Hepatitis Researcher importance of TH1 response

I aked you before in a previous post what, if any, your thoughts were in regards to SVR and a vigorous TH1 favored immune response.  I'm started to beleive that it is exactly this shift from the dominating Th2 response to a more 'viral hungry" TH1 response which determines svr at the end of treatment.  In other words, people who acheive svr are also maintaining a strong Th1 response at the end of treatment which in turn may be keeping any viral remnants in check.  People who fail to acheive svr maybe reverting back to the old virally favorable TH2 arm of the immune system when the drugs are removed from their systems.  Do you think my hypothesis is credible?

[St. George]

This link supplements the above question about TH1/TH2 BALANCE AND FACTORS RELATED TO IT.

   http://www.diagnose-me.com/cond/C104791.html

[St. George]

Another interesting view on th1/th2
  http://www.planetpoz.org/education/period/pozhealth18.html

[Hepatitis Researcher]

The Th 2- Th1 balance concept in immunology is a broad principle that is based on original findings in mice that states that a preponderance of Antibody responses and cytokines ( Il-4 and Il-10) supporting B cell and Ab responses is calles Th2. It is less agressive to the tissues and a defense system against invading pathogens - like soluble antigens and Toxins that can be neutralized by Antibodies.

We are born with a Th2 preponderance.Then by contact with bacteria a natural Th1 shift takes place. If too much hygiene, the shift is prevented and Allergies and Asthma are the consequences....

Once an organism , bacteria or viruses, have penetrated inside host tissues a new form of defense has to be activated to eliminate or kill intracellular microorganisms, even if that means to kill the invaded cell. The cytokines ( Gamma and alpha Interferons, Interleukin 12, Il-1 and many more) stimulate agressive intracellular defense mechanisms as well as cellular immune responses which lead to infiltration, local cytokine production and target specific cytotoxic T cell proliferation and activation which allow the immune system to regognize intracellular antigens by seeing spefic fragments of those - 10mer peptides) on the surface of the infected cells presented by MHC class I presenting molecules.

All in all the Th1 response is much more painful for the host, but necessary to eliminate or reduce the infection once it has advanced to such a stage.

Activation of the TH1 mode of reactivity occurs mostly by regognition of molecular patterns of invading organism by Dendritic cells and Macrophages on their so called " Toll like receptors". These cells in turn activate T helper lymphocytes to assume the "Th1 phenotype" characterized by the above mentioned cytokine secretion patterns. The rest of the response is thus " shifted " towards a "Th1 type".


In HCV therapy the general importance of inducing such a shift is well regognized.

1. Coleys Actilon trials of CpG 10101 together with IFN are the most direct attempt to directly activate the Th1 mode and are quite successfull so far. Anybody here participating in their trial?? this CpG 10101 directly acts upon TLR 9 on dendritic cells, induccing them among other things to produce an enormous amount of IFNalpha directly PLUS inducing the Th1 pathway.

2. Ribavirins action is assumed by many to include a selective activation of the Th1 arm of immune responses.

3. Substances found in maitake, shitake and reishi mushrooms are also mimics of "natural" Toll like receptor stimulators and induce, at least in mice, such a redirection. The extent, toxicity and usefulness of these stimulators is however not well researched - some of these might be good add ons to conventional therapy others might be useless or do more harm than good. Any extract of this nature has to be standardized and it is a long way from "proof of principle" to controlled clinical trials. There are some trials, mostly in China.

4. Thymosin alpha aka Zadaxin is in phase III trials for use in HCV and has a Th1 stimulating activity as part of its action profile.

5. Trials using Interleukin-12 ( the most direct Th-1 shifter) have been performed in HCV as monotherapy, but have not shown clear benefit. The immunological reality is very very complex...

[cuteus]

what happened to comment 4, posted by MH?  did our friend HR speak with Cindy?

[Hepatitis Researcher]

yes HR spoke with Cindy, to clarify his position in hepatitis research.

[cuteus]

and it looks like you passed with flying colors!  our gain!
and thank you for sharing your time here.  Coming to this site gets addictive sometimes,  I am still trying to cut back...

I hope you find the time to continue.
be well

[cuteus]

wait! since you are around for a bit, let me run a scenario by you and you can guess what might be at work.
You have been reading extensive reports by some members here about post tx conditions that they are attributing to a "changed" immune system, caused by the medications and the length of tx, possibly.  
I have been posting that perhaps in some folks the changes are not of the negative type, like the ones we have been reading about.  That some of us, have been left with an immune system with 'superpowers' if you wish.  My contention is based on the fact that for almost 4 yrs, I have not experienced the common cold or influenza, whereas before it took hold of me and would make me quite ill with chest congestion and severe coughing.   What I have been noticing is that the throat will get sore, but not an extreme soreness where you can't swallow, but a milder form that will last 3 days or so, and then go away without developing into a runny nose, congestion, cough, the works.  No fevers, flu aches, nada.  Recently it went as far as a bit sore in the chest, and a soft cough once or twice.  That's it.  This has been puzzling to me, a positive post tx "side effect".  Any thoughts?  I am not the only one who has mentioned the same thing, but the others are not regular pests around here.  Is this an immunology oddity?  or common occurrence?

[jmjm530]

The preceding was supposed to be an apology but on re-reading it ddin't come off that way :) As you can tell I'm not a fan of combo treatment as it currently exists. Hopefully, VX-950 or some other agent(s) can soon significantly cut down the exposure time to interferon and eventually eliminate it from the mix.

[Hepatitis Researcher]

A very astute observation and explanation.
Indeed, the imprint of Interferon long term provides a basic long lasting intensification of general responsivness. Not always a good thing - because autoimmunity syndromes are also enhanced.
Here is the nutshell explanation: the immune system as a whole is a gigantically complex system of potential reactivity and contains hundreds of feedback cycles aimed at quickly reducing exagerated responses as well. Mathematically this would equate to an overall equation of signaling mechanisms that would define a floating state of multiple balanced responses and subsystems with cytokines and surface bound receptor and agonist molecules and cell numbers being the variables and certain constants and terms defining the current "steady state" towards which the subsystems tends to selfregulate.
THESE CONSTANTS ARE PERMANENTLY CHANGED BY LONG TERM INTERFERON OR ANY LONG TERM EXPOSURE TO IMMUNOGENIC ANTIGENS/stimulation.
Thus the systems now seek a new equilibrium, react e.g. faster/more intense towards early damage signaling from a rhinovirus ( a common cold), thus limits viral spread more efficiently and - bingo you have your milder cold....

[jmjm530]

I would prefer my yearly one or two pre-tx "colds" over the post treatment symptons many here report perhaps due to an altered immune system. As to the virus taxing our immune system pre-treatment, I always found my frequency of colds pretty much correlated to my physical condition. If I was exercising on a regular basis, eating well, etc, I would have fewer colds. Conversly, when I smoked, ate badly and didn't exercise, I had more colds.

Speaking of colds, every year or so, John what's his name on 20-20? has his "myth buster" series which usually includes the "myth" that you don't get a cold by being wet and cold, with some Havard study being cited. Yes, I know colds are caused by viruses and not cold water, but I'd certainly like to see John hosed down with cold water in 20 degree weather and stand around for awhile. If he's like me and most everyone I know he will get sick.

For the record, I have gotten one minor "cold" since I stopped treatment and six months of skin problems. Next year I will be happy to have a couple of extra colds and fewer skin problems. Nothing wrong with my immune system before I dated MS Interferon and will be more than happy with a permanent break up.

-- Jim

[jmjm530]

Our posts crossed but we seem to be in the same ballpark here.

Speaking of an altered immune systems, what is your take on TCM, specifically Chinese herbs and acupuncture, to help get the immune system back in "balance" post interferon treatment?

I do understand from previous posts that you may not want to get too specific, but would love to hear whatever take your're comfortable with.

BTW I emailed a couple of my "top docs" regarding the dental work and one responded so far. TopDoc didn't think it was an issue at all at this late point, however he did say if I was uncomfortable I might wait a while. Reading between the lines, I sensed he was not dismissing the idea of waiting outright. Right now I'm nine months post treament and considering putting off the elective procedure another 3-6 months, but like with most decisions hep C, feel like I'm groping in the dark.

All the best,

-- Jim

[jmjm530]

Wanted to clarify a little my response to you yesterday regarding a prophalactive short-course of Interferon pre dental procdure. It occured to me that my answer to you may have seemed bluntly dismissive and it was. Not because I didn't think it might have some theoretically merit, but because of the significant side effects I experienced during my 54 weeks of treatment.

Like some other here, based on my treatment experience, I would have to be convinced of very plausible and serious health consequences before ever taking interferon again. IMO it is a crude and vicious drug whose benefits have to be very carefully weighed against any potential benefits.

-- Jim

[copyman]

i would think that getting sick more before tx was because of the HCV running rampant in your system. your immune system was so taxed trying to fight the hcv that it was left wide open for other infections. just a thought

[Kalio1]

Yes, that is what I am saying!

My problem with the constant "IFN bashing" is that it is not balanced or factual and has the potential to scare people away from treating when in fact IFN treatment could very well be just what they need. I hope they do their own research and don't let fear of these  "long term sx" alone rule their decisions. From all I read far more people benefit from IFN use than those who end up with some post issues. The facts that we know so far show IFN having many positive properties and benefits but they are not without consequence in all people. This is not to say complications or negatives can't also result from it's use in a small number of patients, but the incredible benefits of IFN seem to get lost on this forum at times and even seem lost on those who benefitted greatly from it's use and cleared the virus. There are so many variables,having HCV for decades, other drugs we take at the same time, the dosage amounts, etc. to pinpoint IFN and pull it out of the mix to place blame for these issues is just not realistic to me.

Many of the "post tx sides" people complain of are also problems that are caused by HCV, my thinking is what many of them are left with are caused from having HCV (or from sustained liver damage)for all those years and not from the treatment itself.

Hopefully we will know all the answers eventually or a better treatment will appear.

[jmjm530]

HR: I am toying with the thought, stemming from my understanding of antiviral effectiveness at low doses, that even very very low amounts of Pegasys, too low to cause more than minor discomfort, might be capable of holding down small amounts of virus capable of reactivation.
------------------------
This seems consistent with the approach I believe being taken by Mike Simon's transplant team. Mike has been post transplant serum negative via Heptimax for a number of years. A recent biopsy preceded by a raise in liver enzymes showed HCV virus in liver tissue but not serum. He was and still is on a low dose of Pegasys and I believe 200 mg of riba a day. Hopefully, I got this correct and I'm sure Mike will clarify if he's around.

Interesting your take on TCM. The cunondrum as I see it -- be it TCM or drugs -- is that on one hand it may keep the virus in check by enhancing the immune response, but on the other hand, an enhanced immune response seems to be the culprit in so many post treatment issues. Given the durability of SVR, doesn't it seem that any benefits of charging up the immune system with low doses of Pegasys would be outweighed by the risks -- or are you trying to find some minimal dose that minimizes the risks? I certainly see the logic in special circumstances, like with Mike Simons, but on a personal level, the thought of more interferon is unsettling. Sounds like a real balancing act.

I do agree about acknowledging the restrictions of this format and appreciated your response.  

-- Jim

[Forseegood]

I haven't had any colds, flu or anything of the sort, even though I've been around plenty of people who have, in close quarters. I used to get a flu maybe, every few years, and about a cold a winter, nothing much, but now nothing. For the three years since I've been symptomatic...course I'm not complaining, but it is strange...haven't taken the meds yet either...

[cuteus]

well, it looks like in your case your body is already doing a good balancing act.  Maybe the tx will throw that into havoc?  But from what I have heard and read from others it is not going that way.
  For some people, the "cold" as it was called, is not a benign issue. It turns into bronchitis and severe sinus conditions that warrant antibiotics for secondary infections. I am too familiar with the path this "benign" cold virus takes in susceptible individuals.  I think  that for them, they would rather deal with skin issues than with needing albuterol and other things to help them breathe.  Yes, I think breathing is more pressing for them.  Any state that keeps those things under control, I welcome.  And then, you get folks with pulmonary conditions that get aggravated with this tx.  Such a complex mechanism, our immune system is!

When a scientist sees the intricacies of the human body, how can they truly think that it was  chance and coincidence that produced such machinery?  I am agnostic, with catholic upbringing, and it is reading things posted in immunology that tilts things in the upbringing direction a bit. Funny, that a scientific article produces that effect!
Maybe you have mastered the immune system balancing through years of supplementation and diets?  how was it before you started on the healthier route?

I had not being taking anything post tx, now that I added all the stuff like ginko biloba, alpha lipoic, etc., that is going to be expiring in my cupboards soon, I wonder if I might be altering things and loose the present balance thus making my system vulnerable? not by the substances themselves, but by the possible alteration they might exert, before it becomes part of the functioning immune system.  
Well, I wondered if the hand surgery and the epidural were going to bring back HCV, so why not worry that the supplements will take away the 'protection' the tx brought?
I like worrying sometimes.
Angie, you are not really going to treat, are you?  Geesh! I remember you talking about it at OOB also, and that was a few yrs ago, might as well wait for the newer stuff now.

Ok, back to the mundane task of house decluttering...this is when miracles would come in handy...
take care

[cuteus]

for those with the interest of immunology as it pertains to hcv:

http://hcv.lanl.gov/content/immuno/ctl_search?action=results;cite=Sreenarasimhaiah2003

this is from 2001, perhaps the preparatory stage leading to today's new treating substances, a bit too technical for me:
http://www.blackwell-synergy.com/doi/full/10.1046/j.1365-2567.2001.01209.x

[DoubleDose]

HR said above regarding interferon use:  

THESE CONSTANTS ARE PERMANENTLY CHANGED BY LONG TERM INTERFERON OR ANY LONG TERM EXPOSURE TO IMMUNOGENIC ANTIGENS/stimulation.


My comment:

This sums up what I have been trying to explain in a more verbose, less effective way, over many threads and posts.  Similar to what two of my 'other' doctors have told me (not HCV related doctors), that interferon causes a PERMANENT change in the system, and many, many subsequent generations of cells that come into being will behave as if one is still on interferon.

This, I believe, is what is responsible for the 'milder colds', and unfortunately for the :  joint pains, fatigue, sun sensitivity, brain fog, lack of motivation, gastric disturbances, etc., etc after tx.  In other words, as my Rheumatologist put it, we are now living with a chronic autoimmune condition, without a name or label.  Its not exactly Lupus, or RA, or MS, etc.  But IT IS.

HR put it succinctly.  This is also why I sometimes 'go off the deep end' when people constantly claim that our post-tx problems have nothing to do with all the interferon that we used.  On the contrary, the problems are more likely completely due to the interferon.  Interferon has a track record of changing the system, and its function.  Many doctors are well aware of this.  Oddly, most HCV doctors are not. (Psst, by the way, neither are the drug companies.)   Go figure!

DoubleDose

[Kalio1]

He also talks about te AMOUNT of interferon. You used twice the "normal" dose which could be the reason you have had the response you have had. You can't rule out taking twice the approved amount as the reason either.

He seems to be saying it can produce both positive immune response effects and negative ones, depending on how your individual system responds.

I believe the virus can cause MORE damage than the treatment particularly in those with moderate to severe liver damage. A continuing declining liver status is no walk in the park either and can be responsible for many "after effects" that are blamed on IFN. Also the fact that many have had the HCV virus for decades in their bodies can't be disregarded as a factor in post tx problems or as a factor in their "changed" immune response. The problem is all these factors have to be considered and studied before you can say "IFN did this to me" when in fact there are a host of additional factors involved.

A person with substantial liver damage prior to treating might find more dramatic responses from IFN. that have something to do with their damaged livers.

To say "it's all due to interferon" is far too simplistic, all te factors have to be considered including the AMOUNT of IFN taken, the CONDITION of your liver and overall immune system prior that existed and YOUR response to it. You took double the recommended amount of the drug and also took it for extended periods of time, much longer than the typical patient. As cuteus points out, her immune response has been enhanced in a good way. To my knowledge she did not double dose IFN.
I dont think you can discount taking double the recommended dosages as non significant to post tx situations.

[jmjm530]

No real arguments here other than being an optomist by nature, I believe that the immune system will eventually "settle down" in many/most of us, albeit at a different pace. I mentioned TCM earlier as one means to hasten that process, as well as more natural methods such as exercise, diet, etc.

But along this line of thinking, don't you think this post tx immune response argues for a more cautious approach regarding extended treatment, for example, which you often appear to advocate?

Personally, I think extending tx or "bumping up" the tx drugs only makes sense in those with significant liver damage, regardless of whatever incremental increase in the odds of SVR that a more agressive tx might bring. Again, weighing the risks of extended treatment against the reward of an incrementally better chance of SVR.

Be well,

-- Jim

[jmjm530]

Kalio: I believe the virus can cause MORE damage than the treatment particularly in those with moderate to severe liver damage.
----------------------
Don't mean to be cute here, but are you acknowledging then that treatment can cause more damage than the virus in those with little or no liver damage?

Just not sure what your position has been on this or if any changes. My position has always been that the risks of treatment for those with little or no liver damage probably outweigh the rewards. That said, the decision to treat or not to treat has so many other variable factors that in the end the right decision is the decision someone makes -- assuming they make an educated decision by taking a little time to study the issues.

-- Jim

[jmjm530]

Probably should mentioned that the above remarks were directed mainly to geno 1's because of the lower tx response rate. Not as clear cut with geno 2's and 3's who have little or no liver damage, because they have a significantly better chance of SVR with half the treatment time.

[DoubleDose]

I hear what you are saying.  People all respond in different ways to interferon, and some who did short courses end up having more post-tx problems than some who extended.  Its a 'crapshoot' because we all react differently.  I know you have a number of different variables that 'you think' could be responsible for the post-tx problems.  That's fine.
The one thing that seems to be similar though in the post-tx cases, is that the real problems begin right after using interferon.  Not due to having had the virus for 20 or 30 years, for many people.  Many who develop these post treatment problems have felt fine with the virus for decades.  Any observer would easily note that the one changing variable is the interferon.
This is logically the variable that you would explore...just like lung cancer and cigarette smokers.  Their lung cancer MAY have come from other behaviors, but those three packs a day for thirty years sure warrant some attention, as a cause.

When doctors, researchers, and post-tx SVR's recognize interferon as a likely cause of these problems, your voice can be the opposing view representing those who cannot believe that interferon could do all these things.  Maybe you are right. Maybe doctors and treaters that we hear from don't know what they are talking about.

But I seriously doubt it.

DoubleDose

[cuteus]

the way I read you is that, at this moment, there is no definitive data to assign all the symptoms and conditions to our encounter with SOC, and I agree.  I don't see you dismissing the fact that it could be, just that there is no conclusive proof. am I reading you right? if correct, I honestly don't see where the problem lies.  Except that some folks are 100% certain of the relation to their present status because it was not there before and now it is. It seems that even then, we would need to wait for more conclusive proof as to what else was at work in adittion to the meds.  There are always other contributing factors to everything.
be well

[cuteus]

LOL, OMG! you are going through every one of the fears and gamut of thoughts that we all faced.  Completely on track! It is amazing the similarities of thoughts and fears we all faced.  Almost exact.
and you will reach the right decission for you.

[Myown]

Though I hate the idea of stimulating my immune system through tx and the long term permanent sx it may cause,,,I also am very concerned that my immune system might be in 'constant overdrive' without even having the drugs in my body,as it tries to fight the virus, so to tx is a risk for the immune system, but so is doing nothing.

Then again I don't know enough yet or as much as you guys and I was thinking that maybe the immune system at this point does not recognize the virus as the enemy anymore, Maybe it doesn't fight against the virus as hard as it did upon initial entry?I don't know the answer, but i lean towards the picture of my immune system being in constant overdrive as I stated above. Just guessing. Either way, this whole mess is too many decisions. Every time we turn a corner, pre tx, during tx, post tx,,,we have a life changing decison to make. Nothing is cut and dry,,too much guess work for us AND THE DOCTORS.

I'm hoping that I don't have to go over the 24 weeks. Would like to stop at 16 weeks, but short course scares me. If I am having a hard time, it will be an easy decison to throw in the towel, but if its not a bad ride or tolerable, it will be a tough decision as to stop at 16 or not, even if I was und at 4. The thought of having to do it again longer is horrible. Not telling anyone here anything new. Its everyones fear, but those that have had to, seemed to have gathered the strength to do so, which helps us to move forward when faced with such a disapoinment and heartache.

[sfbaygirl]

One interesting thing HR said today was the fact that people on tx should not just STOP. That tx should be reduced so the immune system doesnt' go into a shock when it is without the interferon from the outside. Trials have ruled SOC and even if there may have been some 'problem outcomes" the SOC tends to follow what the trial did. That what gets approved, whether it is completely good or not. I wish our docs would let us detox from Inf/Riba a bit more slowly than cold turkey, perhaps the sx post tx wouldn't be so bad.

[Hepatitis Researcher]

Interferon is a class of substances that we are naturally producing all the time in small amounts and in larger amounts during infections. I am toying with the thought, stemming from my understanding of antiviral effectiveness at low doses, that even very very low amounts of Pegasys, too low to cause more than minor discomfort, might be capable of holding down small amounts of virus capable of reactivation.

The TCM issue fits well with the above mentioned balancing act of the immune system, but because in itself is an ill defined term/entity, it can be easier discussed in a call/conference call that we might have re some of these issues. The need for dialog and the sheer volume of background concepts  that underlie any valid "opinion" and need to be brought up to explain any position one might have, forbids a meaningful treatment in this restricted format.

[Myown]

Ha ha!! I was afraid to open your post to me when I saw the exclamation mark.lol I thought you were going to yell at me and say,,"stop driving yourself nuts, STOP STOP,STOP it right now, myown!!!" haha

I'm glad to hear my worries are the "norm," IF we can even call it "norm,"... maybe we're ALL just plain ol nuts. ha But seriously,this decision is a hard one for us all,but especially if someone has "time" as they say,,,its good to have time, but having options sometimes can cause you to weigh things too long and too many times.

I think my decision IS to go the 24 if all is well as far as sx. I know the longer interferon is in our system, problems may happen down the road, but I can't see going into this and not tryn' to give it my all. The virus in my system isn't good either and I would rather take the chance of what interferon might do to me, then to not tx and take the chance of what the hep c might do to me in time.  

Everyone that has/is toughin it out has given all of us that haven't tx or currently tx the courage to go forth,,and hopefully I will keep that in the forefront of my mind if the road gets rough.

But thanks for understanding me and not hitting me over the head for my "what if's."
My "what ifs" have always been a part of my life in every area. Everytime I try to erradicate them, they reactivate somehow,,oh well,lol