Genetics in Motion: Putting T Cells in Their Place

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Throughout National Diabetes Month, we will be sharing developments into Joslin’s unique approach for a permanent cure for type 1 diabetes. Our mission is to prevent, treat and cure diabetes so that one day there will be a world free of diabetes and its complications.

This post was originally posted on October 8, 2014.

The mysterious onset of type 1 diabetes may have to do with what’s in your genes. Studies of twins show that if one twin has type 1 diabetes, the other has a 50 to 80 percent likelihood to also get the disease.

In the past 5 years, new technology that screens the whole genetic code allowed researchers to uncover at least 50 diabetes-associated genes. Interestingly, many of those genes also relate to other autoimmune diseases such as multiple sclerosis or celiac disease.
Stephan Kissler, Ph.D., Assistant Investigator in the Section on Immunobiology at Joslin Diabetes Center, studies those genes associated with multiple diseases using some of the newest lab techniques available.

“The goal of my lab is to look at some of those most intriguing genes and to understand how they contribute to disease, what mechanism is involved and how we may be able to use this knowledge to intervene in disease, either to prevent or stop the autoimmune disease that causes type 1 diabetes,” said Kissler.

Kissler and his lab focus on genes associated with multiple diseases in the hopes that they’ll tap into something fundamentally important in autoimmunity. Because some of these genes were recently uncovered, his lab is among the first to explore them in depth.
“Many of these genes have never been looked at before in the context of type 1 diabetes,” said Kissler. “So there are genes we’re looking at that don’t even have a known function and that have never been looked at in any animal.”

All the genes being studied in Kissler’s lab play some role in regulating the immune system. Many of them affect T cells, which patrol the body looking for infections to fight off.

One of the genes they are working on regulates T cell response to signals from tissues that tell the cells how to deal with what they perceive as infection.

“Based on these signals, the cells will decide whether to go back into the blood or go into a lymph node or migrate into a tissue that maybe infected and start clearing infection,” said Kissler.

Cells with the RGS1 gene turned down fluorescing green in one of Dr. Kissler’s experiments.

This gene, called RGS1, is faulty in type 1 diabetes and many other autoimmune diseases. “The reason this gene has been associated not just with type 1 diabetes but also with MS and Celiac disease is that maybe it makes the cells a little bit more likely to actually go into a target organ and start destroying it and in the case of type 1 diabetes that would be the pancreas,” Kissler said. A version of this gene exists in everyone. It allows the T cells to recognize that their help is needed in infected or inflamed tissue—a natural response to an illness or injury. But as with every gene in your body, there are minor tweaks that make it carry out its function slightly differently in your body than in someone else’s.

“We are all 99.9 percent identical. But we have millions of very small differences. For the most part inconsequential. But then there are a lot of obvious differences,” said Kissler, such as hair or eye color. “The same goes for this gene. The function is not that significantly different. It’s just that by a small variation in one person it might be a little be more active in another one it might be a little less active,” he said.

Kissler and his lab think if they could turn down the activity on that overactive RGS1 gene associated with type 1 diabetes they could make the T cells more likely to come out of the pancreas, or less likely to go into the pancreas at all.

A current MS therapy uses a similar approach to prevent cells from entering and destroying the central nervous tissue. The therapy works for MS, but comes with a high risk of a dangerous side-effect—the inability for the T cells to fight off infection. For a patient with severe MS, this could be a risk they’re willing to take. But for a relatively manageable disease such as type 1 diabetes, that treatment isn’t a reasonable course of action.

Kissler’s lab wants to keep the T cells from attacking the cells of the pancreas. “Rather than completely stop them from going in there, we’re just making them more likely to return to the blood stream once they’ve done their job if they actually did have a genuine reason for being in there,” he said.

By turning down the activity on this gene, they’re hoping to make the T cells more responsive to the signals telling them to go home, making them less likely to get stuck in the pancreas, mounting endless attacks on the insulin-secreting beta cells.

They first carried out these experiments in a culture dish where they mixed together T cells with the RGS1 gene at full power and T cells with the RGS1 gene turned down. They made the reduced-RGS1 cells fluoresce green under certain lighting to be able to tell them apart.

“We isolate cells and we make them migrate in a dish and we can see that they migrate differently when we turn the gene off versus when the gene is on,” said Kissler. “This confirms the system works and we’re very confident now that when we do these disease studies we will see a difference.”

They insert a harmless virus into a fertilized egg.

The disease studies, which have recently been supported by a large JDRF grant, will start soon in animal models. They turn off the gene in an animal by inserting a harmless virus into a fertilized egg. When that egg becomes a mouse, they are able to activate the virus with a simple antibiotic in the drinking water which turns the gene on or off, mimicking human drug treatments.

“The beauty of this model is that it’s inducible, so then we can manipulate the expression of RGS1 at different stages and then we can see the role of these proteins and the onset and the progression of the disease,” said Celia Caballero-Franco, Ph.D., Research Fellow in the Kissler lab. She plans to reduce the activity of RGS1 at different times throughout the lifespan, to see if the action of the protein changes the course of diabetes.

If RGS1 proves to have an effect on diabetes onset and progression (first in animal and then in human trials) the transition to a drug therapy could be smooth. Genes that are relatives of RGS1 have been targeted by drugs before, acting as a proof of concept for the ability to target this gene.

Changing the actions of T cells alone would not be enough to cure type 1 diabetes entirely. There may be other genes at play that would also have to be targeted in order to wipe out the autoimmunity. And further research at Joslin explores how to replace the destroyed and damaged beta cells.

“We’re very optimistic that we will figure out how diabetes develops,” said Kissler. “It’s not going to happen overnight but we’re well on our way and with these new genes that have been uncovered we now have so much more information to go after. We’re going to make some good headway and hopefully come up with some new strategies to prevent or cure type 1 diabetes.”

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One Response to Genetics in Motion: Putting T Cells in Their Place

  1. bobby villegas says:

    I am 74 and was diagnosed with diabetes 2 6 months ago. I take one metformin (500)in the
    morning and one at night. I also take an pen insulin injection at a low number 6 every night. I am trying to wean myself from one or both with exercise. should I leave out the metformin first or just start lowering the insulin. my sugar with both is between 89 and 112. ? thank you

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