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Australia Medicine Biotech Science

Immune System Killer Mechanism Identified 88

Posted by samzenpus
from the cancer-killer dept.
traveller.ct writes "Researchers from Melbourne and London have identified the mechanism by which the immune system destroys malignant cells. The notion of killer cells puncturing a malignant cell to inject toxic enzymes has been understood for over a century, but now, using the Australian Synchrotron, researchers have identified the protein which is responsible for forming a pore in the malignant cell: perforin. Perforin resembles the cellular weaponry employed by bacteria such as anthrax, but may have been appropriated by our immune system in our evolutionary past to fight against them. The researchers are now investigating ways to boost perforin for more effective cancer protection and therapy for acute diseases such as cerebral malaria."
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Immune System Killer Mechanism Identified

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  • Doh (Score:5, Funny)

    by Anonymous Coward on Monday November 01, 2010 @03:47AM (#34086490)

    Should have been pretty obvious from the start.

    "Let's see which of the proteins is most likely the one used to perforate other cells.. we have relaxin, movearoundin, respiratin and perforin... hmmm!

    • Re: (Score:3, Informative)

      by mellon (7048)

      Actually, relaxin and respiratin are also important. Relaxin causes the sphincter to relax, respiratin causes it to inhale, and then finally perforin can do its work. :)

      • by EdIII (1114411)

        Actually, relaxin and respiratin are also important. Relaxin causes the sphincter to relax, respiratin causes it to inhale, and then finally perforin can do its work. :)

        Maybe I had one too many beers here, but are you saying that our bodies produce a drug that causes the sphincter to "inhale"? Also, after this never before heard miracle has occurred, that another drug can finally begin its "work"?

        Whatever you are smoking man, pass it over here.

        • Re: (Score:3, Funny)

          by Kilrah_il (1692978)

          Can you hear it? The whisper quiet sound of something Whooshing way above you? Or maybe you just aren't relaxin enough...

      • Re: (Score:3, Interesting)

        by durrr (1316311)
        You're wrong, relaxin increases the motility of sperm: en.wikipedia.org/wiki/relaxin
    • And on a more serious note, maybe they should name it "the Shiva protein"?

    • In computer science one is always warned that if you create a backdoor the bad guys will find it. But apparently it works the other way too in biology.

  • by mellon (7048) on Monday November 01, 2010 @03:47AM (#34086492) Homepage

    When you tweak one thing, something else tends to go out of balance. Still, this is pretty cool, whether it leads directly or indirectly to new treatments.

    • by Kilrah_il (1692978) on Monday November 01, 2010 @04:29AM (#34086602)

      It's not the first time that doctors lowered/raised the level of activity of a protein involved with the immune system. Of course it has side effects, but a drug gets approved when the benefits outweigh the risks.
      For example, TNF [wikipedia.org] is an important mediator of inflammation. Its inhibitors are used for Rheumatoid Arthritis and many other diseases.
      Interleukin-2 [wikipedia.org] is also an important factor in the immune system (esp. in its anti-viral and anti-cancer capacity). A recombinant form of this protein is used to fight several types of cancer.
      So, yes, maybe this approach won't work, but it has potential and it will be a shame if it will not be tried.

      Oh, and by the way, thanks for the Wizard of Earthseas reference. I read this book years ago, and never could remember its name.

    • by gilleain (1310105) on Monday November 01, 2010 @07:11AM (#34087144)

      When you tweak one thing, something else tends to go out of balance. Still, this is pretty cool, whether it leads directly or indirectly to new treatments.

      The best example of this, I think, is the theory of balance between cancer and auto-immune disease. The idea is based on the fact that cancer involves cells growing out of control, while auto-immune disease (like arthritis) involves the immune system attacking the self. So a more active immune system will lead to arthritis, and a less active one to cancer - and you can't just suppress or boost immune cell-killer response without consequence

  • Better HIV drugs (Score:5, Insightful)

    by antifoidulus (807088) on Monday November 01, 2010 @05:34AM (#34086854) Homepage Journal
    I wonder if this finding will help researchers develop better anti HIV drugs. Part of the reason that HIV is almost impossible to remove from the body is its ability to remain latent, HIV viruses don't always start producing new virons and killing the cell right away, sometimes they enter a cell and essentially just sit there, sometimes for up to 5 years. Ordinarily the cell would be marked for execution, but HIV(and other viruses, notably the herpes family) somehow prevent the cell from making the chemicals necessary to let the immune system know that it's time to die. This is why people on HIV treatment can have 0 viral load(the amount of virus in a particular blood sample), but still be infected. They still have HIV just kind of hanging out in a very small number of cells.

    I read a few years back(sorry cannot find the article) that they had some luck using epilepsy medication in combination with a huge dose of anti-HIV medication, patients saw about a 75% reduction in the number of infected cells, but the side effects were so severe that they discontinued the study. Not a single person was totally cured. I wonder if its possible to use the information gathered here to help determine how HIV prevents cell death and how we can stop this.
    • What side effects were they?

      Unless you're talking about actually shortening remaining life span, or causing a permanent and severe chronic pain for the rest of their life, I'm not sure how many side effects there are which are worse than lying in a bed for the remaining few weeks of your life covered in lesions, being overtaken by various cancers, and finally dying typically from pneumonia (which is in itself enough to get most people to make serious lifestyle changes, e.g. stopping smoking).
      • by operagost (62405)
        They may have been people who were HIV-positive, but were not showing any symptoms.
        • So, side effects which are enough to put someone off taking the meds for a disease which will kill them, if untreated?

          Like I said, they must be pretty significant side effects. I'd probably stop short of losing the use of my lower limbs, or severe mental impairment.
          • So, side effects which are enough to put someone off taking the meds for a disease which will kill them, if untreated?

            I am currently on a medication which makes me forget words. An example being a conversation a couple of weeks back where the correct word would have been 'eroded'. The closest thing that I could come up with at the time was 'ground corrosion' which thankfully my friend understood. To my friend this episode was inconsequential but to me it was fucking horrific(having happened more than once and at some very inopportune times). If I had to take this medication for the rest of my life to keep me alive I would

            • Exactly the point of my second paragraph. Severe mental impairment or paraplegia would make me reconsider treatment.

              Quality over quantity, always.
      • by morgauxo (974071)
        A good point but parent post did say that they were not actually cured. Presumably they would have still suffered that fate anyway though maybe not as soon.
        • He also said the trial was discontinued. I wanted to know if that was at the patient's behest ("This explosive diarrhoea is unbearable, please send me to Dignitas so it can be over") or at the Doctors ("These bouts of explosive diarrhoea are costing far too much in laundry bills. Let's knock this one on the head, guys")
          • I managed to dig up the article, you can find it here [webmd.com].
            • From page two:

              ... possible side effects ... include liver damage and, if taken by pregnant women, birth defects. Valproic acid also has dangerous interactions with AIDS drugs. In fact, one of the four patients in the study developed serious anemia because of an interaction with one of the drugs in his HAART regimen.

              Those don't seem so serious to me. If the drug, in combination with other retrovirals, is found to be 100% effective* then the person would probably become viable for liver transplant. Kids who are HIV positive would probably not be eligible for the treatment, but I'd go so far as to suggest that someone who is HIV positive does not intend to get pregnant, and if they are responsible enough would abstain from sexual contact (or take precautions which would prevent pregnancy). All in all, I'd

    • by toppavak (943659)
      Unfortunately, no. Perforin acts by breaching the cell membrane of invading bacteria or parasites, viruses are too small and lack the membrane and internal structure for such an approach to work. Most often, immune cells fight viral infections instead by engulfing as many viral particles as possible and self destructing. Unfortunately HIV undermines critical elements of the immune system itself by selectively depleting naive helper T-cells rendering the immune system unable to respond to any new infection,
  • by The_mad_linguist (1019680) on Monday November 01, 2010 @05:37AM (#34086862)

    Immune System Killer Mechanism Identified

    oh nooooooo

  • by Barny (103770)

    As a sufferer of a hyperactive immune system disease, I would rather see things slide a little the other way, less of this stuff eating away at my good cells please.

    Bit of hope for otherwise incurable diseases though :)

    • by pookemon (909195)
      Hmm, so you have too much perforin then... Step into this grind... *ahem* room please.

      *cue lightning and evil laugh*
      • by Barny (103770)

        Uh, not so far too much of that one thing, just my immune system seems to think my lower intestines are fair game for target practice, need something that will feed it dud ammo for a bit.

        And yeah, I am betting since about 1 in 5000 has something along these lines, it won't be hard to find people willing to test stuff (I would for a start).

        • by TheLink (130905)

          There's some treatment at research stage that might help your case, but there are some minuses...

          http://en.wikipedia.org/wiki/Helminthic_therapy [wikipedia.org]

          • by Barny (103770)

            Yes sir, been looking at that, and even emailed the universities asking if they need test subjects, but all of them are out of my country (Australia).

            But the thought that such a treatment could put this into remission is one that cannot be ignored or hoped for.

            • A quick google search revealed that there is activity related to Helminthic therapy in Australia. A few of them didn't sound very serious to me (web services that deliver hookworms to your door ... that wouldn't be my first choice).

              Anyway, how serious is your disease? What is your prognosis? If it's serious enough, your prognosis isn't good, or it's seriously affecting your life quality, travelling to wherever a treatment is available should be your first priority.

              • by Barny (103770)

                Prognosis, reasonably minor atm, although it spreads down the bowl lining into rather nerve rich territory when it flares, leaving me unable to function without growling and yelling a lot, minor fistula, still able to work though, so unless its reasonably easy to do, and I am not in a major flair up, I would likely not want to travel far (spending large amounts of time sitting down is not a thing I enjoy any more).

                • Well, it's good to know it ain't that bad.

                  Looks like this treatment is growing, I'm sure you'll soon find someone in Australia that can help you. The source of the treatment is a parasite, and when it comes to weird, dangerous and frightening animals, Australia has them all :) So I'm sure you'll find something locally.

                  Best of luck, hope you get better.

        • by vlm (69642)

          Your ratio is about a factor of 50 too low, but symptoms sound similar to my relatives with celiac disease, although guessing over the net is almost as pointless as making a purely symptom based diagnosis vs the blood tests and biopsies that my relatives went thru... Anyway think of the conceptual difference between the trigger and the reaction. I don't think this type of therapy would help celiac folks since you'd still have the gliadin reaction trigger messing with your intestinal walls, its just that t

          • by Barny (103770)

            Crohns here, was only thinking of that (which is 1 in 5000) but yeah, am guessing any hyperactive immune disease could get some help from this.

            Just as the likes of Colazide is used to only target the lower GI maybe an inhibitor for this chemical could be bonded to something like it?

            Or perhaps even harden the lower GI cells to the enzyme.

            Either of which would be better than the cocktail of general immune inhibitors I have to suck down each day atm. Take the teeth out of the dogs rather than having less dogs

            • you probably know all about that idea

              but for anyone not in the know, digestive system immune disorders are maybe imbalances where the missing counterbalance is an intestine full of worms. we evolved with intestines full of worms, and having no worms in our intestines is a recent and abnormal state of affairs. so some people "need" the worms in order for their immune system to perform normally in their digestive system

              • by Barny (103770)

                Yes, Helminthic therapy, interesting as it would be to try, it would be damn hard to keep it in balance (the therapy generally uses specially treated worm larva that cannot reproduce past the full worm stage).

                Also, it would be rather difficult I would imagine to try purchasing some live eggs to try it with.

                • no need to buy anything

                  get your hepatits shots, and take a flight to a certain area of the world, have a glass of the local water, and return home when intestinal invasion is verified

                  on return to home, be ethical and don't expose anyone else. declare one of the bathrooms in your house off limits to anyone else, and take special care in public restrooms

                  if the therapy doesn't work, go to your doctor and get a cheap, readily available antihelminthic drug

                  if it works, you can wear the alien stomach burster hallo

                  • by Barny (103770)

                    ...

                    I am taking immune inhibitors (as my post further up said), having a vaccination while on those is fucking insane.

                    Eg, I get a flu shot, I will actually get the flu, benign weakened virus introduced to my system will not just help my immune system adapt to it, there is not much immune system left.

                    • well yeah

                      if you are going to do worm therapy, you have to get off the immune inhibitors

                      which is of course no small deal

                      so the worm therapy would be a huge jump. only think about trying it someday if you are in a really good spot in life emotionally/ relationship wise/ financially, and can stomach the risk, pun intended

                      good luck man

    • I am not sure this could help your case. Auto-immune diseases are a matter of miss-identification, that is, your immune system attacks your own body. That is, your immune system isn't stronger or so much different from others, it just targets the wrong cells. So, since this protein seems to be just the weapon used by the immune system, anything based on it (if for example you were given a medication to reduce the presence of this protein), that would reduce your entire immune system's ability to fight disea

  • by Invicta{HOG} (38763) on Monday November 01, 2010 @06:09AM (#34086948)

    http://www.ncbi.nlm.nih.gov/pubmed/3874868

    Perforin has been known for 25 years to be the mechanism by which immune cells kill other cells.

    • by The Mysterious Dr. X (1502541) on Monday November 01, 2010 @06:12AM (#34086956)
      I was going to say the same thing, but my article is only from 2007... http://www.ncbi.nlm.nih.gov/pubmed/17717151 [nih.gov]
    • by Anonymous Coward on Monday November 01, 2010 @07:58AM (#34087338)

      Actually, what the researchers have done is produce an X-ray crystal structure of perforin, which enables them to understand how it works and hopefully how to tweak it to our purposes. Could be an interesting drug, recombinantly engineered perforin targeting e.g. malaria or other protozoan diseases. It is of course just another of several attempts to use immune system derived proteins as medicines (antibiotics, anti tumour drugs etc), and will suffer the same problems: hard to administer, breaks down quickly, does not diffuse well through tissue to the target area.

      The summary's statement that the researchers have "identified" perforins as the causative agent of cell membrane perforation is misleading, that has been known for quite some time, as you mention.

      • The summary's statement that the researchers have "identified" perforins as the causative agent of cell membrane perforation is misleading, that has been known for quite some time, as you mention.

        You are quite right. Perhaps the sentence would have been more accurately phrased as the researchers having identified the mechanism of how perforin works. I don't have any experience in this field and this is a mistake on my part. Rest assured that this mis-statement is unintentional and I hope my future submiss

    • After RTFA it seems they knew it was responsible for a century, but these guys figured out the way it worked.

  • Perforin resembles the cellular weaponry employed by bacteria such as anthrax, but may have been appropriated by our immune system in our evolutionary past to fight against them.

    or perhaps anthrax, and others, appropriated perforin from our immune system

    i'm not saying one scenario is more likely than the other, but redirecting virtuous weaponry for evil is just as likely as salvaging malicious weaponry for good. molecular evolution is a highly promiscuous process, so, in the end, it might not even matter which came first, or possible to figure out which came first

    • Since bacteria are so much more numerous and fast-breeding than humans there must have been many more opportunities for this sort of thing to evolve in bacteria than in humans though.
  • by hAckz0r (989977) on Monday November 01, 2010 @06:56AM (#34087088)
    Don't you think that the problem is "targeting" of the right cells rather than the amount of perforin? I don't know about you, but an over abundance of perforin running around randomly in my blood stream does NOT sound like a GOOD thing. It would only take a little to kill you, so the true matter is knowing when and where to apply what we already have. The triggering mechanism is what we should be studying.

    .

    • For what it's worth, this is already the case with most all anti-cancer treatments: they *do* kill every cell in your body, but since cancer cells are replicating much faster, they kill cancer faster than they kill the rest of you. (Except for the cells in your body that are rapidly replicating because they're supposed to, which is why chemo patients lose their hair and their digestive systems fall apart.) Sure, having perforins run around everywhere in your body is a bad idea, but all you need is for it
  • The story confuses me because I swear we learned about the body's use of perforin in my anatomy and physiology class over two years ago. Maybe that lady in the Charlie Chaplin film wrote our textbooks.
  • Perforin perforates the cells. I get the name now.
  • by cinnamon colbert (732724) on Monday November 01, 2010 @10:55AM (#34089264) Journal
    The detailed molecular mechanism has been know for sometime; what these workers did was to create a detailed 3D atom resolution model of the responsible protein perforin, while this will certainly help in understanding how pore forming proteins, which are widespread and often act as agents of disease, work, it is not consistent with the title.

    oh, overblown article headline , taken from PR pretending to be news, on slashdot. Why am I surprised ?

    note - I coudn't get the DOI at the bottom of the article to work , so if this is not published, it is not even *science*
    Here is a review by author whisstock The structure and function of mammalian membrane-attack complex/perforin-like proteins. Kondos SC, Hatfaludi T, Voskoboinik I, Trapani JA, Law RH, Whisstock JC, Dunstone MA. Tissue Antigens. 2010 Sep 22. doi: 10.1111/j.1399-0039.2010.01566.x. [Epub ahead of print]PMID: 2086058
  • Cerebral malaria is the worst. Always going on about "I say, I do believe I shall induce splenomegaly, hepatomegaly, ischemia, hypoglycemia, and hemoglobinuria with renal failure." It's like dude, speak English.

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