MS and TGF-beta

(Transforming Growth Factor Beta)

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The study of TGF-beta revealed interesting aspects general for autoimmune diseases but remained so far void of therapeutic recommendations for MS. At the present stage, the reader is therefore warned against spending too much time on this document, the existence of which is rather explained by the laborous search I have performed. My interest was awoken by a screening for enteral immunomodulation where it was mentioned as a therapeutic approach to Crohn's disease, where the cytokine TGF-beta-2 is claimed to be an important dietary supplement, available also in mothermilk and cowmilk. The amount available in cowmilk was not very high (whatever that might be), and TGF-beta-2 did not survive various preparations of milk - though it remains unknown to me whether this involved pasteurization and if the level was possibly still interesting in, e.g. skimmed milk and youghurt.

The TGF-beta family of proteins are a set of pleiotropic secreted signaling molecules with unique and potent immunoregulatory properties. TGF-beta exists in three isotypes (-1,-2,-3) which may furthermore be active or latent. It has been found that biologically active TGF-beta-1 in serum is reduced in MS patients compared to controls [1,2]. Among its many effects, Both glucocorticoids [3] and IFN-beta [4] have been found to increase the level of this cytokine experimentally but TGF-beta-1 can also induce IL-6 production [5]. Vitamine D3(environmental factors) administration to mice increases was found to increase IL-4 transcripts by 3- to 25-fold and TGF-beta-1 transcripts by 4- to 24-fold [6]. Moreover, it was found that dietary supplementation with fish oil could favourably modulate the expression of TGF-beta [7]. Although any therapeutical approach must currently be considered unsuccessfull, more specific drugs are still searched for. In an experimental study of i.m. dosage, the levels of TGF-beta-1 produced were sufficient to exert immunosuppressive effects, influencing the disease cource of mice with an autoimmune disease [8]. It was also found that experimental autoimmune diabetes can be completely prevented by the paracrine TGF-beta-1 [9].

Mice genetically manipulated to be unable to synthetized TGF-beta often dies intrauterinely, and among the survivors, various autoimmune diseases prevails [10], leading to a fatal course within 6 months, unless the cytokine is supplemented. Except for the intestinal mucosa in Crohn's disease, this factor does not seem to be actually lacking in humans. It deserves attention that cytokine regulation differs between different cell types. TGF-beta is a potent immunomodulator which both promotes and counteracts inflammation [11]. In one study, it was described that "TGF-beta-1 is considered the most important mediator of hepatic fibrogenesis. At the same time, TGF-beta-1 is an immunosuppressive cytokine" [12]. More importantly, TGF-beta is synthetized from many different cells and it is virtually impossible to replace this synthetization with exogenously supplied TGF-beta without getting an undesirable effect in "normal tissues" (see similarities to MMP-I). Finally, the levels of TGF-beta are found to be increased in most ongoing autoimmune lesions, perhaps due to accelerated repair mechanisms, perhaps while this cytokine is not so beneficial as some experimental studies may make us believe, but the upregulation may, of course, simply reflect repairing processes. More confusing is the statement "While TGF-beta-1 expressed early in the disease by T-cells may contribute to inflammatory lesion development, microglial cells may potentially contribute to recovery by expressing immunosuppressive TGF-beta-1 during remission" [13].

Beck et al. [17] found in a longitudinal study on MS that TGF-beta like activity was increased in 87% of patients during the period of regression of the symptoms, suggesting a role in regeneration processes of MS. In many publications, TGF-beta is associated with oral tolerance, where it has been established as a principal mediator [14]. The same reference claims that "clinical therapies based on modulation of this cytokine represent an important new approach to the treatment of disorders of immune function." So far, we are still waiting for these drugs.

In a recent study [15], it was shown that common immunoglobulins are rich in TGF-beta-1 and -2 but absent of TGF-beta-3 and a number of cytokines also investigated. Therapy with immunoglobulines was associated with a moderate increase in the levels TGF-beta-1 & -2 in humans. However, it is doubtful if that explains immunoglobuline's mode of action, since blocking TGF-beta experimentally had no effect on the inhibitory action of these drugs [16].

Revised April 5th, 2001.

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  1. Rollnik JD, Sindern E, Schweppe C, Malin JP. Biologically active TGF-beta 1 is increased in cerebrospinal fluid while it is reduced in serum in multiple sclerosis patients. Acta Neurol Scand 1997;96:101-5.
  2. Mokhtarian F, Shi Y, Shirazian D, Morgante L, Miller A, Grob D. Defective production of anti-inflammatory cytokine, TGF-beta by T cell lines of patients with active multiple sclerosis. J Immunology 1994;152:6003-10.
  3. Almawi WY, Hess DA, Rieder MJ. Multiplicity of glucocorticoid action in inhibiting allograft rejection. Cell Transplantation 1998;7:511-23.
  4. Yasuda CL, Al-Sabbagh A, Oliveira EC, Diaz-Bardales BM, Garcia AA, Santos LM. Interferon beta modulates experimental autoimmune encephalomyelitis by altering the pattern of cytokine secretion. Immunological Investigations 1999;28:115-26.
  5. Mazzarelli P, Scuderi F, Mistretta G, Provenzano C, Bartoccioni E. Effect of transforming growth factor-beta1 on interleukin-6 secretion in human myoblasts. J Neuroimmunology 1998;87:185-8.
  6. Cantorna MT, Woodward WD, Hayes CE, DeLuca HF. 1,25-dihydroxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunology 1998;160:5314-9.
  7. Chandrasekar B, Troyer DA, Venkatraman JT, Fernandes G. Dietary omega-3 lipids delay the onset and progression of autoimmune lupus nephritis by inhibiting transforming growth factor beta mRNA and protein expression. J Autoimmunity 1995;8:381-93.
  8. Piccirillo CA, Chang Y, Prud'homme GJ. TGF-beta1 somatic gene therapy prevents autoimmune disease in nonobese diabetic mice. J Immunology 1998;161:3950-6.
  9. Moritani M, Yoshimoto K, Wong SF, Tanaka C, Yamaoka T, Sano T, Komagata Y, Miyazaki J, Kikutani H, Itakura M. Abrogation of autoimmune diabetes in nonobese diabetic mice and protection against effector lymphocytes by transgenic paracrine TGF-beta-1. J Clin Invest 1998;102:499-506.
  10. Letterio JJ, Geiser AG, Kulkarni AB, Dang H, Kong L, Nakabayashi T, Mackall CL, Gress RE, Roberts AB. Autoimmunity associated with TGF-beta1-deficiency in mice is dependent on MHC class II antigen expression. J Clin Invest 1996;98:2109-19.
  11. Song XY, Gu M, Jin WW, Klinman DM, Wahl SM. Plasmid DNA encoding transforming growth factor-beta1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model. J Clin Invest 1998;101:2615-21.
  12. Buschenfelde KH, Dienes HP, Lohse AW. Transforming growth factor-beta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity. J Hepatology 1998;28:803-11.
  13. Kiefer R, Schweitzer T, Jung S, Toyka KV, Hartung HP. Sequential expression of transforming growth factor-beta1 by T-cells, macrophages, and microglia in rat spinal cord during autoimmune inflammation. J Neuropathol Exp Neurol 1998;57:385-95.
  14. Letterio JJ, Roberts AB. Regulation of immune responses by TGF-beta. Ann Review Immunology 1998;16:137-61.
  15. Kekow J, Reinhold D, Pap T, Ansorge S. Intravenous immunoglobulins and transforming growth factor b. Lancet 1998;351:184-5.
  16. Van Schalk N, Vermeulen M, Brand A. Intravenous immunoglobulins and transforming growth factor b. Lancet 1998;351:1288.
  17. Beck J, Rondot P, Jullien P, Wietzerbin J, Lawrence DA. TGF-beta-like activity produced during regression of exacerbations in multiple sclerosis. Acta Neurol Scand 1991;84:452-5.
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Revised April 4, 2001