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| Physiological changes in T1D vs a healthy person (inability to control glucose levels due to lack of insulin being produced) |
Type 1 diabetes (T1D) is a serious, yet often overlooked,
autoimmune disease that affects approximately 3 million Americans. It is often lumped into the general
category of “diabetes” alongside type 2 diabetes, even though T1D is generally more
serious and isn’t preventable. In
people with T1D, islet, or beta (β) cells, in
the pancreas are slowly destroyed by the body. These cells are responsible for producing insulin, which
controls blood glucose levels and keeps them at a healthy level. People with T1D have to constantly
monitor their blood sugar and inject themselves with insulin in order to
control their glucose levels or risk serious complications such as blindness,
foot amputation, or even coma. As
of now, there is no cure for the disease.
Recent research has focused on trying to find a way to prevent the body
from attacking itself through manipulation of the immune system and/or to
restore β cell function. However, even an improvement in treatment would greatly
increase the quality of life for T1D patients.
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| Creation of Insulin: proinsulin cleaved to produce active insulin and C-peptide |
Autoimmune
diseases are more complex to treat since it’s often very difficult to suppress
only the part of the immune system that isn’t functioning. Similar to cancer, it’s hard to
kill only the bad cells in the body without affecting the good ones. Roep et al have taken a step in the
direction of successful immunosupression of the bad immune cells involved with
T1D. In order to understand their
work, it’s first necessary to understand a little more about insulin and the
immune system. Insulin isn’t
synthesized in its functional state.
It is synthesized as pro-insulin and then cleaved into an active portion
with the A and B peptides, which is insulin, and an inactive portion, called
C-peptide; you can’t have one without the other (as seen in the figure to the left). When doctors want to measure β-cell function, they look at
C-peptide levels. So the
researchers use C-peptide levels to determine if their methods are preventing
immune cells from destroying insulin-producing cells.
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| Function of CD8+ T cells. T cell being activated (#1), being put on the path of a CD8+ T cell (#2), and destroying a "bad" cell (#3) |
Within the
immune system, there are cells called T cells, with a specific subset called
CD8+ T cells. These T cells are in
charge of killing off bad cells in the body, whether they are tumorgenic or
have become infected with virus (as seen in the figure to the right).
There are supposed to be mechanisms in the immune system that create
what’s called tolerance, or the ability to recognize and not react to self. In T1D patients, this mechanism has
gone haywire and the CD8+ T cells that are auto-reactive are not being filtered
out by the immune system and instead go and attack the β cells in the pancreas. The authors use a plasmid (circular
piece of DNA) called BHT-3021 that encodes for proinsulin (A+B+C) to try and
lower the frequency of islet specific CD8+ T cells. Islet-specific T cells can target multiple immune response
causing molecules (or antigens) in the pancreas. The important thing to note about this plasmid is that it
was created to produce a proinsulin molecule with fewer sites on the protein
where faulty immune cells usually react. In simpler terms, the proinsulin created by the scientists shouldn't react with the faulty CD8+ T cells. The T cells reactive to other antigens on the pancreas shouldn’t be
affected either, since they aren't changing any other antigens. They also simultaneously
tested the safety of this peptide in humans by giving it via an intramuscular
injection.
Subjects in
the study were given a weekly dose for 12 weeks of either 4 varying amounts of
BHT-3021 (0.3mg, 1.0mg, 3.0mg, 6.0mg) or a placebo and their β-cell function
and other immune responses were measured each week, 4 weeks after the end of
the trial, and a year after the start of the trial. This was to see the short and long-term effects of the
plasmid as well as to track safety.
The 1.0mg and 3.0mg group showed an increased level of C-peptide during
the 12-week period as well as up to 3 months after the treatment was
stopped. On the other hand, the
placebo group showed a strong decrease in C-peptide levels, further confirming
that the plasmid was, at a basic level, working. Unfortunately,
the treatment groups eventually started losing C-peptide after the treatment
was stopped for an extended period of time. Interestingly, the 1.0mg group also reported a decrease in
total insulin usage during treatment, and the treatment groups in general
reported stable blood-glucose levels during the trial and for an extra 3 weeks
post-trial.
Next, the
authors wanted to see if the CD8+ T cells specific for proinsulin were reduced
in relation to the increase in C-peptide levels. They also looked at whether or not CD8+ T cells specific for
other pancreas antigens were affected.
They isolated T cells specific for 9 different β cell antigens and
tested reactivity. The proinsulin
specific T cells from the treatment groups showed a decrease in frequency in
relation to an increase in C-peptide levels. The cells specific for other antigens showed no change in
frequency in relation to changing C-peptide levels. So the increase in C-peptide levels was due to the reduction
of proinsulin specific T-cells by BHT-3021. The authors also looked at antibodies to other islet cell
antigens and found no changes, which is consistent with the plasmid affecting T
cells, which don’t produce antibodies.
They also had the safety evaluated by an independent board, which deemed
the plasmid safe in this trial.
Although it’s
not a cure, the BHT-3021 plasmid showed promise for immunotherapy for T1D. As of now, the only current way to
manage T1D is by giving insulin injections, a painful and inconvenient way to
live life. The authors were able
to show how subjects C-peptide levels increased under treatment with this
plasmid. They also showed a
decrease in the cells that were attacking the pancreas in the first place and
more controlled blood-glucose levels.
However, the subjects they used were all diagnosed within 5 years of the
study occurring. This means they
probably still had islet cell function.
A larger problem remains with the people who have been living with T1D
for many years and don’t have any functioning islet cells left. There would have to be a way to not
only prevent the T cells from attacking the pancreas but also a way to
stimulate the growth of islet cells again. The discovery of this plasmid is just one small branch on
the bigger T1D tree. However,
should this pan out, it would still be beneficial to new people being diagnosed
with T1D. It would be interesting
to follow up with these authors and see if they had any new breakthroughs.
Main article:
http://stm.sciencemag.org/content/5/191/191ra82.short
Other sources:
Human Physiology: An Integrated Approach, Fifth Edition, D. U. Silverthorn
More information about Type 1 Diabetes:
http://www.mayoclinic.com/health/type-1-diabetes/DS00329/DSECTION=complications
http://jdrf.org/about-jdrf/fact-sheets/type-1-diabetes-facts/
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