Monday, October 21, 2013

Immunosupression of Type 1 Diabetes

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.
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.

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:

Other sources:
Human Physiology: An Integrated Approach, Fifth Edition, D. U. Silverthorn

More information about Type 1 Diabetes:

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