Balance the Th1/Th2 Immune System
From a talk by Paul Cheney, MD
Transcription by Dallas-Ft Worth CFS Support Group
Written by our group facilitator, this issue's articles are based on tapes of her October 2000 visit. Dr. Cheney gave permission to share this information, but has not reviewed or edited it. Articles on other topics will be in the April 2001 newsletter and will soon be available on our website in the section on Dr. Cheney. These articles likely apply also to FMs patients experience cognitive difficulties in addition to pain and fatigue, since Dr. Cheney believes they may also have CFIDS. Dr. Cheney plans to speak in the Dallas - Ft. Worth area on October 20, 2001. Contact the DFW support group for information, particularly about the videos that will be available of the seminar.
CFIDS patients are Th2 activated. This means they over-respond to toxins, allergens, normal bacteria and parasites, and under-respond to viruses, yeast, cancer and intracellular bacteria. Dr. Cheney suggests six products that can help rebalance the immune system.
Dr. Cheney explained that the immune system has two different modes of attack, based on the type of invader. One is Th1 (T Helper 1). It goes after organisms that get inside our cells intracellular pathogens. It is also known as cell-mediated immunity. The other is Th2 (T Helper 2). It attacks extracellular pathogens organisms that are found outside the cells in blood and other body fluids. Some call this humoral or antibody-mediated immunity. A healthy immune system is dynamic, able to switch back and forth as needed, quickly eradicating one threat and then resting before responding to the next.
(Dr. Cheney began this conversation by drawing a large inverted "V". At the top point he wrote "Th0", which he called "Th naught". The left arrow pointed down to "Th1" and the right arrow to "Th2". The arrow on the right was much darker and thicker, indicating that CFIDS patients are Th2 activated.)
Th0 are the naive, or unformed, cells of the immune system. They are resting, just waiting for an invader. When infection occurs, they convert to either Th1 or Th2, depending on the type of threat. When the resting cell is exposed to a virus, cancer, yeast, or intracellular bacteria (like mycoplasma or chlamydia pneumonia), the Th1 response is initiated. (Dr. Cheney wrote these organisms beside the left arrow.) The weapons of the Th1 system include cytotoxic T cells and Natural Killer (NK) cells. (Cheney drew these below "Th1".)
On the other side are normal bacteria, parasites, toxins, and allergens. (Likewise written beside the right arrow.) These trigger a predominately Th2 response. Its weapons include eosinophiles (Eos), polymononuclear cells (PMN), and antibody secreting cells (Ab). (Likewise written below "Th2".)
How does the naive cell know which pathway to take? It depends on the cytokine information received. The presence of any organism from the left side triggers production of a cytokine called Interleukin 12. IL-12 causes the Th0 cell to move down the Th1 path. On the other hand, organisms on the right side trigger the production of Interleukin 10 (IL-10), which causes the Th0 cell to move down the Th2 path. (Cheney added small vertical dotted lines on each side, pointing upward to "IL-12" on the left and "IL-10" on the right. He then drew horizontal dotted arrows from "IL-12" and "IL-10", each pointing inward toward the "Th0", indicating that these cytokines determine whether it will become Th1 or Th2.)
Cheney said this is the point where it gets very interesting. Viruses, especially herpes viruses like EBV, CMV and HHV6, make proteins that mimic IL-10. The virus deceives the immune system into thinking that the threat is coming from the opposite side! So the immune system shifts from the Th1 mode that attacks viruses to the Th2 mode that does not. The virus increases its chances of survival by diverting the immune system. It is now thought that many, if not most, pathogens have this ability. (To represent this effect, Cheney drew a horizontal arrow about half way down the inverted "V", originating from the left side and pointing toward, but not quite touching, the right side. The line was labeled "IL-10 like peptides". Below it he drew a similar arrow from the right side that almost reached the left side. It was labeled "IL-12 like peptides".)
Researchers have demonstrated that most CFIDS patients end up stuck in Th2 mode. This has several consequences. When the Th2 system activates, it blocks the Th1 system. This suppresses the Th1 weapons, particularly NK function. Accordingly, there is also an increase in the Th2 weapons - the white cells and antibodies. Most notable is increased antibody production. Dr. Cheney said that if you measure antibodies to anything a CFIDS patient has ever been exposed to, they will very likely be elevated. (At this point he drew small arrows beside the "weapons": They pointed down on the left side to indicated suppression / lower levels; and they pointed up on the right side to indicate activation / higher levels.)
Cheney notes that other problems ensue. Patients get into trouble on both sides: they overreact to things on the right side and under-react to those on the left. When they are Th2 activated, they no longer have the defense mechanisms to keep dormant all the things they caught in the past. They cannot suppress or control them anymore, and the EBV, chlamydia pneumonia, CMV, etc. reactivate. The yeast also begins to appear.
The only defense against being eaten alive at this point is RNase L. (For more information about RNase-L, see The Three Phases of CFIDS and other articles in the Cheney section of our website.) RNase-L cannot kill any of these things. It only stops them from reproducing. According to Cheney, "It's a line in the sand saying 'No more replication', and it waits for Th1 to come and kill them. But Th1 never comes. RNase L sits there and grinds away, possibly going up and down as the pathogens activate and reactivate. But they never get wiped out. RNase L holds the line, waiting for the cavalry that never arrives."
While it is valiantly trying to hold the line, it is also chewing up human messenger RNA, inhibiting all the enzymes in the body, disrupting protein synthesis, and generally making patients miserable. As RNase-L grinds away, it eventually shifts into "after-burner" desperation mode - the more powerful and deadly low molecular weight form discovered in CFIDS patients by Suhaldonik.
Cheney commented "RNase-L is a very good anti-cancer defense. So as long as you're involved in this scenario, you don't get cancer. But a lack of growth hormone will wipe out RNase-L, and we now know there is profound loss of growth hormone in CFIDS. Growth hormone is responsible for protein synthesis, and RNase L is a protein. So if you lose growth hormone, you lose protein synthesis, including RNase L. That may explain why, as the disease wears on and you get more injury, you stop seeing high levels of RNase L. You can't make it anymore."
He believes this is a very scary situation. Patients are Th2 activated and Th1 suppressed. The things on the left come out and there is nothing to stop them. There is no Th1, and eventually no Rnase L. He also believes patients need to balance the immune system - to push it a little more towards Th1. That way they will lose some of the overreaction on the right and gain some control on the left.
Cheney recommends the following to help shift the immune system from one mode to another. They are called "right to left shifters". Three of them are published, or near publication.
1) Kutapressin (published, prescription) Kutapressin is an immune modulator and a broad spectrum anti-viral. Dr. Cheney has found that it is most effective when the dose is varied or "pulsed". The dose should vary from 1 to 4 cc daily; see the section on Isoprinosine for this theory. Dr. Cheney strongly suspects Ampligen is a right-to-left shifter also. He has said in the past that Kutapressin is rather like a weak form of Ampligen.
2) Isoprinosine (published, prescription) Published for use in CFIDS, this anti-viral enhances NK function. Dr. Cheney believes it would also be good against intracellular bacteria since it is a Th2 - Th1 shifter. It appears to raise IL-12 and lower IL-10, which turns off Th2 and turns on Th1.
It is also called Imunovir and is very nontoxic, very safe. It has been approved in Europe and Canada for just about any viral infection for 18 years. It is not approved in the US (for political reasons not safety concerns) but is easy to get from Ireland with a prescription. Week one, take 6 tablets a day, Monday through Friday, and none on the weekend. Week two, take 2 tablets a day, Monday through Friday, and none on the weekend. Repeat this cycle. But do not treat every month. Do two months on and then one month off of this "pulsing" dose. This medicine works best when you do not treat regularly. If you treat continuously at the same dose, it stops working. It is an immune modulator, and Dr. Cheney suspects all immuno-modulators are like this. If taken continuously they stop working. The dose must vary so the immune system never knows what to expect.
3) Pine Cone Extract. Cheney said, "They make a tea from this in Southern Japan and they have significantly reduced cancer rates. It's thought to work at the gene level in lymphocytes, where it turns on IL-12. It also shuts down IL-10 at the gene level, and that causes a shift towards Th1. Pine Cone extract is expensive, but at just 10 drops a day (in the morning), of all the possibilities, it's probably the cheapest per day." It is called PineExtra, and 1 oz is about $60, but it lasts a long time.
4) Earth Dragon Peptides (supplement, www.nutricology.com, www.needs.com) Earth Dragon is round worm peptides. It causes a shift to the left, and is believed to be very similar to IL-12. There has been a huge surge in the use of ED peptides to treat Inflammatory Bowel Disease, specifically Crohn's Disease. One professor at UNC treats all his Crohn's Disease patients with Earth Dragon. It is very non-toxic and safe. This is a good choice for those who want to balance their immune system and also have bowel problems. Earth Dragon is about $36 for 150 caps. The dose is two a day.
5) Heparin (prescription). Heparin is a Th2 - Th1 shifter. One advantage for many patients is that it is also an anticoagulant. Dr. Cheney only recommends this if a patient has a coagulopathy. About half of his patients do, according to the ISAC test.
6) Formula 560 Transfer Factor (to be published, supplement, www.immunitytoday.com) Formula 560 is an immune modulator. Dr. Cheney likes this product. It reportedly works against HHV6 and Lyme Disease, as well as other problems. It costs about $585 for the first three months, then the dose drops one-third. It averages out to about $130 a month for the first six months, and $65 thereafter. (The cost of this product has reported dropped since this was first published.)
Which should you use? Cheney recommends that you pick one and see what it does to your NK function. It is a question of whether it will work and how much it costs. NK levels will rise if there is a shift from Th2 towards Th1. Before beginning one of these products it is best to get a baseline on NK function. Then test again after having been on the product for one to three months. Dr. Cheney uses the lab of Mary Ann Fletcher, an NK specialist and colleague of renowned researcher Nancy Klimas, at the University of Miami. Her lab is no more expensive than commercial labs, and is top quality. Cheney emphasizes that you must have a quality lab do this test: do not use just any lab. For test information, phone 305-243-6288 or fax 305-243-4674. The test is called "Natural Killer Cell Function Assay" and costs $350.
Note: This is not medical advice. See your healthcare provider for medical advice.
I searched the 'net and found the following resources for the drugs/herbs/supplements recommended by Cheney for the Th1/Th2 protocol.
Earth Dragon Peptides (Lumbricus Tonic): roundworm peptide useful in some immune-related bowel diseases such as Crohn's.
Heparin: an injectible anticoagulant/blood thinner.
Isoprinosine (Imunovir; Inosine Pranobex): by prescription outside of the U.S. (Similar product available as Inosine) Those in the U.S. may order it from:
Kutapressin: an injectible drug not currently labled for use in the US.
Pine Cone Extract: immune system stimulant with anti-tumor and antiviral properties.
Transfer Factor Formula 560: immune modulator effective in Lyme Disease and HHV6.
Natural Killer Cell Assay
Other names for Isoprinosine include: Isoprinosine Pranobex.
Ask your doctor, nurse, or pharmacist if you need more information about this medicine or if any information in this leaflet concerns you.
To store this medicine:
Other Possible Side
What does it do?
Where is it found?
Who is likely to
How much is usually
Are there any side
effects or interactions?
1. Starling RD, Trappe
TA, Short KR, et al. Effect of inosine supplementation on aerobic and
anaerobic cycling performance. Med Sci Sports Ex 1996;28(9):119398.
From The Body
There is no way to know what the proper dose is. However the clinical studies thus far have examined between 1 - 4 grams per day. The Danish study used 1 gram three times a day. The tablets we distribute are 500 MG each. To take the doses used in the studies, you would take between 2 and 8 tablets every day. To our knowledge, only one study has evaluated how isoprinosine is absorbed and excreted in humans. This study demonstrated that isoprinosine doesn't stay in the body very long. To keep consistent levels of isoprinosine in the body would require fairly frequent oral doses, three or more times a day. Taking isoprinosine as an injection or an enema may deliver initially higher doses into the blood, but the body eliminates this isoprinosine just as quickly. We don't know whether the body requires consistent levels of an immune modulator in order to respond to it, but if it does, oral dosing is the easiest way to acheive this.
Again, Cheney's recommended dosing and frequency for Th1/Th2 dysregulation:
Week one, take 6 tablets a day, Monday through Friday, and none on the weekend. Week two, take 2 tablets a day, Monday through Friday, and none on the weekend. Repeat this cycle. But do not treat every month. Do two months on and then one month off of this "pulsing" dose. This medicine works best when you do not treat regularly. If you treat continuously at the same dose, it stops working. It is an immune modulator, and Dr. Cheney suspects all immuno-modulators are like this. If taken continuously they stop working. The dose must vary so the immune system never knows what to expect.
Byron Hyde MD's preliminary report on isoprinosine research can be found at his Nightingale Foundation site.
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