macrophages that can break down oxidised LDL in the plaques that build up in blood vessels in atherosclerosis.

    Reason, author of the Fightaging.org blog, founded Repair Biotechnologies.

    https://www.fightaging.org/archives/2021/02/a-profile-of-repair-biotechnologies-working-to-end-atherosclerosis/

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