Inducing tolerance to transplanted cells could make stem-cell therapy more enduring and versatile
For cell therapies to work, the transplanted cells must survive. But in patients with active immune systems, cells recognized as foreign will be attacked. Ann Chidgey and Richard Boyd from Monash University and Norwood Immunology, Victoria, Australia, describe how stem cells could, one day, be used both as therapies themselves and as a means of protecting transplanted cells from rejection1.
Why do you need to combine stem cell therapy with a tolerance strategy?
Basically, we want to re-educate the patients' immune systems so that they will accept donor cells as their own.
Boyd: If you've differentiated an embryonic stem (ES) cell properly, it should take on the properties of a mature cell and express proteins that will make it a target for rejection. Basically, we want to re-educate the patients' immune systems so that they will accept donor cells as their own.
Why do you think this can be done?
Boyd: There was a girl in Australia who made world headlines last month. She had received a liver transplant at age 9, and by age 16 she had completely accepted the liver. They checked her immune system and it was all donor cells. The liver is a big organ with lots of blood cells and contained donor haematopoietic stem cells (HSCs). We think these built up the thymus, and her immune system became derived from the donor stem cells. So of course she didn't reject the liver.
Also, David Sachs, one of our colleagues, did a very interesting experiment. He had six [young] patients with leukaemia or lymphoma, and they had to have full chemotherapy and a bone marrow transplant. Later, they needed organ transplants, which is quite common. David said, “They've got chimaeric immune systems, maybe we could go for the same donors as the bone marrow transplant.” They did the transplants and put the patients on immunosuppressants. David and his team then waited three or four months for something to happen and couldn't see any sign of rejection. They eased the patients off the immunosuppressive drugs and saw absolutely no sign of rejection. It was actually the right combination, a bone marrow transplant and an active thymus create tolerance, and then you can do a transplant.
Chidgey: The older the patient becomes, the more atrophied the immune system is. And the more difficult it is to create tolerance, but if you could do that by activating the thymus, then you could improve the engraftment.
So how would you use this for, say, cell therapies in neural disease?
Boyd: If you have ES cells, you could force them down the line to neural progenitor cells and inject them into the patient. If you could also make HSCs from the same ES cell line, [and give them to the patient] you'd have two systems working at once: the neural cell addressing the disease and the HSCs, along with thymic reactivation, providing the tolerance.
I thought you couldn't make HSCs from embryonic stem cells.
Boyd: It is difficult. People are trying to generate HSCs from ES cells. No one has achieved that yet. People have been able to make red blood cells, but there is no proof of them going through an HSC stage.
Another way around it is to go to the cord-blood bank for HSCs. You could match cord blood to the other cells. It's a very sensible thing to do, but it's never been done.
For an adult, it's difficult to get enough HSCs from umbilical cord blood, which is only about 80–100 millilitres. There's preliminary evidence that once we've reactivated the bone marrow and the thymus, that might reduce the number of HSCs required for a successful transplant. That might make cord blood applicable in adults.
Could it work for organ transplants too?
Boyd: The rules we're using can be applied to stem cells or solid organs. Stem cells might be a little easier, because a stem cell might make a single cell type, so you can identify molecules on that cell that may activate the immune system before it's transplanted, and you can control for that.
You've written that combining these technologies would be a powerful way to address disease.
Boyd: Let's consider first how multiple therapies would work for an autoimmune disease such as multiple sclerosis, which will be the hardest type of case. First you'd switch off the autoimmunity; then replace the damaged material using stem cell therapy; and then rebuild the immune system by reactivating the thymus and introducing HSCs.
Now let's dream. Say you had a way to make HSCs en masse from ES cells as an off-the-shelf product. And say you could introduce a gene for HIV resistance into the ES cellsYou would then have millions of HSCs carrying the anti-HIV gene, which you could introduce into the HIV-infected patient. Their immune system would now be HIV resistant and could target the virus without being destroyed itself. This would be important, as even if an anti-HIV vaccine could be made to work, it wouldn't normally get a chance to work in HIV patients because their immune systems have been destroyed.
Chidgey, A. P. et al. Evolving tolerance strategies to enable stem cell based therapies. Nature, 453, 330–337 (2008).
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Baker, M. Richard Boyd and Ann Chidgey: Protecting cells from immune attack. Nat Rep Stem Cells (2008). https://doi.org/10.1038/stemcells.2008.79