FUDiabetes

Erythrocyte decoration as a path to immune tolerogenesis

autoimmune

#1

Hi All,

I am relatively new T1 Dad and I have been using my work experience in biotech startups as a method for helping to see the light at the end of the tunnel. I am writing this here as a good part of my own personal therapy to convince myself that a cure is quite possible and there will be an end to this and so that perhaps I can share this hope with a couple of T1D sufferers.

Anyway, getting off the pity pot, it seems like everyone seems to have their favorite therapy which they think is going to work so I am now going to unabashedly promote my own favorite which I read in a journal described as erythrocyte (red blood cell) decoration.

As this is an immuno-therapy the end goal of this technique is to halt the auto-immune attack on the beta cells. Upon success there is an underlying that either a natural recovery will occur (a’la Daniel Darkes) for some lucky few while other will have to go through a more assisted regenerative process. Since I have only been able to find the single individual to reverse the autoimmunity it’s hard to base as conclusions other than it’s “possible”?

Erythrocyte decoration is based on the process of cell death which red blood cells go through en mass on a daily basis. Red blood cells have a unique property to them in which they are considered inert by the immune system since they don’t have DNA (evolution got rid of their nucleoli ages ago so they can hold more oxygen) and thus they go through a special process. The take home of which is that any antigens present on them are automatically accepted as “self” and are therefore tolerated. I have been reading a bunch of papers on the subject and it seems to work like a charm on … (sigh) mice, but it’s something.

Doing my research I have found three different biotech startups which are using this technique.

  • Kanyos Bio/Anokion: Using a technique of binding T1D antigens to red blood cells and they are still in the discovery phase of the pipeline.
  • SQZ Biotech: They have a really cool technology to disrupt the permeability of erythrocyte cell membranes to allow for the diffusion of T1D antigens into the red blood cell.
  • Rubius Therapuetics: I have to look into these folks more but they seems to be using engineered RBC’s to present T1D antigens, but I need to look into them more.

I have been looking for anything in the clinic data which supports this technique but so far I have not found anything and SQZ Biotech is the only one who has goeen further than “discovery” in the pipeline, but I am hopeful.

Because this could not only be used for autoimmune disease but also more common place food and environmental allergies as well as cancer drug rejection, this would give someone who masters this technique and getting it through FDA a really vast market for a single technology.

ps: Sorry for the TL;DR nature of this post.


#2

Hi @DoubleBee, interesting idea!

I would wonder if this tolerogenesis extends throughout the body or has varying degrees of effectiveness depending on what type of cell you’re talking about. But I agree that some method of essentially wiping out the “kill” command that targets something in the beta cells sounds like the key. Because even if you don’t have any beta cells left, you can theoretically then get new ones without having to suppress the immune system. That said, do we actually know what the body targets in T1D? We know the autoantibodies to test for but we don’t know if these are actually the immune system targets but rather an epiphenomenon, right? And it’s possible that different types of type 1 have different immune system targets right.

But it is certainly interesting to see these innovative ideas. I personally believe that somewhere out there are already several *cures or treatments that work for individual people with Type 1 but that we have no way of identifying what small subset of people might respond to them as yet. I know of one or two siblings at diabetes camp who, for instance, went on an experimental treatment plan when diagnosed in honeymoon, stopped having positive antibody tests and have been free of disease for years. Those studies failed but that doesn’t mean there was no effect in any of those people; it just means that statistically, across an average population, the effects weren’t detectable.

As an aside, I would be skeptical of Darkes’ claims, for one. From what I can tell no one following or reporting on his case has been able to actually speak to doctors.


#3

Hi @TiaG, thanks for the great feedback! We actually do know the antigens (the target of the antibodies) in quite a bit of detail at this point and one of the aforementioned biotech’s in past the discovery phase which indicates that they have found some good candidates. You are correct that not all T1D individuals have antibodies and I am interested if they will give the full regimen as it should “theoretically” be just fine to those who only have a subset but I look forward to the phase I trials to sort that out. Anyway, i do take your meaning about the different mechanisms of action of the immune system which may not be universal across all T1D but the hope that this is far up enough in the immunologic chain of events that it will cover the widest number of circumstances.

Right now my biggest concern is the “Biotech Death Valley” in which there is a fundamentally good idea (whether it’s this one or a totally different idea) but no venture capital will or foresight to invest. Unfortunately the desire to see progress towards a cure has very little to do with venture capital interests, if you can excuse my cynicism.


#4

Thanks @DoubleBee, I’m happy to find out they do know the exact antigens. I guess I’d read a few places something different but perhaps that’s not the case: From this paper, which is a little old:

It does not yet appear the case that there is a single primary islet antigen driving the autoimmune process in type 1 diabetes, nor is it known which islet antigens lead to pathogenic autoreactivity or bystander islet autoimmunity (Achenbach et al. 2005; Steck et al. 2011).

Maybe, however, when they say they don’t know they just mean the exact sequence of steps that go from initial targeting to broad autoimmunity?

i guess the other thing I’m intrigued by is the fact that these cellular components are expressed throughout the body and yet trigger autoimmunity only in the beta cells. For instance, our son recently had a case of autoimmune encephalitis. GAd-65 was a strong suspect in the case initially given his positive antibody tests at diagnosis. But he did not exhibit any positive GAD65 in CSF. So I would wonder if tolerogenic treatment would need to be more targeted – that systemic treatment maybe wouldn’t be effective?

In terms of repertoire of (candidate) autoantigens, it is still a mystery why loss of tolerance to certain proteins expressed in islets as well as other tissues leads to tissue-specific pathology and disease. Whereas type 1 diabetes shows comorbidity with other inflammatory conditions, such as thyroiditis, celiac disease, Sjögren’s syndrome, and Addison’s disease, the vast majority of patients show islet destruction only. Yet, all known islet autoantigens are expressed elsewhere: preproinsulin (PPI) and IGRP are also expressed in the thymus; GAD65 and IA-2 are neuroenzymes expressed variably in the CNS, neurons, testis, and ovary; chromogranin A is expressed in neurons and non-β endocrine cells, and heat shock protein 60 is expressed in all cells carrying mitochondria. Perhaps even more of an enigma, murine β cells do not express GAD65, yet, immunotherapy with this protein prevents autoimmune diabetes (Karlsen et al. 1992; Kaufman et al. 1993). Whatever the mechanism, tolerance is broken and there follows activation and recruitment of cohorts of T lymphocytes recognizing islet autoantigens, which have an intricate involvement in the disease process.

Anyways this is very interesting to me and I’m happy to learn more about it and have new information and misconceptions corrected. The immune system is so complicated and I really only understand the very very basics of it. But my son has now been diagnosed with two autoimmune conditions and he is only 4. We’ve been wondering in the back of our heads – is this just the beginning of a long snowball effect where he develops more autoimmune diseases? As a result I have become very interested in learning about treatments that could not only cure or treat his T1D, but also prevent the cascade of further autoimmunity.


#5

This was a very interesting post @DoubleBee. I was not aware of this research direction. It is good to hear of another possible direction with some promise for a cure.

I, like @TiaG, also understood that these antigens were unknown. Do you have any good sources of that? I would be very interested in reading more about it.


#6

Hi @Michel and @TiaG.

My heart breaks for your son. My own son went through Asthma and food allergies before T1D at age 11 so I am very familiar with your concern of what comes next.

As to that Roep paper there is a lot of scientist “CYA” in that in which he is mostly just stating that there is no “primary” antigen known and later on that we can’t be sure if we have a conclusive list. Rather I would encourage you to consider if the current information is actionable and please don’t just trust me as I am just a voice on the internet. Instead of would point to all of the immunologists who are leading the antigens specific immunotolerogensis. Disease heterogeneity will also be an issue and you are right to bear it in mind but it should not stand in the way of a good therapy. For example, the Caladrius Treg cell therapy Phase II data should be released soon (Q1 2019) and I would be surprised if their work was not based on this very data to generate their polyconal Tregs.

I know that many T1D sufferers/parent are wary of hope but for whatever it’s worth I do think there is reason here.

ps: I also know of this paper on additional (novel) antigens from 2017


#7

This was an interesting (2013) paper, with good info on antigen research. It included a list of recently discovered antigens (PDX1, ZnT8, CHGA, IIAP), although some of them had been around for a while, such as ZnT8. Thansk for sharing it!

I am possibly reading it in a different way, though :slight_smile: this article implies since several were recently discovered, that there may be quite a few left! The targets themselves associated with AAGs (autoantigens) are a fast growing list:

The list of the targets associated with beta cell-specific AAgs is continuously growing.

So I do think there is a lot more to discover about T1D-specific AAGs. However, I am still glad to see research pursuing an interesting track! And—we dont need to know all causal effects before discovering solutions to them.

We are all very different, I think, about how we deal with T1D in our children! I find it counterproductive for me, or my son, to encourage ourselves to believe that a cure is around the corner. People have been saying for the past 50 years! On the other hand, I am very optimistic about closed-loop BG control: I am certain the next few years will bring up extraordinary progress in self-management, and save large amounts of time and sleep to PWDs, for whom diabetes management is an always-on task. So I am very optimistic about much better and much more time-effective treatment—just not about a cure.

I am not sure if you are aware of a fantastic resource on research about a cure. @joshualevy keeps up a remarkable blog about ALL the research about a diabetes cure, and often posts here on FUD. Do check his blog out if you have not already:

There are many of us parents on FUD, I think because FUD gathers the most cutting edge participants and info on treatment, and does not spend much time on self-pity. I really look forward to reading more of your posts!