Wednesday, April 4, 2012

0 Notes Posted On VGV-L

I posted some of my notes on VGV-L on LNE, related to the previous entry on VGV-L which I posted on Monday. While there is a lot I posted about VGV-L based on interviews, press releases, and patents - and while I outlined how the immune system normally should work - I did not give a concise explanation of how the immune system doesn't work relative to polyclonal b cell activation.

I think another entry on this topic is in order. But in the meantime, I have decided to share the notes I posted on LNE about VGV-L here before I write a more concise post on the immune system and polyclonal b cell activation...

I did as much poking around about Viral Genetics' new chronic Lyme disease candidate drug, VGV-L, as I could and it wasn't easy. One CV, several patents, and a few Dr. Karen Newell Roger interviews later, and the best I could get out of it is that it is not just a synthetic thymus peptide that they patented but a method of replacing a peptide, CLIP, on the surface of B cells with this synthetic thymus peptide (which somehow maps to the MHC genetic type (HLA) of the patient) so that it activates Treg cells. The activation of these Treg cells is supposed to lead to reduction of non-specific B cells (polyclonal B cell activation).

In the patent, there is also mention of using bacterial antigens and antibiotics as adjunct treatments which are optional. The impression I'm left with is the bacterial antigens are used to prime new B cells and if there is any existing infection, antibiotics are used.

So the entire method of treating patients may be: a) VGV-L alone, b) VGV-L and antigen exposure, or c) VGV-L, antigen exposure, and antibiotics are used. (antivirals and antiparasitics may also be used, depending on the patient's diagnosis)

[...] I don't get the impression after reading everything I've read thus far that chronic Lyme disease is a pure B-cell disorder. But maybe it's a variant on that? Maybe cell-mediated immunity is somehow affected by B. burgdorferi?

I've made a major edit on my blog entry. I still think I need a revised version of the post to be made in the future, but I am so exhausted at the moment that I think it won't be for a few days at least. Maybe call it the revised executive summary version, because the current post is rambling even relative to rambling for me.

Why do I mention this edit here? Because it is very important to note, relative to how I infer the way VGV-L has been hypothesized to work:

The edit was about Tunev and Barthold's research on lymphadenopathy in Borrelia burgdorferi infection in mice. In their research, they noticed an outsized B-cell response to the presence of spirochetes. However, what they found differed from what has been found in polyclonal B-cell activation in other infections - where it's clear runaway non-specific polyclonal B-cell activation leads to autoimmune disorders. In Tunev and Barthold's research, the outsized immune response had B-cells which were specific for Borrelia burgdorferi yet were of low quality. This is notably different from typical polyclonal B-cell activation.

Edited to add - V. important to SEE:

Excerpt from the above link:
"From their observations, the authors speculated that B. burgdorferi somehow subverted B cell activation in the lymph node so that the end result was a large number of plasma cells secreting antibodies of poor quality. By poor "quality," I assume that the authors meant that the affinity of the antibody for B. burgdorferi proteins was low and that the "wrong" subclasses of IgG antibodies were expressed. The most abundant IgG subclasses being produced in the draining lymph node at its most swollen state were IgG2b and IgG3. Whether other IgG subclasses would be more effective at clearing B. burgdorferi from the host and whether the affinities of the antibodies for B. burgdorferi proteins were poor still need to be determined experimentally. Perhaps a classic T-cell dependent B cell response involving the formation of germinal centers accompanied by somatic hypermutation, affinity maturation, and appropriate class switching would have led to production of "high" quality antibodies. If the authors are correct, they have revealed yet another means by which B. burgdorferi could persist in the host."
I don't know how this difference in response would work with VGV-L. It isn't clear to me, and I have to read through more research to understand it - at least hypothetically. I also want to know if anyone else has used similar technology to treat pure B-cell disorders and if so, what the pros and cons were. If this is a completely novel invention, then it's harder to evaluate and all one can do is look at the animal trials if one has access to them and examine the underlying hypothesis for its application.

The paper that this technology primarily appears to be based on is this one:

M. K. Newell, R. P. Tobin, J. H. Cabrera, M. B. Sorensen, A. Huckstep, E. M. VillalobosMenuey, M. Burnett, E. McCrea, C. P. Harvey, A. Buddiga, A. Bar-Or, M. S. Freedman, J. Nalbantoglu, N. Arbour, S. S. Zamvil, and J. P. Antel. 2010. TLR-Mediated B Cell Activation Results in Ectopic CLIP Expression that Promotes B Cell-Dependent Inflammation. Journal of Leukocyte Biology. Online e-Pub. July 14, 2010.

Link to free full text of this publication:

I'll just post the abstract here, and you can read the entire text at the link above:


Infectious pathogens produce compounds called Toll ligands that activate TLRs on lymphocytes. Acute activation triggered by certain TLRs appears to "jump start" the innate immune response, characterized by the release of inflammatory cytokines and cellular expansion.

In some individuals, there is a failure to control acute inflammation, resulting in postinfectious, chronic inflammation. Susceptibility to chronic inflammation is strongly associated with an individual's MHC genes. Recent clinical trials for several autoimmune diseases characterized by chronic inflammation suggest that B lymphocyte depletion therapies dampen chronic immune activation. However, currently, there is no known mechanism that accounts for the correlation among TLR activation, MHC genetics, and a pathological role for B-lymphocytes.

Our hypothesis is that TLR-activated B cells (B cells that have been polyclonally activated in the absence of antigen-specific signals) are not controlled properly by T cell-dependent B cell death, thereby causing B cell-dependent chronic inflammation.

Here, we show that treatment with Toll ligands results in polyclonal B cell activation accompanied by ectopic expression of CLIP. Furthermore, by adoptively transferring purified CLIP+ B cells in syngeneic animals, we find that CLIP+ B cells induce production of TNF-α by host T cells. Finally, we demonstrate that CLIP-targeted peptide competition results in the death of polyclonally activated CLIP+ B cells.

I think I know at this point what my missing pieces are now:

- describe the role of Treg cells (regulatory T cells) and how they relate to killing off B cells and generating more targeted immune responses.

- describe the hypothesis that Foxp3+ Treg generation in the thymus is somehow dysfunctional in those with persisting symptoms (I think this has some relationship to the core hypothesis behind VGV-L's use).

- And I have to more clearly state that even if the Foxp3+ Treg generation is what it is happening, there may be some risk involved in proceeding with this kind of treatment. Wikipedia managed to explain some of it, and while Wikipedia is not the most reliable resource on everything, it is relatively easy to follow and this particular entry (so far) jives with what I've seen in other sources:

This is also not half bad, and recommend checking it out:

Plus, of course, there are the papers I link to on the blog.

The more I delve into this, the more questions I have... Tunev and Barthold's paper, in particular, lead me to wonder if the hypothesis underlying VGV-L's design developed with the scenario described in their research being taken into account. Between T & B's research plus other publications, I get the impression that in at least the animal model of immune response to Bb, that there is a mixed state response to it - It is both immune suppressing and immune stimulating. Some research has even indicated a certain amount of tolerizing is involved. ( - anergy plus inflammation; see also for a more detailed explanation)

Adding a bacterial antigen/adjuvant (and possibly antimicrobial medicine) to the treatment may be a way of working around this combination, in order to produce new B cells which are stimulated and respond specifically to Bb and not be nonspecific - and in order to eliminate any remaining infection if there is one present.

This is complicated - and while more and more is being learned about immunology every day, there are still an enormous number of unknowns...


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