Over the past decade, clinical evidence has been
accumulating that VD3 and its analogs are effective
in the treatment of Th1 immunity mediated disease.
Our opinion is that RSA is also Th1 immunity
disease. The mechanism of VD3 activity, however,
is not yet fully understood since this vitamin is
pleiotropic. VD3 is thought to exhibit anti-inflammatory
properties, and has been shown to inhibit T
cell proliferation and the production of cytokines,
such as interleukin IL-2 and interferon IFN-γ, and
TNF-α. Some authors have already reported that
VD3 downregulate the production of inflammatory
cytokines, such as IL-1, IL-6 and IL-8, stimulated
with TNF-α and IFN-γ [15,16].
Human naive Th and cytotoxic (Tc) T cells, which
only produce IL-2, may differentiate into Th1/Tc1
or Th2/Tc2 like lymphocytes, characterized by their
cytokine production profile. VD3 has been reported
to inhibit Th1/Tc1 related, but increase Th2/Tc2
associated cytokines in T cells from adults. VD3 also
inhibits not only IL-12 generated IFN-γ production,
but also suppresses IL-4 and IL-13 expression induced
by IL-4 [17,18]. The T cell response to alloantigen
is dependent on T cell receptor activation
and costimulation via engagement of CD28 and
CD40. A short treatment with fusion proteins and
antibodies disrupting these co-stimulatory pathways
has been shown to prevent indefinitely acute
and chronic allograft rejection in rodents and primates,
stimulating the search for low molecular
weight compounds able to achieve tolerance induction
by co-stimulation blockade. The unique
capacity of dendritic cells (DC) to activate naive T
cells correlates with elevated expression of MHC
antigens and costimulatory molecules, rendering
them attractive targets for co-stimulation blockade.
VD3 inhibits the ability of antigen presenting
cells (APCs) to induce T cell activation and downregulate
APCs costimulatory molecules expression
[15,18]. Treatment of human DC during their
differentiation from monocytes in the presence of
GM-CSF and IL-4 with VD3 inhibited markedly the
expression of CD80, CD86 and CD40, and partially of
class II MHC molecules, leading to an immature DC
phenotype characterized by high mannose receptor
and low CD83 expression. The inhibitory effect of
VD3 on DC maturation was comparable to that induced
by IL-10, a cytokine which inhibits APC at
different levels, including secretion of IL-12
[16,18]. The reduced expression of class II MHC and
co-stimulatory molecules decrease the capacity of
DC to activate alloreactive T cells, as determined by
the decreased proliferation and abrogation of IFN-α
secretion in MLR. These results suggest that the
ability of VD3 to decrease expression of co-stimulatory
molecules on human DC might contribute to
its inhibitory effect on APCs dependent T cell activation
and its immunosuppressive properties in allograft
and trophoblast rejection. In the absence of
ConA stimulation, peripheral blood mononuclear
cells (PBMC) did not secrete detectable levels of
IFN-γ. When ConA was employed in the stimulation
of the cells, these cells synthesized detectable
levels of IFN-γ [18]. If VD3 was presented in the
medium, the vitamin significantly suppressed the
ConA stimulated IFN-γ production by PBMC. In
the absence of ConA, PBMC secreted small amounts
of TNF-α. VD3 significantly downregulate the ConA
stimulated TNF-α by PBMC. Pichler et al. [18] used
RT-PCR to investigate the effects of VD3 on the
transcription of cytokines [18]. Although IL-6 and IL-
8 mRNA was detected in the freshly isolated PBMC,
in the PBMC cultured for 24 and 48 hrs in the absence
of ConA stimulation, VD3 decrease the expression of
IFN-γ, IL-8, TNF-α, IL-2 and IL-6 mRNA to below
detectable levels [17,18].
Because effects of VD3 are very similar with
immunomodulatory effects of IL-10, we have tested VD3 on several patients with RSA in preparation for
the next pregnancy. We treated the patients with
VD3 in doses of 5–10 lg/kg of body weight, with or
without immunosuppressive/anticoagulant therapy.
First results of our investigation are very encouraging.
We also believe that VD3 can be usable
as local immunomodulatory drug. Actually, we have
opinion that VD3 can be used for direct treatment
of endometrium in preparation for the pregnancy.
Furthermore, VD3 can be used as immunomodulatory
agent in preparation for IVF/ET or treatment of
preeclamptic and eclamptic patients.
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