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future celiac therapies?
Jul. 30th, 2010 10:38 pmSince I know multiple people with celiac disease or other strong food sensitivities, I was very interested when I saw a notice of a paper finding that just three peptides were responsible for most people's gluten reactions (free abstract only). I found it a bit confusing, so I thought I'd post my explanation. I am a plant molecular biologist, not an immunologist, but I hope the following is both intelligible and correct.
Their methods: Find over 200 adults with celiac disease; pay them, I hope, a lot of money, because the next step is to feed them cereals (wheat, barley, or rye). Take their blood 6 days into the cereal doom phase and pull immunoreactive T cells out of it, then find out what peptides those T cells like to bind to (using a hierarchical, cleverly designed set of synthetic peptides that made this possible despite the hundreds of candidates). Those will be the peptides responsible for the immune reaction.
Interesting results: The T cells produced were both highly grain-specific ones and ones that were common among all the grains. Reactions to rye and barley were actually stronger than reactions to wheat in the people examined. Over 70% of the total T cells produced were specific to three peptides.
Possible fixes or therapies for celiac disease mentioned in the paper:
1. Genetically engineering cereals without the protein characteristics that mess people up. As someone who works with transgenic plants, I have to say that this doesn't seem feasible considering the sheer number of protein-coding genes involved.
2. Food tests that detect the bad proteins. Potentially very useful to people who want to eat in restaurants, if a quick and reliable detection test can be marketed.
3. Peptide-based immunotherapy. (I had to go to other papers to find out that this wasn't just allergy shots, for which you wouldn't need protein sequences; it's much cooler.) There are suppressor T cells as well as activator T cells, and apparently changing certain amino acids in the peptides they're reacting to can cause the suppressors to respond; the mechanism for that seems to be unknown, and I'm not sure who tried it first or why. So the immune system actually re-regulates itself in almost the way it initially overreacted. The activators are still there, but they're balanced out. Free full text.
Another possibility: If we could find an enzyme that would cleave these three peptides, it might be possible to pretreat foods, rendering them mostly safe. If the enzyme would work in the digestive system (none of those we make in our bodies will cut the antigens, or it wouldn't be a problem), we could have lactaid-style pills to break down the immunotoxic peptides before any reaction became severe.
I agree that the peptide-based immunotherapy, if it can be made to work, holds the most promise. The others are ways to do better what people with celiac disease have to do now: avoid the bad proteins entirely. Hacking the immune system, though, would be incredibly cool, and I think most people would be willing to have the treatment even if it took a fair amount of time and money. I wonder if the treatment would have to be repeated periodically, but it'd probably still be worth it!
"Comprehensive, Quantitative Mapping of T Cell Epitopes in Gluten in Celiac Disease"
Tye-Din et al., Sci Transl Med 2 (41) 41ra51.
Their methods: Find over 200 adults with celiac disease; pay them, I hope, a lot of money, because the next step is to feed them cereals (wheat, barley, or rye). Take their blood 6 days into the cereal doom phase and pull immunoreactive T cells out of it, then find out what peptides those T cells like to bind to (using a hierarchical, cleverly designed set of synthetic peptides that made this possible despite the hundreds of candidates). Those will be the peptides responsible for the immune reaction.
Interesting results: The T cells produced were both highly grain-specific ones and ones that were common among all the grains. Reactions to rye and barley were actually stronger than reactions to wheat in the people examined. Over 70% of the total T cells produced were specific to three peptides.
Possible fixes or therapies for celiac disease mentioned in the paper:
1. Genetically engineering cereals without the protein characteristics that mess people up. As someone who works with transgenic plants, I have to say that this doesn't seem feasible considering the sheer number of protein-coding genes involved.
2. Food tests that detect the bad proteins. Potentially very useful to people who want to eat in restaurants, if a quick and reliable detection test can be marketed.
3. Peptide-based immunotherapy. (I had to go to other papers to find out that this wasn't just allergy shots, for which you wouldn't need protein sequences; it's much cooler.) There are suppressor T cells as well as activator T cells, and apparently changing certain amino acids in the peptides they're reacting to can cause the suppressors to respond; the mechanism for that seems to be unknown, and I'm not sure who tried it first or why. So the immune system actually re-regulates itself in almost the way it initially overreacted. The activators are still there, but they're balanced out. Free full text.
Another possibility: If we could find an enzyme that would cleave these three peptides, it might be possible to pretreat foods, rendering them mostly safe. If the enzyme would work in the digestive system (none of those we make in our bodies will cut the antigens, or it wouldn't be a problem), we could have lactaid-style pills to break down the immunotoxic peptides before any reaction became severe.
I agree that the peptide-based immunotherapy, if it can be made to work, holds the most promise. The others are ways to do better what people with celiac disease have to do now: avoid the bad proteins entirely. Hacking the immune system, though, would be incredibly cool, and I think most people would be willing to have the treatment even if it took a fair amount of time and money. I wonder if the treatment would have to be repeated periodically, but it'd probably still be worth it!
"Comprehensive, Quantitative Mapping of T Cell Epitopes in Gluten in Celiac Disease"
Tye-Din et al., Sci Transl Med 2 (41) 41ra51.
