Tailored MS Treatment (& more on interferons)

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Tailored MS Treatment (& more on interferons)

Postby OddDuck » Sat Feb 12, 2005 9:23 am

We have talked many times in the past about "tailored" treatment of MS, when referring to influencing the cytokines (immune system response), and which ones you want to try to influence and how.

We also today (in another thread) have mentioned the HPA axis hyperactivity in MS.

To recap, some of the main points regarding influencing specific cytokines and the immune system in MS, what has been found is that you want to control NK cells (inhibition), reduce IL1b, reduce TNFa, reduce IL6, increase IL10 as much as possible (this strengthens the BBB), and even perhaps more importantly, we have recently found that in progressive MS, we want to decrease the hyperactivity of the HPA.

Look at this regarding interferon 1b (i.e. Betaseron). I have run across this before regarding the interferons, but this is the first time (don't ask me why) I have run across all of this information in one publication. Is this why for the most part, the interferons are NOT prescribed for progressive MS?

Deb

Psychoneuroendocrinology. 2002 Nov;27( 8 ):881-92. Related Articles, Links

Acute interferon beta-1b administration alters hypothalamic-pituitary-adrenal axis activity, plasma cytokines and leukocyte distribution in healthy subjects.

Goebel MU, Baase J, Pithan V, Exton M, Saller B, Schedlowski M, Limmroth V.

Department of Medical Psychology, Medical Faculty, University of Essen, Hufelandstr 55, 45122, Essen, Germany. marion.goebel@uni-essen.de

It has been suggested that the immune-endocrine communication plays an important role in development and progression of multiple sclerosis (MS). Interferon beta (IFN beta-1b) treatment is the therapy of choice in patients suffering from relapsing remitting or secondary chronic progressive multiple sclerosis. While typical adverse events of IFN beta-1b treatment such as flu-like symptoms or fatigue are well studied, little is known about the acute changes in the immune and neuroendocrine system. Therefore, we analyzed the short-term effects of IFN beta-1b on cortisol, epinephrine, norepinephrine, prolactin and growth hormone (GH) plasma levels before and 4, 8 and 24 h after IFN beta-1b administration in healthy subjects. Moreover, we determined heart rate, blood pressure, body temperature, leukocyte and lymphocyte subsets and plasma levels of interleukin (IL)-1 beta, IL-6, IL-10 and tumor necrosis factor (TNF)-alpha. IFN beta-1b led to an increase in body temperature and heart rate, and in parallel, elevated cortisol, prolactin and GH plasma levels at 4 and 8 h after IFN beta-1b injection. There were no significant alterations in blood pressure, norepinephrine or epinephrine plasma levels. Simultaneously, IFN beta-1b injection led to an immediate granulocytosis while concomitantly decreasing peripheral lymphocytes, especially natural killer (NK) cells. At the same time, IL-6, IL-10 and TNF-alpha plasma levels showed an overall increase. Overall, cytokine administration exerts strong stimulatory effects on the hypothalamic-pituitary-adrenal (HPA)-axis that may contribute to the side effects of IFN beta-1b therapy and affect the efficacy of IFN beta-1b treatment.

PMID: 12383450 [PubMed - indexed for MEDLINE]
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Re: Tailored MS Treatment (& more on interferons)

Postby NHE » Sun Feb 13, 2005 11:53 pm

OddDuck wrote:Is this why for the most part, the interferons are NOT prescribed for progressive MS?

I can't answer this question. There have been studies on interferons and progressive MS and, to the best of my recollection, the interferons were found to not be effective. I don't remember the precise reasons why, but I'm sure that the study results can be found in the PubMed database.

With respect to the abstract you posted, there is another paper which discusses similar finding but was performed for a longer duration. Although this paper discusses interferon beta 1a (Avonex) and not 1b (Betaseron), it might still be relevant. This paper reports that the increase in inflammatory responses was attenuated by week 12 and not present at 32 weeks.

Immunol Lett. 2001 Jan 15;75(3):191-7.
Interferon-beta1a administration results in a transient increase of serum amyloid A protein and C-reactive protein: comparison with other markers of inflammation.

Boylan MT, Crockard AD, Duddy ME, Armstrong MA, McMillan SA, Hawkins SA.

Department of Microbiology and Immunobiology, The Queen's University of Belfast, Microbiology Building, Royal Group of Hospitals Trust, Grosvenor Road, BT12 6BA, Belfast, Northern Ireland, UK. m.boylan@qub.ac.uk

Putative markers of inflammation such as serum beta2-microglobulin and neopterin have been shown to be transiently upregulated following interferon-beta (IFN-beta) administration to multiple sclerosis (MS) patients. However, to date the role of the important inflammatory mediators serum amyloid A protein (SAA) and C-reactive protein (CRP) have not been described. Here we show that SAA but not CRP is elevated in relapsing-remitting MS patients compared to normal healthy individuals, and furthermore that both are transiently upregulated following intramuscular injection with IFN-beta1a (Avonex). This pattern of expression was found to parallel that of beta2-microglobulin and neopterin following injection and was mirrored by a selective activation of peripheral monocytes with respect to upregulation of receptors known to be involved in the inflammatory response (HLA-DR, CD16 and CD86). Injection of saline solution intramuscularly to six healthy control individuals did not produce a similar upregulation of any of the inflammatory markers investigated. Following IFN-beta1a injection, all inflammatory responses were attenuated at week 12 of therapy in comparison to those following the initial injection in a group of follow-up patients. In addition, IFN-beta1a injected on a weekly basis did not produce a sustained modulation of any of the markers investigated in patients treated for 32 weeks.


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Postby OddDuck » Mon Feb 14, 2005 4:48 am

Hi, NHE!

Yes, I know there are many studies regarding how the interferons affect "inflammation" (that would be for RRMS). Progressive MS doesn't involve inflammation the way RRMS does, and the study I posted spoke about things that didn't involve inflammation processes, either.

The HPA axis doesn't involve "inflammation" per se, and IL10 (which is technically an interleukin) also has to do with the strength of the BBB. The same holds true with TNFa (i.e. tumor necrosis factor). It also is not specific for inflammation.

The HPA axis isn't involved that often in RRMS. See what I mean?

If you break down each specific individual cytokine involved in both the innate and the adaptive immune system (whether they are raised or lowered) that the interferons affect and then compare that to the cytokines that NEED to be raised or lowered in progressive MS or even affected at all, you don't get a match with the interferons.

Yes, the interferons ARE effective for "some" (you could probably even say "many") patterns of MS that involve inflammation caused by the immune system. It is progressive MS that I mainly focus on, which exhibits a totally different biological and physiological dysfunction (even though the symptoms exhibited are similar). The first abstract talked about the neuroendocrine system, not the immune system.

Interesting, huh?

Deb
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Postby OddDuck » Mon Feb 14, 2005 5:22 am

You know, here is one of my "frustrations" regarding MS and determining the type of treatment to be on for disease modification. Especially RRMS (there isn't much available yet for progressive MS).

Ok, there is testing that can be done (but is NOT done) on RRMSers called an ELISPOT that will tell doctors exactly what your immune system is doing. It shows which cytokines are increased and which ones are decreased in your body. Different interferons affect the immune system in slightly different ways. They also know which cytokines are affected with each interferon (and with Copaxone).

Ok..........WHY do they NOT perform the ELISPOT on MSers, if only to help determine which drug will best suit individual patients based on exactly what that patient's immune system is doing? AND, they can do the ELISPOT periodically to see how the injectable is affecting the immune system AFTER taking it.

I will never understand that.

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Postby OddDuck » Mon Feb 14, 2005 5:43 am

Ok....let me get back for a second to IL6. IL6 can be a double-edged sword, just like IL4. And this will again show why I think the cytokine levels in MSers should be tested before prescribing any drugs that either inhibit or increase certain interleukins.

This is a great website that I would recommend everyone take a look at when you have time: http://www.copewithcytokines.de/cope.cgi?lex_i

The page where IL6 is described is at: http://www.copewithcytokines.de/cope.cgi?5108

Let's just take a look how IL6 interacts specifically with the HPA axis:

....IL6, like IL1 , stimulates the synthesis of ACTH (Corticotropin ) in the pituitary. Glucocorticoids synthesized in response to ACTH inhibit the production of IL6, IL1 and TNF in vivo, thus establishing a sort of negative feedback loop between the immune system and neuroendocrine functions. In astrocytes IL6 induces the synthesis of NGF.

IL6 is a B-cell differentiation factor in vivo and in vitro (see also: BCDF ) and an activation factor for T-cells (see also: Cell activation ). In the presence of IL2 IL6 induces the differentiation of mature and immature T-cells into cytotoxic T-cells. IL6 also induces the proliferation of thymocytes and probably plays a role in the development of thymic T-cells.
….

Intracerebral overexpression of IL6 in Transgenic mice has been shown to be associated with neurological syndromes the severity of which correlate with the levels of IL6 expression. These mice are characterized by runting, tremor, neurodegeneration, astrocytosis, angiogenesis , and induction of acute-phase proteins production, suggesting a direct pathogenic role of IL6 in inflammatory, infectious, and neurodegenerative CNS diseases (see also: Inflammation ).

Brett et al have used a transgenic mouse model to express IL6 in brain astrocytes. They demonstrate an extensive break down of the blood brain barrier. Depending upon expression levels and age the animals show a leptomeningeal inflammatory infiltrate, vacuolated astrocytic foot processes and endothelial abnormalities, parenchymal inflammation , gliosis, spongiform change, axonal degeneration and macrophage accumulation.


Just from the above descriptions, we can see how in progressive MS, raising IL6 probably would not be a good thing to do.

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