Tysabri & the Immune System

A board to discuss the newly-released drug Tysabri, (formerly known as Antegren) as a treatment for Multiple Sclerosis

Tysabri & the Immune System

Postby HarryZ » Fri Mar 04, 2005 7:52 pm

This is a link to a VERY interesting article about Tysabri and what possibilities can take place when tinkering with the immune system.

http://www.businessweek.com/magazine/co ... _mz011.htm

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Postby flora68 » Fri Mar 04, 2005 11:34 pm

Great article! Thanks Harry :) .
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Postby OddDuck » Sat Mar 05, 2005 5:24 am

Yes, terrific find, Harry!

And might I add.............all that in that article was simple common sense! Even for us "non-medical" people. :evil: It didn't take a mental giant to figure out what blocking ALL the T cells would do!

And they "experimented" with it anyway. We knew the risk (from all the postings here), they must have, too. Or we all need degrees and they need theirs taken away.

They could have stayed with mice for a while longer and figured it out that way. Especially if they just plain didn't want to take the time to read (i.e. everything I/we did.) And I'm sure the pro-Biogen people will be after me again, but my opinion still is that $$$$ was a more important consideration.

I'm SO glad all my research is on "paper" AND on this website and DATED. I can't say that often enough. I can't WAIT for them to explain how it was that I knew and predicted some things and they are saying they "did not". Yeah, right.

The FDA should have just read my letter, then. And they can't say they didn't receive it. I've got proof.

Man, tell me I couldn't be put on the stand in court!

(Pardon my frustration.)

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Postby OddDuck » Sat Mar 05, 2005 6:09 am

Oh, yeah, the article at the end points out:

Either way, the overall lesson is still a sobering one. The human immune system is "incredibly tricky," says Miller. Trying to alter its action to produce a beneficial effect may have unforeseen and dangerous consequences. And the challenge for drugmakers and doctors is always to figure out how to make the benefits exceed the harm.


Here's another common sense item I'd like to express to them (and oh, darn, Harry...........that above came from the doctor from the NMSS!):

PLEASE JUST SIMPLY DISCLOSE TO PEOPLE ALL OF THE KNOWN OR HIGHLY SUSPECTED RISKS INVOLVED IN THE FIRST PLACE!

If their attorneys couldn't/didn't advise them ALL of that up front, then they all need to find new attorneys. That is the quickest, easiest, most honorable thing to do. What is so hard about that?

(I wonder if Dr. Miller knows that I also wrote and faxed all of my concerns to the NMSS, too. I was THAT adamant about this whole thing.) How are they explaining me and my warnings?

Call me crazy, but I think they are all digging deeper holes for themselves. 8O :?

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Postby HarryZ » Sat Mar 05, 2005 6:56 am

OddDuck,

I think it will only be a matter of time before the litigation lawyers dig up all kinds of information for their case against Biogen. I'm sure they will be hiring some very energetic law students who will leave no stone unturned in their search for data. I would think that this is the last thing that Biogen would have wanted to happen but when you take risks like they did, you have to be prepared for the consequences.

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Postby OddDuck » Sat Mar 05, 2005 7:20 am

I hear ya, Harry.

And boy, don't I know that! I just mentioned to someone about the fact that it is way too quiet "out there", which means the "SEC and attorneys are in discovery and gathering evidence".

And all that needs to be shown in court (in any type of case) is that Biogen Idec/Elan knew "or should have known". And in this matter, it's a slam dunk.

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Had dinner with 8 neurologists..

Postby better2gether » Sat Mar 05, 2005 11:24 am

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Comments from a neurologist

Had dinner with 8 neurologists..

Meeting was for another purpose but we talked about Tysabri for a few minutes. Between us we follow 600 MS patients and had about 65 to 70 patients on Tysabri (with another 30 to 40 waiting authorization), all but three were on monotherapy.

Unbelievably, we all came to the same conclusion.

(1)Tysabri combo will not be in the future. Not just interferon but Tysabri + steroid, Tysabri plus methotrexate, Ty plus copaxone.

(2) We all felt that if there were no cases on monotherapy that risk is significantly small to restart many patients. We would preferentially use in those patients who either were failing or not tolerating other therapies. We would use an informed consent form similar to what we already use for Novantrone. We need to know the risk, but once the approximate risk is known we can discuss risk/reward with patients.

(3) Tysabri monotherapy would be used as firstline therapy only in patients who appear to be presenting more aggressively, at first. If risk remains very low (<1/1000 or so on monotherapy) after a few years, we would use more for first line as well.

(4) We had several patients who do not want to go back on under any circumstance and more patients saying 'give me the consent form and a pen' wanting to get back on immediately. The balance are more in the wait and see camp.

(5) Risk of not being treated or suboptimally being treated is higher than risk of tysabri.

(6) The two other neurologists with more immunology knowledge agreed with my thought that the combination of TH1 to TH2 shift caused by Avonex, combined with the reduction in circulation of active cells through the brain (Tysabri) was the culprit (see my 3/1/5 posts with references).
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Avonex TH1 to TH2 shift may be key

Postby better2gether » Sat Mar 05, 2005 11:43 am

.
This is the 3/1/05 post from the same neurologist.

Avonex TH1 to TH2 shift may be key

IF Nbeta1a (Avonex/Rebif) cause a TH1 to TH2 shift. This is felt to be one of the good mechanisms in MS treatment. However, TH1 to TH2 shift may lead to PML...... THus there is a mechanism as to why combo could be worse than mono. Tysabri reduces the trafficking of activated lymphocytes into the brain

Clin Neurol Neurosurg. 2004 Jun;106(3):255-8. Related Articles, Links


IFN-beta1a and IFN-beta1b have different patterns of influence on cytokines.

Sega S, Wraber B, Mesec A, Horvat A, Ihan A.

Multiple sclerosis is characterized by elevated levels of proinflammatory cytokines produced by Th1 cells and decreased levels of anti-inflammatory cytokines produced by Th2 cells. IFN-beta treatment shifts the immune response from the Th1 to Th2 pattern, thus enhancing the production of anti-inflammatory Th2 cytokines such as IL-4, IL-10, and decreasing the production of proinflammatory Th1 cytokines such as IFN-gamma. To determine which IFN-beta has the stronger immunomodulatory effect we compared the levels of IL-4, IL-10, and IFN-gamma of 12 relapsing-remiting MS patients treated with IFN-beta1b (Betaferon) with those of 10 patients treated with IFN-beta1a (Avonex).

There were no statistically significant differences in duration of disease, number of relapses before and during treatment, and in EDSS after 2 years of treatment. After 1 year of treatment the concentration of IFN-gamma was significantly lower in the Betaferon group, and concentrations of IL-4 and IL-10 were significantly higher in the Avonex group. It appears that IFN-beta1b has a downregulatory effect on both Th1 and Th2 cytokines, while IFN-beta1a causes a shift of the cytokine profile toward the Th2 phenotype.

These two IFN have different influences on the pattern of cytokines in MS: IFN-beta1a enhances the production of anti-inflammatory cytokines IL-4 and IL-10 and IFN-beta1b decreases the production of the proinflammatory cytokine IFN-gamma.
PMID: 15177779 [PubMed - indexed for MEDLINE]


Ann Neurol. 2001 May;49(5):636-42. Related Articles, Links


Cellular and humoral immune response in progressive multifocal leukoencephalopathy.

Weber F, Goldmann C, Kramer M, Kaup FJ, Pickhardt M, Young P, Petry H, Weber T, Luke W.

Department of Neurology, University of Gottingen, Germany. fweber@mpipsykl.mpg.de

Progressive multifocal leukoencephalopathy (PML) is a fatal, demyelinating disease caused by JC virus (JCV) in patients with severe immunosuppression. We studied the JCV-specific cellular and humoral immune response in 7 healthy donors (HD), 6 human immunodeficiency virus-1 (HIV-1)-infected patients without PML (HIV), 4 HIV-1-negative patients with PML (PML), and 8 HIV-1-positive patients with PML (HIV/PML).

As antigens, recombinant virus-like particles of the major structural protein VP1 (VP1-VLP) of JCV, tetanus toxoid (TT), or the mitogen phytohemagglutinin (PHA) were used. Proliferation of peripheral blood mononuclear cells (PBMC) after stimulation with the VP1-VLP was significantly suppressed in PML and HIV/PML patients compared to HD. After antigen stimulation the production of interferon-gamma (IFN-gamma) was reduced in PML, in HIV/PML, and in HIV patients.

The production of interleukin-10 (IL-10), however, was elevated in HIV/PML patients. Neither proliferation nor cytokine production correlated with the presence of JCV DNA in PBMC. The immunoglobulin G serum antibody titer to the VP1-VLP was slightly elevated in HIV, elevated in PML, and highly elevated in HIV/PML patients compared to HD. The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity.
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Re: Had dinner with 8 neurologists..

Postby HarryZ » Sat Mar 05, 2005 12:36 pm

Better,

A lot of interesting info and comments from the MS docs.

But until the researchers get to the bottom of this, and that may take quite some time, nobody knows what happened with the patients who ran into trouble or died. And Tysabri won't be allowed back for general use until the answers are found.

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Postby OddDuck » Sat Mar 05, 2005 12:43 pm

IFN-beta1a enhances the production of anti-inflammatory cytokines IL-4 and IL-10....


Sure, they've done plenty of research over the past few years to know EXACTLY what the interferons do. We all know that.

....Neither proliferation nor cytokine production correlated with the presence of JCV DNA in PBMC.....


Note the word "presence". Which basically means that cytokines themselves do not "cause" the JCV virus.

....The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity.


Note the word "development" of PML. Note the words "general impairment".

I do agree with Dr. Miller. It's "tricky" messing with the immune system, allright. You need "balance".

Bottom line then? Based on the above scenario? Here is what I personally surmise from that:

The immune system balance was too drastically affected all at once and over time (i.e. due to chronic use of Tysabri). Tysabri, due to its extreme suppression of the immune system (you could say) via its mechanisms of action in blocking ANY T cells at all from entering the brain, prohibited Avonex's BENEFICIAL anti-inflammatory presence from attempting to destroy the PML "antigen" that crossed over into the brain. (Plus, please note that increasing IL10 ALSO strengthens the BBB. Oh, goody.......double up the effects of Tysabri.) The PML virus mutated and was released, attached to antigen presenting cells (APCs) which were NOT prohibited from crossing the BBB by Tysabri; and Avonex, even though it did raise the anti-inflammatory components of the immune system, those components could not GET there to possibly help destroy the APCs because Tysabri blocked ALL T cells from entering the BBB.

That could be just ONE of probably quite a few problems that would be obvious if you combine the two drugs together. IF the proper research had been done FIRST, that is.

And when again were these research findings published??? 2001 for the one, and June of 2004 for the other? Both before FDA approval?

I rest my case! Sure..............they didn't "know" or have any way to highly "suspect" what this combination might do, did they? Did they try this combo in mice first?

Hence also why I continually advocate "selective targetted" cytokine manipulation, if you are going to mess with the immune system at all.

Once more, I rest my case.

(And I also say that they might find that IL4 should be inhibited in MS as a general rule, not increased.) BUT, I have posted the whys and what-fors many times already for that particular opinion of mine, so I won't reiterate again.

Bottom line? I say the following regarding regulation of cytokines in MS, if you are going to manipulate the traditional immune system at all, and this is only in order to bring the immune system back into balance in MS. Note that never do I say the word or words "totally blocked".

TNFa needs to be inhibited.
IL1b = inhibit
IL2 = increase
IL4 = inhibit
IL5 = uncertain - not enough known, but probably want it stable or increased
IL6 = inhibit
IL12 = increase
IL13 = increase
IL15 = inhibit
IL10 = increase
IFNgamma = inhibit

And just for extra good measure: Increase cAMP, decrease Ca2 influx, maintain sodium density, inhibit caspase 3, increase BDNF, inhibit Nogo, increase GAP43, stabilize the HPA axis, just to name a few.

This is ONLY my personal opinion.

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Postby Arron » Sat Mar 05, 2005 1:04 pm

nice find Harry and nice summary Deb :)
Disclaimer: Any information you find on this site should not be considered medical advice. All decisions should be made with the consent of your doctor, otherwise you are at your own risk.
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What the literature tells us.

Postby better2gether » Sat Mar 05, 2005 1:45 pm

.
I also found this interesting information from today.


"What the literature tells us


First some facts to put the tysabri/avonex versus PML in a little clearer light

1. tysabri does not immune suppress patients beyond a slight amount - risk of infection was 2.1% for patients on tysabri versus 1.5% for patients on placebo

THUS TYSABRI IS NOT A POTENT IMMUNOSUPPRESSANT ON ITS OWN - AND THAT IS WHY PML HAS NOT BEEN SEEN IN TYSABRI MONOTHERAPY PATIENTS

2. that is not enough immunosuppression to allow PML to develop from unchecked JC virus replication

3. in the articles I posted last night it seems that beta interferon treatment shifts the Th1/Th2 helper balance in favor of the Th2 (suppressive versus cytolytic T cells) helper cells - this is accompanied by an increased serum level of IL-10 - this is very similar to the shift in Th2 helper cells and IL-10 serum increases seen in HIV patients - but this is not enough to trigger PML as can be supported by the fact that PML has never been seen in avonex treated patients

THIS IS A COMPLETELY DIFFERENT IMMUNOSUPPRESSIVE MECHANISM AND ACTS ON THE T-CELLS THAT REACH THE BRAIN DESPITE TYSABRI TREATMENT - BUT NOW WHEREAS TYSABRI REDUCES THE AMOUNT OF T-CELLS THAT CAN GAIN ACCESS TO THE CNS TO ATTACK THE MYELIN ON NEURONS AND MAKE MS PLAQUES THE ADDITION OF BETA INTERFERON SHIFTS THE ENTIRE BALANCE OF T HELPER CELLS TOWARDS THE TH2 TYPE - THESE ARE SUPPRESSIVE AND FAVOR THE PRODUCTION OF ANTIBODIES VERSUS CYTOLYTIC T CELLS

this quote is from Weber F et al , annals of neurology 2001

"The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity." -

THIS IS PRECISELY THE SHIFT THAT AVONEX CAUSES - THE ACTION OF AVONEX IS TO IMPAIR TH1 HELPER CELLS AND FAVOR TH2 HELPER CELLS

***** THUS AVONEX TREATMENT IS A DRUG THAT IMPROVES THE CYTOKINE/HELPER CELL ENVIRONMENT BECOME MORE FAVORABLE FOR PML/JC VIRUS ACTIVATION


4. that is where tysabri comes in - it limits T cell passage through the blood brain barrier in the brain - thus it reduces the numbers of T cells present to cause MS plaques but also control JC virus - alone it also doesn't seem to put patients at risk for PML according tothe monotherapy data

5. it seems that when you add the two together you shift the Th1 vs Th2 helper cell ratio in favor of the Th2 helpers (suppressive) (avonex) at the same time you limit the access of T cells (tysabri) - so the immunosupressive risk is additive

6. then you add on the other immunosuppressive treatments that these patients may have had (MS patients that are progressing despite avonex are usually treated with steroids for each flare-up and novantrone or other chemo drugs and all of these are immunosuppressive) - so this is another additive risk for immunosuppression

THUS IT IS A CASE OF ADDITIVE IMMUNOSUPPRESSION - AND THUS TYSABRI MONOTHERAPY SHOULD BE PROVEN TO NOT BE A CAUSE OF THE PML AND THAT IS WHY IT HAS NOT BEEN SEEN IN ANY TYSABRI ALONE PATIENTS

PLUS YOU ALSO HAVE TO FACTOR IN THE PML RISK - even in patients with AIDS the PML rate is only 1-5% thus there is an additional risk factor that is probably patients specific "
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Last edited by better2gether on Sat Mar 05, 2005 2:13 pm, edited 1 time in total.
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Postby OddDuck » Sat Mar 05, 2005 2:11 pm

Yep.........that's what I said.

I reiterate............"activation" of PML and "cause" of PML are two different things.

Correct. Neither Tysabri or Avonex "causes" PML.

I also said Tysabri's MOA was not truly immunosuppression, it blocks T cells from crossing the BBB. So, that's also what I said.

Etc., etc.

We agree. I just said it simpler.

Bottom line, no matter how you twist or turn it, they knew enough, didn't they, to be able to fairly accurately predict what was highly probable that would happen. The more you post, the more you confirm that they knew WAY more than enough to be able to fairly accurately predict the probable consequences of combining the two.

Nothing so far is anything "new" that they suddenly found AFTER the fact.

Thanks!

Deb

EDIT: By the way, please go look at what all the neurologists are saying. 80% of the population has dormant JC virus in their system. Pretty high risk, I'd say. Not to mention.........what about all the other dormant viruses?

Lots more study needed, I'd speculate, before they try this again. BUT, as I've mentioned before, as long as they TELL people EXACTLY what the risks are (which you have confirmed they can deduce scientifically), they are fine to market Tysabri.
Last edited by OddDuck on Sat Mar 05, 2005 2:15 pm, edited 2 times in total.
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Postby coolycat » Sat Mar 05, 2005 2:13 pm

Thanks b2g! Great info :)
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Postby OddDuck » Sat Mar 05, 2005 2:34 pm

Just to clarify myself for a second.

Ok, we all agree that the combination of Tysabri + Avonex is bad (which they should have known, especially based on all the information we just now reviewed). In this case, let's say just for agreement's sake that it was the AVONEX, due to it suppressing the Th1 immune response, caused PML to "develop".

Ok...........now let's take Tysabri alone now. As monotherapy. Let's say another virus (forget PML - let's pretend we've got a patient who doesn't have the JC virus at all) either proliferates or you catch a new virus somehow. And there it goes, right across the BBB into the brain. Now the immune system AGAIN (this time the "good guys" for this situation only, i.e. the Th1 cytokines) wants to come to the rescue!

Question: Can they? Can they cross the BBB to get to that "new" virus or pathogen? Or is Tysabri, due to its MOA of blocking ALL T cells from crossing the BBB, likely to stop the T cells, thereby allowing another infection to do its damage?

Just pondering...............

Deb

EDIT: And remember, we haven't even gotten to the fact of how Tysabri affects and interacts with integrins. Which very little is known about integrins biologically in the first place, except for their extreme complexity. Again, more study needed, so the experts say.
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