Another Step Towards Immune Cell Infusions as Therapy

Researchers here demonstrate a more efficient path to the production of large numbers of patient-matched immune cells. Delivering large numbers of immune cells via infusion on a regular basis may prove to be a useful treatment for older individuals suffering the characteristic immune dsyfunction that accompanies aging, a near-term way to restore vital immune functions ranging from clearance of unwanted cells to defense against pathogens, a stop-gap to be used until the underlying causes of immune aging can be reversed. The cost of generating the necessary cells is a big determinant of whether or not a therapy is developed for widespread use, however.

Though immune therapy and regenerative medicine are promising areas of research for future medical therapies, they are limited today by the difficulty of creating stem cells, and scientists around the world are searching for ways to create somatic stem cells in the easiest way possible. Researchers have now found that in immune cells, simply blocking a transcription factor that leads to differentiation is sufficient to keep cells in a multipotent stem cell-like state where they can continue to proliferate and can later differentiate into various cell types. Efforts in the past to create stem cells have typically involved finding ways to take target cells and "dedifferentiate" them into multipotent cells, but this is typically a painstaking process.

The team took mouse hematopoetic progenitor cells - cells that give rise to white blood cells - and modified them to overexpress a protein called Id3. Id3 inhibits the expression of E-proteins, which are involved in differentiation in somatic cells. They then placed the cells into culture conditions containing certain cytokines, and instead of differentiating into B-cells, the cells continued to divide as stem cells. When placed in a culture that did not contain those cytokines, the cells differentiated into various immune cells. To test whether the cells would maintain their multipotency in living animals, the researchers transplanted them into mice whose white blood cells had been depleted, and showed that the new cells could expand and differentiate into various types of white blood cells.

To explore the potential for application, the group then attempted a similar experiment using human blood stem cells taken from umbilical cords, which they transfected with a vector encoding human Id3. They found that like the mouse cells, these human cells could be maintained in a dividing state and then prompted to differentiate by changing the conditions. "This is both a useful tool for giving us a better understanding of the genetic and epigenetic program controlling the self-renewal of stem cells, and on a practical side, it could allow us to inexpensively produce large numbers of immune cells, which could then be used for regenerative medicine or immune therapy."



The key would be to entirely automate the generation of the cells. In any case, computers can be more precise and make fewer errors than lab technicians. They also do not bring in contaminants. You would still need people at the point of care, and these people are expensive, but if you prevent otherwise expensive diseases, it can be a net win.

Posted by: Daniel Lemire at October 23rd, 2015 2:30 PM

I know you have posted links to articles on Valter Longo's "periodic fasting", i.e., cycles of 3 day fasts for mice and 5 day fasts for humans. I've read his papers and he makes a strong case that his method restores mice and aged human immune systems to a "young" least as measured by biomarkers, immune cell type distributions, responses to vaccines, and HSC regeneration capacity.

Given that evidence why don't you view his fasting approach as a means for rejuvenating the immune system?

Posted by: Owen Palmer at October 23rd, 2015 5:12 PM

@Owen Palmer: For the same reason that if I had to travel a thousand miles across an ocean, I wouldn't see walking as a viable approach. It would get me a little of the way, to the shore, and then cannot take me further.

Calorie restriction, however packaged, cannot do more than take us a bit of the way to where we need to go. Given that every year counts in a time of rapid progress in medicine, it is worth doing because it might just be the difference between dying too early or living to see real rejuvenation treatments. That and being healthier is better than being less healthy. But those are the only reasons.

Don't be distracted by what can be done now, the walking, just because it can be done now, when what we need is to build boats and planes.

Posted by: Reason at October 23rd, 2015 5:30 PM

Reason, good answer. Thanks.

Longo personally follows and does recommend a daily "intermittent" fasting diet which he refers to as "skipping one meal a day". Such a diet does appear to produce similar good biomarker changes and lifespan expansion similar to those seen with caloric restriction. However, the "rejuvenation" of the immune system required a more sustained fast. The other fasting approaches didn't alter HSCs activity or immune cell distributions or improve chemotherapy outcomes. Periodic fasting even without chemotherapy appears to be effective (but less than fasting+chemo) against some cancers.

Potential downsides are that during the fast immune function declines and also for some people, especially the very old, such fasting is too stressful and could be dangerous. Longo has focused on a "fast mimicking" diet that has similar effects, is less stressful, and is easier to follow. More studies with aged humans are ongoing.

His rodent data for "water" fast compared to "fast mimicking" looked similar but the human data seemed to show less of a response to the "fast mimicking" diet. Over the years that I've been following his research I've noticed that he is focusing more on protein restriction than he did earlier.

Posted by: Owen Palmer at October 24th, 2015 9:11 AM

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