The Role of IL4 in MS (Antegren vs. Aimspro)

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

The Role of IL4 in MS (Antegren vs. Aimspro)

Postby OddDuck » Sat Oct 16, 2004 5:40 am

I have a question to throw out there. (Wesley, I hope you read this also, this should be a good exercise for you.)

IL4 and its role in MS is very controversial right now. I have my own opinion on it, but I'd be interested to see what others think.

I see two very distinct totally opposite theories regarding MS therapy between two of the newest drugs. Antegren and Aimspro. A goal of Antegren is to decrease IL4 in MS. A goal of Aimspro is to increase IL4.

I'm going to paste some publications here. If anyone has an opinion, please post!! Thanks!

Warning: The choice of these particular posts are designed to make you "think" really hard, and probably have to do some additional research on your own. :wink: There is no right or wrong answer, either. I'm just curious as to people's thoughts.

The bottom line poll question here is: Do you think IL4 should be increased or decreased in MS?

Deb

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J Immunol. 2004 Oct 1;173(7):4529-38. Related Articles, Links

Transcription of Ig germline genes in single human B cells and the role of cytokines in isotype determination.

Fear DJ, McCloskey N, O'Connor B, Felsenfeld G, Gould HJ.

The Randall Center, King's College London, United Kingdom.

We have developed a critical test of the chromatin accessibility model of Ig isotype determination in which local unfolding of chromatin higher order structure (chromatin accessibility) in the region of specific germline genes in the H chain locus determines the Ab class to be expressed in the B cell. We show that multiple germline genes are constitutively transcribed in the majority of naive human B cells in a population. Thus, because chromatin in its higher order structure cannot be transcribed, the entire Ig H chain locus must be unfolded in naive B cells. We have also established that IL-4 and anti-CD40 act by enhancing transcription in the majority of cells, rather than by activating transcription in more of the cells. Transcriptional activity in the human H chain locus rules out the perturbation of chromatin higher order structure as a factor in isotype determination. We have also found that the levels of germline gene transcription cannot fully account for the levels of secretion of the different Ig isotypes, and that secretion of IgE, in particular, is suppressed relative to that of IgG.

PMID: 15383585 [PubMed - in process]

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J Immunol. 2004 Oct 1;173(7):4561-7. Related Articles, Links


IL-4-induced gene-1 is a leukocyte L-amino acid oxidase with an unusual acidic pH preference and lysosomal localization.

Mason JM, Naidu MD, Barcia M, Porti D, Chavan SS, Chu CC.

Gene Therapy Vector Laboratory, North Shore-Long Island Jewish Research Institute, Department of Medicine, North Shore University Hospital and New York University School of Medicine, Manhasset, NY 11030, USA.

IL-4-induced gene-1 (Il4i1 or Fig1) initially isolated as a gene of unknown function from mouse B lymphocytes, is limited in expression to primarily immune tissues and genetically maps to a region of susceptibility to autoimmune disease. The predicted Il4i1 protein (IL4I1) sequence is most similar to apoptosis-inducing protein and Apoxin I, both l-amino acid oxidases (LAAO; Enzyme Commission 1.4.3.2). We demonstrate that IL4I1 has unique LAAO properties. IL4I1 has preference for aromatic amino acid substrates, having highest specific activity with phenylalanine. In support of this selectivity, IL4I1 is inhibited by aromatic competitors (benzoic acid and para-aminobenzoic acid), but not by nonaromatic LAAO inhibitors. Il4i1 protein and enzyme activity is found in the insoluble fraction of transient transfections, implying an association with cell membrane and possibly intracellular organelles. Indeed, IL4I1 has the unique property of being most active at acidic pH (pH 4), suggesting it may reside preferentially in lysosomes. IL4I1 is N-linked glycosylated, a requirement for lysosomal localization. Confocal microscopy of cells expressing IL4I1 translationally fused to red fluorescent protein demonstrated that IL4I1 colocalized with GFP targeted to lysosomes and with acriflavine, a green fluorescent dye that is taken up into lysosomes. Thus, IL4I1 is a unique mammalian LAAO targeted to lysosomes, an important subcellular compartment involved in Ag processing.

PMID: 15383589 [PubMed - in process]

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J Immunol. 2004 Oct 1;173(7):4433-42. Related Articles, Links


Human plasmacytoid dendritic cells activated by CpG oligodeoxynucleotides induce the generation of CD4+CD25+ regulatory T cells.

Moseman EA, Liang X, Dawson AJ, Panoskaltsis-Mortari A, Krieg AM, Liu YJ, Blazar BR, Chen W.

University of Minnesota Cancer Center and Department of Pediatrics, and Division of Hematology, Oncology, and Bone Marrow Transplantation, Minneapolis, MN 55455, USA.

Plasmacytoid dendritic cells (PDCs) are key effectors in host innate immunity and orchestrate adaptive immune responses. CpG oligodeoxynucleotides (ODN) have potent immunostimulatory effects on PDCs through TLR9 recognition and signaling. Little is known about the effects of CpG ODN on human PDC-mediated T cell priming. Here we show that type B CpG ODN effectively promotes PDCs to prime allogeneic naive CD4(+)CD25(-) T cells to differentiate into CD4(+)CD25(+) regulatory T (Treg) cells. The CD4(+)CD25(+) T cells induced by CpG ODN-activated PDCs express forkhead transcription factor 3 and produce IL-10, TGF-beta, IFN-gamma, and IL-6, but low IL-2 and IL-4. These CD4(+)CD25(+) T cells are hyporesponsive to secondary alloantigen stimulation and strongly inhibit proliferation of autologous or allogeneic naive CD4(+) T cells in an Ag-nonspecific manner. CpG ODN-activated PDCs require direct contact with T cells to induce CD4(+)CD25(+) Treg cells. Interestingly, IL-10 and TGF-beta were undetectable in the supernatants of CpG ODN-stimulated PDC cultures. Both CpG-A and CpG-C ODN-activated PDCs similarly induced the generation of CD4(+)CD25(+) Treg cells with strong immune suppressive function. This study demonstrates that TLR9 stimulation can promote PDC-mediated generation of CD4(+)CD25(+) Treg cells and suggests PDCs may play an important role in the maintenance of immunological tolerance.

PMID: 15383574 [PubMed - in process]

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Immunol Allergy Clin North Am. 2004 Nov;24(4):599-614. Related Articles, Links


Anti-interleukin-4 therapy.


Steinke JW.

Asthma and Allergic Diseases Center, Bierne Carter Center for Immunology, University of Virginia Health System, Lane Road, MR4 Building, Room 5031, Box 801355, Charlottesville, VA 22908-1355, USA.

Interleukin 4 (IL-4) mediates important pro-inflammatory functions in asthma, including T helper cell type 2 lymphocyte differentiation, induction of IgE production, up-regulation of IgE receptors, expression of vascular cell-adhesion molecule 1, promotion of eosinophil transmigration into the lungs, inhibition of T-lymphocyte apoptosis, and mucus hypersecretion. The role of IL-4 in the pathogenesis of asthma is supported by identification of polymorphisms linked to asthma in the IL-4 gene promoter and proteins involved in IL-4 signaling. Several approaches to IL-4 antagonism are or have been in clinical development. This article examines IL-4 and the antagonists that have been developed. Early trial results and the future of anti-IL-4 therapy are discussed.

PMID: 15474861 [PubMed - in process]

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Postby Nemotoday » Tue Oct 19, 2004 7:42 am

Hi OddDuck,

You say "A goal of Antegren is to decrease IL4 in MS. A goal of Aimspro is to increase IL4".

Not having seen any published material for peer review, or any other for that matter on "Aimspro", I am wondering if you could either publish here or direct me to the source of your most interesting argument.

I am fascinated as what the "Aimspro" mechanism of action might be and would really appreciate your help with this.

Kindest Regards

Nemo



:D :D
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Postby OddDuck » Tue Oct 19, 2004 8:32 am

Hi. I'll do this sort of quickly, so it may not be the best correlations.

Aimspro (goat serum) increases levels of IL-4 (which IS part of the TH2 response, BUT there is controversy about whether IL-4 helps or hurts MS). I could probably do better with finding all of the substantive material on this, but for now this should do. (The intent of the exercise was for people to research this themselves. :wink: )

Antegren inibits VCAM-1 and Alpha 4 integrin, thereby decreasing levels of IL-4.

I hope this helps. If you do a search, you can probably find more and perhaps better correlations than this (and perhaps even better ones). I'm doing this on the fly, as they say. :P My good research on this is not with me here. (I came across this originally when I did my research regarding desipramine.)

Deb

Goat serum:

J Exp Med. 2004 Oct 4;200(7):857-70. Related Articles, Links


Basophils Initiate IL-4 Production during a Memory T-dependent Response.

Khodoun MV, Orekhova T, Potter C, Morris S, Finkelman FD.

Dept. of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267. ffinkelman@pol.net.

Experiments were performed to characterize and identify the cellular sources of the secondary interleukin (IL)-4 response to a T cell-dependent antigen. Mice were primed by immunization with goat anti-mouse immunoglobulin (Ig)D antibody (GaMD), which stimulates naive CD4(+) T cells to secrete IL-4 in 3-4 d. When challenged with goat serum 14 d after immunization, GaMD-primed mice generated an IL-4 response that exceeded the primary response by approximately 100-fold, started in <2 h, and lasted for 4 d. Studies with 4get mice, in which cells with an accessible Il4 gene express a green fluorescent protein (GFP), revealed CD4(+) memory T cells, natural killer T cells, basophils, mast cells, and eosinophils as possible rapid producers of IL-4. GFP(+)CD4(+) T cells and basophils expanded more in the spleen than the other cell types during the primary response to GaMD. Quantitation of in vivo IL-4 production by the in vivo cytokine capture assay after individual cell types were selectively stimulated or deleted demonstrated that basophils and memory CD4(+) T cells account for most of the secondary IL-4 response, with basophils initiating that response through IgE/FcepsilonRI-mediated signaling but secreting IL-4 for <4 h and memory T cells secreting IL-4 within 4 h and continuing to secrete this cytokine for 4 d.

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Immunobiology. 1996;196(4):449-62. Related Articles, Links


Down-regulation of Listeria monocytogenes-specific Th1 cytokine response by treatment of mice with goat antibody to mouse IgD.
Song F, Matsuzaki G, Nomoto K.

Department of Immunology, Kyushu University, Fukuoka, Japan.

Injection of goat anti-mouse IgD antibody (G alpha M IgD) to mice has been shown to induce polyclonal IgG1 and IgE production by B cells and IL-4 production by goat Ig-specific T cells. Surface IgD crosslinking also activates function of B cells as antigen presenting cells. Although the G alpha M IgD treatment is a well established system for regulation of immune response against antigens that bind to B cell receptor, we found that the G alpha M IgD treatment also influences immune response against irrelevant bacterial antigen. The T cells from the G alpha M IgD-treated Listeria monocytogenes-infected mice showed increased IL-4 production and decreased IFN-gamma and IL-2 production against listerial antigen compared with those from control L. monocytogenes-infected mice. Interestingly, changes were also found in antigen presenting cells in the G alpha M IgD-treated mice. MHC class II expression of both B cells and macrophages decreased significantly in the G alpha M IgD-treated mice, suggesting cytokine induced by G alpha M IgD-treatment may suppress MHC class II expression and modulate APC function in the G alpha M IgD-treated mice. In accordance with the assumption, T cells from the G alpha M IgD-treated mice produced high amount of IL-4 and IL-10 in in vitro culture with goat serum which contain goat Ig. These result suggest that G alpha M IgD treatment may modulate APC function in the G alpha M IgD-treated mice through Th2 type cytokine(s) produced by goat Ig-specific T cells, which results in changes of Th response against irrelevant antigen.

PMID: 9061384 [PubMed - indexed for MEDLINE]

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Natalizumab (Antegren):

Curr Opin Investig Drugs. 2003 Nov;4(11):1354-62. Related Articles, Links


Natalizumab. Elan/Biogen.

Elices MJ.

PharmaMar USA, 320 Putnam Avenue, Cambridge, MA 02139, USA. melices@pharmamarusa.com

Natalizumab is a humanized monoclonal antibody to alpha 4 beta 1 integrin (VLA-4) currently under development by Elan and Biogen for the treatment of Crohn's disease and multiple sclerosis. Phase II trials in both indications have been completed, and by December 2002 phase III trials in Crohn's disease and multiple sclerosis had been initiated.

Publication Types:
Review
Review, Tutorial

PMID: 14758775 [PubMed - indexed for MEDLINE]

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Drugs R D. 2004;5(2):102-7. Related Articles, Links


Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody.

[No authors listed]

Natalizumab [AN 100226, anti-alpha4 integrin monoclonal antibody, Antegren] is a humanised monoclonal antibody that blocks alpha4beta1 integrin-mediated leukocyte migration. Natalizumab is in phase III trials for the treatment of multiple sclerosis in North America and the UK, and for the treatment of Crohn's disease also in the UK. It may have potential in the treatment of other immune-related inflammatory disease. Elan Corporation intends to examine the potential of natalizumab in rheumatoid arthritis and ulcerative colitis. 4beta1 integrin on circulating leukocytes binds to vascular cell adhesion molecule-1, which is expressed at high levels in the blood vessels in the CNS during exacerbations of multiple sclerosis. This allows leukocytes expressing alpha4beta1 integrin (very late antigen-4) to move from the peripheral blood into the CNS. Inflammatory proteins and other factors released from lymphocytes in the brain lead to the progression of symptoms. A limitation of natalizumab is that it must be injected and cannot be administered orally. Scientists have transformed the large anti-alpha4 monoclonal antibody into much smaller, drug-like molecules suitable for oral administration. Protein Design Labs has granted a worldwide nonexclusive licence under its antibody humanisation patents to Elan Pharmaceuticals for natalizumab. Biogen Inc. has entered into an agreement with Elan for a worldwide exclusive collaboration to develop, manufacture and commercialise natalizumab for multiple sclerosis and Crohn's disease and rheumatoid arthritis. Development of natalizumab is also being funded, in part, by Axogen (acquired by Elan in 1999). In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Elan repurchased royalty rights on a package of products, including natalizumab, from Autoimmune Disease Research Company. Elan and Genzyme Transgenics Corporation signed an agreement to produce natalizumab in GTC's genetically engineered goats, which will express the compound in their milk. Genzyme Transgenics Corporation changed its name to GTC Biotherapeutics in June 2002; it is no longer a subsidiary of Genzyme Corporation. Following discussions with the US FDA, Elan completed enrolment in a second phase III trial, involving approximately 420 patients with Crohn's disease. This Evaluation of Natalizumab as Continuous Therapy-2 (ENACT-2) trial evaluated the effect of natalizumab on duration of response and remission in patients with Crohn's disease. In January 2004, Elan Corporation and Biogen Idec announced that the phase III, ENACT-2 maintenance trial of natalizumab in Crohn's disease met the primary endpoint of maintenance of response. Elan and Biogen Idec will discuss these data with regulatory authorities in both the US and Europe and determine the appropriate path forward for natalizumab in Crohn's disease. An NDA for Antegren in Crohn's disease was expected to be filed at the end of 2003; however, due to failing to meet the primary endpoint in the induction trial, Elan is unable to predict when and if a regulatory filing will be made. Earlier, on 23 January 2001, the Wall Street Journal reported that the Biogen CEO expects Antegren to become a blockbuster drug, with sales of at least $US1 billion. He also predicted that Antegren could be on the market as early as 2003 for the indication of Crohn's disease and in 2004 for multiple sclerosis. The Journal stated that Biogen is under pressure to develop new drugs since its flagship product Avonex will be losing its US Orphan Drug Act protection in 2003. Antegren has a different mechanism to that of Avonex and could be used either alone or as a combination therapy.

PMID: 15293871 [PubMed - in process]
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Blood. 2002 Apr 15;99( 8 ):2890-6. Related Articles, Links


Human mast cell progenitors use alpha4-integrin, VCAM-1, and PSGL-1 E-selectin for adhesive interactions with human vascular endothelium under flow conditions.


Boyce JA, Mellor EA, Perkins B, Lim YC, Luscinskas FW.

Department of Medicine, Harvard Medical School, Boston, MA, USA.

Mast cells (MCs) are central to asthma and other allergic diseases, and for responses to infection and tissue injuries. MCs arise from committed progenitors (PrMCs) that migrate from the circulation to tissues by incompletely characterized mechanisms, and differentiate in situ in perivascular connective tissues of multiple organs. PrMCs derived in vitro from human cord blood were examined for adhesion molecule expression and their ability to adhere to human umbilical vein endothelial cells (HUVECs) under conditions that mimic physiologic shear flow. The PrMCs expressed alpha(4)beta(1), low levels of beta7, and the beta2-integrins alphaLbeta2 and alphaMbeta2. The PrMCs also expressed PSGL-1, but not L-selectin. At low (0.5 dynes/cm(2)-1.0 dynes/cm(2)) shear stress, PrMCs attached and rolled on recombinant E-selectin and P-selectin and VCAM-1. An anti-PSGL-1 monoclonal antibody (mAb) blocked essentially all adhesion to P-selectin but reduced adhesion to E-selectin by only 40%, suggesting PrMCs express other ligands for E-selectin. PrMCs adhered strongly to tumor necrosis factor-alpha (TNF-alpha)-activated HUVECs, whereas adhesion to interleukin 4 (IL-4)-activated HUVECs was lower. PrMC adhesion to IL-4-activated HUVECs was totally alpha4-integrin- and VCAM-1-dependent. Adhesion to TNF-alpha-activated HUVECs was blocked by 50% by mAbs against alpha4-integrin, vascular cell adhesion molecule-1 (VCAM-1), E-selectin, or PSGL-1, whereas combinations of mAbs to alpha4-integrin plus PSGL-1, or VCAM-1 plus E-selectin, blocked adhesion by greater than 70%. Thus, PrMCs derived in vitro predominantly use alpha4-integrin, VCAM-1, PSGL-1, and other ligands that bind E-selectin for adhesion to cytokine-activated HUVEC monolayers. These observations may explain the abundance of MCs at sites of mucosal inflammation, where VCAM-1 and E-selectin are important inducible receptors.

PMID: 11929779 [PubMed - indexed for MEDLINE]
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Int Immunol. 2002 Feb;14(2):177-87. Related Articles, Links


BCR signal through alpha 4 is involved in S6 kinase activation and required for B cell maturation including isotype switching and V region somatic hypermutation.

Inui S, Maeda K, Hua DR, Yamashita T, Yamamoto H, Miyamoto E, Aizawa S, Sakaguchi N.

Department of Immunology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan.

alpha 4 potentially mediates BCR signals through a rapamycin-sensitive TOR pathway. To investigate a potential role for alpha 4 in B cell activation, the alpha 4 gene was disrupted conditionally in B cells by mating male CD19-Cre mice with female alpha 4-floxed mice. CD19-Cre+/alpha 4flox mice showed loss of alpha 4 protein in B lineage cells and a decreased number of phenotypically normal mature B cells. Compared to normal B cells, alpha 4(-) B cells showed a decreased proliferation in response to the B cell stimulants (anti-IgM antibody plus IL-4, anti-CD40 mAb and lipopolysaccharide), and a reduced S6 kinase activation and rapamycin sensitivity. While CD19-Cre+/alpha 4flox mice showed impaired antibody responses to both T cell-independent and T cell-dependent (TD) antigens, the TD antigen response was markedly impaired as demonstrated by reduced isotype switching, reduced germinal center formation and reduced V region somatic hypermutation. These results show that alpha 4 plays a pivotal role in antigen-specific signal transduction during B cell activation and differentiation in vivo.

PMID: 11809737 [PubMed - indexed for MEDLINE]
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Postby OddDuck » Tue Oct 19, 2004 8:35 am

hmmmmmmmmmm.....I just now ran across this regarding Aimspro. I wonder what's going on???

Investigation of complaints about advertising:
Aimspro (goat serum) advertising on Daval International website - July 2004
Last updated 29/09/04

The website of Daval International Limited was brought to the attention of the MHRA in July 2004. It was alleged that Aimspro, a product that did not have a valid marketing authorisation in force, was being promoted on the website.

The complaint was upheld. The website was subsequently amended to remove promotional elements.

Date complaint raised: 1 July 2004
Date resolved: 13 August 2004
Date of publication: 29 September 2004

Contact for further information
Anyone who has concerns about misleading advertising of medicines should contact the MHRA Advertising Unit, 14-112, Market Towers, Vauxhall, London SW8 5NQ. Alternatively, contact the pharmaceutical self-regulatory bodies, the Proprietary Association of Great Britain (PAGB) for advertising for over the counter medicines, or the Prescription Medicines Code of Practice Authority (PMCPA) for advertisements to health professionals for prescription medicines.
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Postby OddDuck » Tue Oct 19, 2004 8:43 am

Oh, yea.........just FYI. I have no real comment on either drug. I have no idea myself whether or how either of them will work.

My focus was strictly on how IL-4 affects MS, mainly. It was just interesting that these two newest drugs are so basically opposite from each other.

Have a good one!

Deb
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Postby Nemotoday » Tue Oct 19, 2004 2:08 pm

Hi Deb,

Thanks for the reply.

In regard to Aimspro and the papers mentioned by you.

Immunobiology. 1996;196(4):449-62.

"Mice were primed by immunization with goat anti-mouse immunoglobulin (Ig)D antibody (GaMD), which stimulates naive CD4(+) T cells to secrete IL-4 in 3-4 d. When challenged with goat serum 14 d after immunization, GaMD-primed mice generated an IL-4 response that exceeded the primary response by approximately 100-fold, started in <2 h, and lasted for 4 d. Studies with 4get mice, in which cells with an accessible Il4 gene express a green fluorescent protein (GFP), revealed CD4(+) memory T cells, natural killer T cells, basophils, mast cells, and eosinophils as possible rapid producers of IL-4. "

A very interesting piece, but I'm not sure as to how it fits with the Aimspro puzzle, since.

The mice were primed with goat anti mouse Ig D and then challenged it would seem after 14 days with normal commercially available goat serum, we are told that Aimspro is made with a serum extracted from a goat whose immune system has been challenged by some proprietary cocktail (a group of virii perhaps).

With Aimspro, in separating the proteins, to make their product it may well be that the protein or group of proteins that caused the rapid production of IL-4 are separated out and discarded.

I guess that we will have to wait and see, but an interesting question posed by you anyway.

Kindest Regards

Nemo
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Postby OddDuck » Tue Oct 19, 2004 2:40 pm

Nemo,

Exactly. Too many facts are still unknown, huh?

And the IL-4 actions in MS (and/or whether you want that particular cytokine to be increased or decreased in MS) is HIGHLY controversial and not settled, either. It sort of boils down to what I call "selective immunotherapy". Raising some cytokines, lowering others. Not complex at all! 8O HAH! LOL

Yes, it will be interesting to see what else comes down the pike about all this. I was throwing it out there as a topic for discussion is all. Sometimes I'm interested into the "why" behind support of one drug over another, and upon what criteria such support is based, etc.

Thanks, Nemo, for your question and participation!

Best always,

Deb
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Postby BioDocFL » Tue Oct 19, 2004 7:27 pm

OddDuck,
I didn't have time to read all of the abstracts you posted, but several points I could mention in passing:
1) I worked on interleukins briefly, a gene therapy type project where we were transfecting individual IL genes into mouse kidney cells, inserting the cells back under the thin membrane covering another mouse's kidney, let him go for 2 weeks then sacrifice him and look at what T cells, etc. had been recruited to the site. The different interleukins have different effects and there appears to be groupings of interleukins that have similar effects and perhaps work in concert. The problems we always had were: a) getting consistent expression of the interleukin from the cells and being sure it continued when transplanted, b) doing the surgery correctly, typically losing 1/4 or 1/3 of mice due to the delicate skill needed to do it right (working with ether to keep them under was difficult because after two or three mice in a row, the ether was getting to me too), c) knowing whether the interleukin was having an effect or whether there were other complications of the surgery having an effect. It has been quite a while and I did not enjoy that project, felt it was a waste of time and mice so I moved on to something else. What was coming out of other labs at the time was that groups of interleukins work together so that there could be some overlap in effects. Also it was coming out that too high or too low of expression of an interleukin type can have quite opposite effects. I don't remember much of the details of the different interleukins though. Sorry.
2) Gary Felsenfeld, one of the authors, did alot of work on nucleosome dynamics. He held that the 8 histones remain together when the RNA polymerase passes through. My PhD mentor held that the histones can come off in dimers and quatramers giving the nucleosome more dynamics. I don't think it has been resolved. They both have their supporters. I believe my mentor's work but it is probably one of those cases where they are each right in different situations.
3) Now, the thing I really want to get into, the oligodeoxynucleotides stimulating the immune system. That is what I am getting to with my hypothesis. I believe I can give a good explanation and references for what is different about the DNA, even though it is endogenous. Again, it will be relative to lupus primarily but you might be able to visualize something similar going on in MS, just that the immune system doesn't have quite the same accessibility. I will try to get a lot written and posted this weekend on some more of the hypothesis.
Wesley
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Postby OddDuck » Wed Oct 20, 2004 4:46 am

(working with ether to keep them under was difficult because after two or three mice in a row, the ether was getting to me too),


LOL...... :lol: I can imagine!!!

Yea, usually IL-4 and IL-10 work in concert (at least that's what I found from my reading habits..... :wink: ), but they aren't dependent upon one another, which I believe is a good thing in MS for purposes of immune modulation.

The thing is, in MY opinion (and I ran across this while researching the drug desipramine and hence why I went off on sidelines regarding individual cytokines) that you want to raise levels of IL-10 (anti-inflammatory, and it helps to reverse the blood/brain barrier permeability); but lower levels of IL-4 for reasons of inhibiting CD4 attacks on myelin, and IL-4 enhances MHCII binding (APCs), so again, keeping IL-4 lower should (note I say "should", this again is totally unproven, and still controversial) also be adjunctive and beneficial because you definitely want to regulate MHCII. Higher levels of IL-4 correlates with lymphoma, also. Keeping IL-4 on the low end (or perhaps maintaining status quo levels of IL-4 in MS, once it is determined what the optimum levels of IL-4 should be in MS) helps to maintain or increase VIP. Without going into another long dissertation about VIP/PACAP, I'll quote from my original research: VIP/PACAP contributes to the initiation of TH2-type immunity, whereas in the presence of a full-blown, inflammatory reaction, VIP/PACAP act as anti-inflammatory agents.

Keeping the immune system predominantly on the TH2 side of the equation is desirable (from what I can find) in MS (whether that holds true in ALL patterns of MS, is yet to be determined).

Ok....here's the odd part about IL-4. There ARE different suppositions about IL-4 in MS. Copaxone, for one, raises levels of IL-4 and IL-10. Interferon appears to maintain or decrease levels of IL-4. The problem with the interferons in my mind (which is another topic of discussion) is that it was found that over time IFN-beta 1b also increases some pro-inflammatory cytokines, IL-6 for one, which is part of the problem that contributes to the side-effects, and apparently could potentially counteract its beneficial immunomodulatory effects. Odd, huh?

I found that desipramine decreases (or maintains) IL-4 and increases IL-10. Both, in MY sole opinion, to be desirable for MS treatment (or therapy, if it can ever be ascertained via clinical trials on MS).

Plus, this is only pertaining to the immune side of the equation in MS (or some forms of MS). The genetic, environmental toxin, and pathogen sides, which are also pieces of this complex puzzle, aren't even factored in with this.

I still say to clinical researchers everywhere: Do an ELISPOT on each of your MS patients periodically, so we can correlate the findings and see what we come up with! That just MIGHT weed out a few, anyway, of the ongoing theories over cytokines and MS, correct?

Art: Isn't THAT an idea?

hmmmmmmmm..........Deb's putting on her thinking cap again. hehehe...........

Deb
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