MS and TGF-beta
(Transforming Growth Factor Beta)
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  and IFN-beta  have been found to increase the
level of this cytokine experimentally but TGF-beta-1 can also induce IL-6
production . 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
. Moreover, it was found that dietary supplementation with fish oil
could favourably modulate the expression of TGF-beta . 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
. It was also found that experimental autoimmune diabetes can be completely
prevented by the paracrine TGF-beta-1 .
Mice genetically manipulated to be unable to synthetized
TGF-beta often dies intrauterinely, and among the survivors, various autoimmune
diseases prevails , 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 . 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" . 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" .
Beck et al.  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 . 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 , 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 .
Revised April 5th, 2001.
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Revised April 4, 2001