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Recurrent spontaneous abortion (RSA) is serious health problem affecting 2–5% of reproducing couples …

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Immunomodulatory effects of VD3
- 1-alpha,25-dihydroxy-vitamin-D3 asnew immunotherapy in treatment ofrecurrent spontaneous abortion

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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