TLDR: Making antibodies attach to transplanted cells the wrong way helps hide the cells from the immune system, letting the cells live longer and do their job

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Cell therapies are a new type of treatment being used to treat cancer, diabetes, and sickle cell disease. More and more cell therapies are being created as we get better at engineering cell functions.

One major problem cell therapies face is that the patient’s native cells kill the transplanted cells. Obviously, the therapy doesn’t work if all the cells are dead. Keeping transplanted cells alive is a major challenge and has attracted a lot of research attention. Part of my PhD work has been on designing materials systems to help transplanted cells survive.

Organ transplants and cell therapies share some of the same clinical hurdles. The main one is the outright rejection of the transplant. Transplant rejection is when the patient’s immune system doesn’t accept the transplant and attacks it, leading to many problems (including the transplant not working).

Rejection occurs for many reasons. The patient’s antibodies tell the immune system to attack the transplant. Antibodies recognize and attach to specific markers. Foreign cells (like a transplant) have different markers than our natural cells do, letting antibodies recognize and attach to them.

Antibodies are a tool your immune system uses to fight foreign invaders. During a transplant rejection, your body views the transplanted cells as a foreign entity and decides to get rid of them. This decision is communicated when antibodies attach in a specific way to the transplanted cells, letting the immune cells know they’re a target to eliminate.

This system relies on antibodies to show the host immune system where to attack. One side of an antibody attaches to a specific target (the Fab domain) and then the other side (the Fc domain) signals the host’s immune system to attack the cell it’s attached to.

This week’s paper took advantage of the antibody orientation being important to effectively hide the transplanted cells from the host’s immune system.

The authors made it so that the wrong side of the antibody attached to the transplant cells. With the Fc side attached to the transplanted cell instead of the normal Fab side, the antibodies can’t signal the immune system to attack. Without this signal, the immune system never decides that the transplant needs to be destroyed.

They did this by making the transplant cells produce a protein called CD64 (proteins either have really cool or really boring names). This protein attaches to the Fc domain of many antibodies, causing the antibodies to be oriented the wrong way. This makes them unable to signal the immune system and protects the transplanted cells.

They tested this in a variety of cell culture studies looking at the response of different immune cells to the transplant cells. The immune cells didn’t attack when the immune cells had the backwards antibodies.

Next, they tested if their modified transplant cells evaded being killed after being delivered to a mouse. To track cell survival, they made the transplant cells produce a fluorescent protein that they could see with a microscope. The cells produce a fluorescent protein when they’re alive, making them glow when imaged through a microscope. So, more signal=more alive cells.

As you can see above, many, many more cells survived with the backwards antibodies. Normal transplant cells died off within the first 2-3 days (right graph) but the backwards antibody transplant cells lasted out until at least 28 days (left graph)! That’s an incredible improvement for a relatively simple fix.

Three major uses of cell therapies are for cancer, diabetes, and thyroid conditions. Researchers have previously figured out how to engineer cells to treat each of these diseases. However, like you probably guessed, the transplanted engineered cells die quickly. And dead cells equal an underperforming therapy.

So, the authors tried their backwards antibody trick with engineered cells for cancer, diabetes, and thyroid conditions. They did similar experiments to the one from the graph above and found very similar and very promising results.

Without being attacked and destroyed, the transplanted cells can do their job! One thing I love about this work is its versatility. It seems like any cell therapy could benefit from this design. Hopefully we see other researchers using this technique in their studies soon.

See you next week for more science,

Neil

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