We previously discussed the concept of DNA vaccination for antigen-specific modulation of the immune system in conditions of autoimmunity such as multiple sclerosis.  In essence, it appears that DNA-based administration of the same proteins that are targets of the immune system during autoimmunity seem to suppress the immune response in a specific manner.  This is different than other immune modulators such as anti-CD25 antibody or Tysabri which suppresses in a non-specific manner.

A published Phase I/II trial of BHT-3009, Bayhill Therapeutics DNA vaccine for myelin basic protein in 30 patients with either secondary progressive or relapse-remitting multiple sclerosis was performed in which antigen-specific immune modulation was seen, and safety of the vaccine was demonstrated.  Here we will discuss a larger trial by the same group that was recently published (Garren et al. Phase 2 trial of a DNA vaccine encoding myelin basic protein for multiple sclerosis. Ann Neurol 2008 May;63(5):611-20).

This trial was much larger than the previous trial (267 patients), and was limited to patients with relapse-remitting multiple sclerosis.  The patients were randomized to receive either placebo, or two doses (0.5 mg and 1.5 mg) of the DNA vaccine (BHT-3009).  DNA vaccination was performed intramuscularly at the timepoints of initiation, after 2 weeks, after 4 weeks and subsequently given for every month until the 44th week. 

The data demonstrated that in comparison to patients receiving placebo there were no positive effects of the 1.5 mg dose.  In contrast, the 0.5 mg dose caused a 50-61% reduction in new lesion formation as detected by MRI and profound reduction of anti-myelin antibodies.

These data support further expansion of the DNA vaccine approach into phase III clinical trials.  These data, as well as other antigen-specific tolerogenic vaccines may be one of the reasons why entered a $350 million deal with Genetech.

Autoimmunity, such as multiple sclerosis, is characterized by the immune system attacking components of the body.  Normally the body has numerous mechanisms of protecting itself from this, which we have previously discussed.  One way that the immune system “self regulates” itself is by a special type of T cell, called that T regulatory (Treg) cell.  The T cell receptor (TCR) of Treg cells is usually activated by recognition of proteins of the body.  This is an interesting point.  “Normal” T cells are usually turned on when their T cell receptor recognizes parts of proteins (called peptides) that are found on components that do not belong in the body.  Unfortunately in situations such as multiple sclerosis, rheumatoid arthritis, or Type 1 Diabetes, the T cells that are suppose to be activated by foreign peptides are activated by peptides that belong to the body (in multiple sclerosis the T cells are attacking components of the myelin basic protein which acts as an insulator around axons of the nerves).  The Treg cells, which recognize myelin basic protein are activated by the myelin basic protein components as well as by the presence of the conventional T cells being activitated.  What occurs is that the Treg cells attempt to suppress the destruction of the myelin by the normal T cells, through producing various chemical mediators, called cytokines, that suppress the effects of the conventional T cells.

So to try to state it in another way:  Conventional T cells activate the immune response and cause damage.  In the healthy situation, the conventional T cells cause damage to bacteria, virus infected cells, and cancer cells.  In the healthy situation Treg cells act as a protective mechanism so that in the cases that the conventional T cells start attacking components of the body, the Treg cells then inhibit the conventional T cells from doing this.  So another way of thinking about it is that the Treg cells are a “safety backup” so that the body does not attack itself.

So the question then becomes, what is going on in autoimmunity in general and specifically in conditions such as multiple sclerosis?  Are these Treg cells not doing their job properly?

There is a recent paper that was published (Korporal et al. Interferon beta-induced restoration of regulatory T-cell function in multiple sclerosis is prompted by an increase in newly generated naive regulatory T cells. Arch Neurol. 2008 Nov;65(11):1434-9) assessing Treg activity in 18 healthy volunteers and 20 patients with relapse-remitting multiple sclerosis. 

When comparing Treg activity between the healthy volunteers and the relapse remitting multiple sclerosis patients they found that ability of Treg to suppress immune response was deficient in the multiple sclerosis patients as compared to controls.

But the investigators then took the study a step further.  They assessed the Treg activity in patients before and after starting to take interferon beta therapy (Avonex is a type of interferon beta).  They found that both at 3 and 6 months after administration of interferon beta the suppressive activity of the Treg was restored to normal levels.  See figure below. 

Restoration of Treg Activity after Interferon beta Therapy

Given that mesenchymal stem cells have been demonstrated to induce Treg activity, and that adipose stem cells actually have high concentrations of Treg, two interesting questions arise.  Firstly, can interferon beta therapy synergize with stem cells?  Secondly, can autologous adipose stem cell therapy serve as a substitute for interferon beta therapy? 

Other thoughts come to mind as well, such as, can if indeed Vitamin D is associated with Treg activity, would it synergize or antagonize the effects of interferon beta on the Treg and actually on the clinical situation?