One of the rock-solid assumptions of an entire industry of donor stem cell companies seeking FDA approval is the idea that stem cells are immune privileged. This is a fancy way of stating that someone’s stem cells when injected or implanted in your body cause no immune response. However, as I’ve blogged before, there have been scattered published studies that have questioned this foundational issue. This week I heard an excellent presentation by Ashlee Watts of Texas A&M University that may be a big problem for an entire industry.
Autologous vs Allogeneic
Your stem cells have always been considered the safest possible source. In medicine, these cells are called autologous. However, many academics and industry have argued that culturing your cells is much more expensive and from an investment standpoint, what we need is a donor stem cell that can be grown in bioreactors and used in everyone. This type of therapy that uses someone else’s cells is called allogeneic. Add into that the idea that the stem cell numbers in our bodies decline with age and the rationale for mass producing allogeneic cells gets even more convincing.
The Issue of Rejection
Most of us would know that you can’t take someone else’s random blood sample and infuse it into yourself. The early medical pioneers soon figured out that there were blood types and that you had to match donor blood to the patient or there would be a massive and oftentimes deadly immune response. In addition, most of us likely know that you can’t take a friend’s kidney and stick into your body without some rejection. You may know that powerful immune suppressant drugs are often used to reduce rejection in organ recipients.
The reason you can’t get someone else’s tissue is due to HLA antigens. These are cell surface proteins that allow your immune system to identify your cells versus a foreign intruder. Think of these like an ID card for the cell. The immune system challenges each cell and then requires that it shows ID. If the cell has the right ID, it gets a pass. If the cell has the wrong ID, it gets targeted for destruction.
To reduce rejection with organ transplants, doctors try to match these ID cards on the donor cells to the recipient. There are 153 different main types of ID card combinations and when one is matched to another that is the same, it’s called an HLA match. Meaning those donor cells will mostly pass the ID check challenge posed by the recipient’s immune system. However, when the ID cards on the donor cells don’t match what the immune system is used to seeing on its own cells, that’s called an HLA mismatch.
Immunoprivileged Stem Cells
One of the great things about stem cells was that they are supposed to be immunoprivileged. Meaning, they should be able to fake out the host’s immune system and pass the ID check challenge. In fact, we have billions of dollars of bench and clinical research based on this concept. Many companies trying to get mass produced stem cells approved as a drug have literally bet the farm on this idea. However, is this true?
We have had Ashlee Watts, a Ph.D. DVM researcher from Texas A&M lecture at the IOF conferences in the past. This is a prior published study by Dr. Watts on a similar topic. This last week she was also a participant in the CSU Havemeyer Stem Cell Translational Thinktank (aka Symposium). The data she presented on horses from her lab was pretty startling and if it pans out in humans, would mean that those billions being spent on allogeneic stem cell products may be wasted.
What did she find? The image above tells the story. Basically, when stem cells were taken from another horse who was HLA mismatched to the recipient, the stem cells and their local stimulated brethren were decimated by an immune response (blank culture dish to the right showing no stem cells). When autologous stem cells were used, no such reaction happened (culture dish to the left full of cells). In addition, this immune response gets worse the second time, which is always the case with the immune system. Meaning, our immune systems learn about foreign tissue and mount a bigger response the second time they see it.
What Else Has Been Published?
We do have information from other authors on this topic of allogeneic stem cell immune responses. Take for example this 2014 study that demonstrated that allogeneic stem cells produced a host immune response when they differentiated into cartilage cells. We also know that this happens with umbilical cord blood. Take this recent study that tied the poor outcomes of umbilical cord blood used to treat leukemia to HLA mismatch.
The Implications of this Research Are Major
First, for the companies spending huge bucks on allogeneic stem cells, if this study is repeated in humans, they have a huge problem. This may explain the lackluster clinical trial results that seem to be all over the map. Meaning if your stem cell donor was more universal (if such a thing exists), you may get better clinical results than one that is not.
However, this also extends to the business concepts behind these allogeneic companies. If this is verified in humans, then they should be growing cells of many different HLA types and matching those to recipients. The problem? This will put a major dent in many company spreadsheets. Or they should be searching for a stem cell that can act as a universal donor.
For the umbilical cord blood treatments that are happening around the United States, this is also a big issue. Meaning, these cells likely should be HLA typed and matched to the patient, but none of that is happening. While the first treatment might give only a small immune response, the second may be wiping out many of the cells (for those few products that have any live cells). In addition, in kids, this can get dangerous as the foreign stem cell immunity mounts.
Finally, let’s think about all of the rich people out there getting stem cell treatments for anti-aging. Those patients should be careful, especially if they’re traveling out of the country to get live cells infused IV. If these are not matched to their HLA antigens, while they may not get super sick, the cells they’re counting on to make them live longer may be getting decimated by their immune system.
The upshot? These findings and others like it may have huge impacts. Lots of people are investing and spending huge bucks on the idea that you can easily use another person’s stem cells and this will work. However, if that’s not true, then the scientists and physicians have truly put the cart before the horse.