Hey eveyone,
This post is in regard to what Prof. Cohen mentioned in class on Tuesday regarding IgG as an anti-inflammatory. I'm curious to know more about this. I did a study on morphine last year, learning how continuous doses of morphine causes tolerance, and (believe it our not) more pain. When injected intrathecally, morphine attaches to TLR-4 receptors on glia in the spinal cord. Glia then release IL-1, causing inflammation, which inhibits the analgesic properties of morphine acting on neurons. If you co-administer an anti-inflammatory like IL-10 with morphine, analgesia increases. It's bizzare to think that morphine can cause more pain when used chronically.
Anyway, what I'm curious about is the role IgG plays (ie the mechanism) in having anti-inflammatory effects. I'm wondering if an endogenous substance of the body (IgG), when injected and used as an anti-inflammatory, can cause tolerance, or resistance, similar to the type of tolerance caused by chronic morphine.
In a sense, my question is could our bodies become immune to the anti-inflammatory effects of IgG, if it is used over long periods of time?
I need to look into this still...I just needed to type this while its fresh on my mind.
A reference:
Norman Cousins Lecture. Glia as the "bad guys": implications for improving clinical pain control and the clinical utility of opioids.
Watkins LR, Hutchinson MR, Ledeboer A, Wieseler-Frank J, Milligan ED, Maier SF
Brain Behav Immun. 2007 Feb;21(2):131-46. Epub 2006 Dec 18
Chris Altmann
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3 comments:
I am well aware of the morphine induced tolerance related to glial effects. I didn't necessarily connect that with IvIg treatment.
I do personally know several patients with multiple sclerosis that swear by it. And, not so strangely enough, they can 'feel' the effects wearing off in about a month (~ the half life of IgG). That's how often they have administration. It's quite viscous and takes several hours, not to mention it's about $50K/month. No kidding it's pricey stuff (I haven't personally looked into the price lately). But then it must take a lot of time, etc to get such purified IgG.
This is one of the off label uses mentioned in class. Several neurologists I've talked with about this treatment have said it isn't really known why it works. But some patients seem to have fewer symptoms etc.
Would it be that much different than treatment with mAbs? A small percent of patients still react to humanized mAbs.
IVIg costs about $30 a gram, and a normal dose might be 50 grams, though some protocols require more. That would be $1500 or more a month, a huge sum compared to, say, the annual per capita health budget of Rwanda.
The best guess as to how it works is by engaging inhibitory Fc receptors on macrophages. Normal FcRgammaI are pro-inflammatory; they are the ones involved in opsonization and phagocytosis; but FcRgammaII, when bound, inhibit macrophage activation. The other Dr. Cohen knows a lot about this...
There's still a lot about the mechanisms of IVIg that aren't fully understood. It seems to work in off-label conditions such as MS,and rheumatoid arthritis, as well as issues such as acne.
Because it's so expensive, there is a lot of work being done to figure out how it works so that a synthetic version can be made. The Canadian Blood Services has a team of scientists working on this issue.
Siragam V. et al. Intervenous immunoglobulin ameliorates ITP via activating Fc receptors on dendritic cells. Nat Med 2006;12:688-692
...for more, just do a medline search on Lazarus AH...
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