FUDiabetes

New technique could remove need for immunosuppressants in Beta cell grafts

cure

#1

Warning: this technique has only been tried with mice so far :slight_smile:

Scientists at the University of California San Francisco have developed a new method to minimize the likelihood that a person’s body will reject stem cells during a transplant. Using the CRISPR gene editing tools, the scientists managed to create stem cells that are effectively invisible to the body’s immune system.
[…]
The process is done by using the powerful and occasionally controversial CRISPR technology to delete two genes, major histocompatibility complex (MHC) class I and II, that would typically signal to the immune system that a cell is foreign. The scientists then added CD47, a cell protein that essentially tells the immune system not to destroy a cell.

We all look at Beta cell transplants with cynicism because of the need for immuno-suppressants. At the same time, the “City of Hope” process is the only one I have ever found that shows some success at suppressing the need for exogenous insulin. The present research project shows, for me, very interesting potential, at least in the direction it is opening.

[EDIT] Here is the UCSF press release that has significantly more detail. I should have providing this link earlier:

Here is the study abstract for the published paper. But the full paper is not available that I can find.

https://www.nature.com/articles/s41587-019-0016-3

Thoughts?


New process grows insulin-producing Beta cells from stem cells
#2

Definitely a cool use of CRISPR.

I am a little concerned over the potential of the cells becoming cancerous though… I would have to think on it more but I know changes in MHC class | have been tied to cancerous cells avoiding the immune system.


#3

And class II also:

https://www.cancernetwork.com/immuno-oncology/significance-mhc-ii-immunotherapy

Patient-specific variations in MHC-II molecules have as much, if not more, of an impact on the mutations that arise in tumors as MHC-I variations

And, to confirm your statement about MHC-1:

Immune escape strategies aimed to avoid T-cell recognition, including the loss of tumor MHC class I expression, are commonly found in malignant cells.

But it seems to me this is the game you have to play. Somehow, until you figure out to fix the immune system itself in T1 diabetes, the Beta cells you transplant must somehow avoid detection by the immune system, whether it be by physical barriers (not solved yet) or by T-cell avoidance games. In both cases, cancer risk becomes an issue—although, in this case, physical barriers, if we could ever solve them, become useful in stopping cancer spread.

However, there is another, totally different way to approach it: reprogram patient cells to regress to stem cells (we know how to do that), then to turn into insulin-generating cells. I have always thought it was the right way to go because it will never require anti-reject meds—but it is much more expensive (must be done per patient), and does not solve the issue of diabetes’ auto-immune future attacks on these beta cells (you still have to take immuno-suppressants for that). The interesting thing is that the second step has now been successfully accomplished in this study, by the very same UCSF team.


#4

The engadget story is very unclear on exactly what parts are edited…is the entire MHC class molecule deleted? Because that seems like an extreme step with lots of knock-on effects? And are those genes edited throughout the body or just in a few places? I think whether this has any potential or not is very much in those types of details.


#5

I am assuming it’s just in the edited Beta cells to be transplanted, engineering of humans is very frowned upon at this point


#6

well but this was all in mice anyways, so it might be easier to do germline editing to change the MHC genes, I don’t know relaly…


#7

I just added in the original post the link to the UCSF press release, which has significantly more details.

I also added a link to the paper abstract. But I cannot find access the full paper.


#8

The methods span several pages. Maybe I can find some time later today to figure out which sections are relevant.


#9

From the detailed press release quoted above:

[…] after the activity of just three genes was altered, iPSCs were able to avoid rejection after being transplanted into histocompatibility-mismatched recipients with fully functional immune systems. […]

[…]The researchers first used CRISPR to delete two genes that are essential for the proper functioning of a family of proteins known as major histocompatibility complex (MHC) class I and II. MHC proteins sit on the surface of almost all cells and display molecular signals that help the immune system distinguish an interloper from a native. Cells that are missing MHC genes don’t present these signals, so they don’t register as foreign. However, cells that are missing MHC proteins become targets of immune cells known as natural killer (NK) cells.[…]

Schrepfer’s team found that CD47, a cell surface protein that acts as a “do not eat me” signal against immune cells called macrophages, also has a strong inhibitory effect on NK cells. Believing that CD47 might hold the key to completely shutting down rejection, the researchers loaded the CD47 gene into a virus, which delivered extra copies of the gene into mouse and human stem cells in which the MHC proteins had been knocked out. […]

When the researchers transplanted their triple-engineered mouse stem cells into mismatched mice with normal immune systems, they observed no rejection. They then transplanted similarly engineered human stem cells into so-called humanized mice – mice whose immune systems have been replaced with components of the human immune system to mimic human immunity – and once again observed no rejection.

Et voila! With this recipe, I could probably duplicate it all in my kitchen in a couple of days :slight_smile:

My guess, however, is that human trials will find there are still quite a few pieces missing to make it work with a real human immune system. But who knows?


#10

As luck would have it, I just ran into this really interesting other article, that discusses suicide genes for stem cell transplants. It does not exactly asnwer your concern, but it is close: it enables the research team to compel cell suicide upon a certain number of criteria: tumorigenic cell, cell that does not generate insulin etc.:

The team focuses on beta cell production btw.

There is a lot going on in this research domain!


#11

Only induced pluripotent stem cells were genetically modified. First the coding sequence of β2 microglobulin, a component of the MHC class I molecule, was deleted using CRISPR-Cas9. So not the whole MHC I molecule was edited out, but they made it dysfunctional. Then, in these MHC I deficient cells they targeted the Ciita gene, which they call ‘the master regulator of MHC class II molecules’, again using CRISPR-Cas9. That should completely block MHC II expression. Finally, CD47 overexpression was induced using a lentivirus.
These stem cells were injected into mice to generate teratomas. Wild type cell grafts of course elicited an immune response and were rejected, whereas the genetically modified stem cells evaded the immune system.


#12

@Boerenkool, thanks so much for looking it up! That was a great explanation!


#13

I had a G.I.S.T. removed from my stomach about 10 years ago… non cancerous tumor… supposedly the body keeps making them…read briefly because I’m very influenced by what I read…so I started researching who what where why and the insulin I was on said in the pamphlet something about tumor activity. so I stopped taking any insulin that was “gmo”. It is more difficult to control the diabetes and like a dance… BUT. no reoccurrence of G.I.S.T. and last one,7.1 HgA1c…so far so good… would like to get lower but feel scared to try any other insulin…thoughts you scientists out there… now don’t go putting any negative thoughts in me… lol