Immunomodulation by dydrogesterone
Expert discusses novel therapy for pregnancy failure
Until recently, there was little doctors could do to deal with recurrent spontaneous abortion (RSA). While chromosomal defects, hormonal problems, or abnormalities of the uterus provide some answers, 60 percent of the time the etiology is unknown. New research, however, suggests that "unexplained" losses may be attributable to immunologic factors--and with these factors in mind, some therapies are enabling those affected to carry a baby to term.
"For the last two to three decades people have been looking at the cell-mediated or cellular immune etiology of pregnancy failure," said Dr. Raj Raghupathy, professor of immunology at Kuwait University and fellow of the Royal College of Pathology in the United Kingdom. "And in the last 10 years or so, a great deal of attention has been focused on cytokine-mediated pregnancy loss, mainly Th1 and Th2 cytokines." Raghupathy spoke in a symposium organized by Solvay Pharma during the annual convention of the Philippine Obstetrical and Gynecological Society.
Cytokines and immune regulation
Cytokines are secreted molecules involved in the development of humoral and cell-mediated responses; cell proliferation, differentiation, and apoptosis; hematopoiesis and wound healing; and mediation of inflammatory responses.
Type 1 responses (Th1), mediated by the cytokines IFN-gamma, IL-2, TNF beta, and TNF alpha, are generally involved in inducing strong cellular-mediated immune (CMI) responses while weakly affecting humoral immune (HI) responses. Type 2 responses, on the other hand, are mediated by IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. They exert strong HI responses while suppressing CMI response.
Anecdotal references point to an increased Type 2 reactivity during normal pregnancy, noted as a weakening or down-regulation of CMI response while the HI response is conversely enhanced.
Fetoplacental tissues are also known to secrete Th2 cytokines, with an increase in the number of IL-4 producing T cells and decreasing levels of IFN and IL-2-producing cells.
On the other hand, since Th1 cytokines are involved in allograft rejection, delayed-type hypersensitivity, and in mediating the response to autoimmune diseases, they have an important role in pregnancy. Said Raghupathy: "Th1 reactivity was proposed to be antagonistic to successful pregnancy, and that is a fact shown [by] research over the years."
For example, TNF alpha, IFN-gamma, and IL-2 were all shown to induce abortion in rodent models, while TNF and IFN both caused apoptosis of trophoblast cells and prevented their outgrowth. A higher expression of IFN-gamma and IL-2 was also noted among women with unexplained recurrent abortion.
Dydrogesterone immunomodulation
Over the years, investigators have identified natural molecules that appear to modulate the immune response during pregnancy. Since 1975, progesterone has captured the imagination as one of nature's immunosuppressants, with varied effects at CMI suppression. More recently, its immunomodulatory effects have been de-monstrated against the Th1 cytokines TNF-alpha, IFN-gamma, and IL-2.
Tested the effects of dydrogesterone (Duphaston) on Th1 and Th2 cytokine production by mitogen-activated lymphocytes among women with unexplained RSAs, Raghupathy and his colleagues saw a profound inhibition of the Th1 cytokines IFN-gamma and TNF-alpha.
Among the Th2-type cytokines, on the other hand, progesterone and dydrogesterone clearly upregulated the production of IL-4 and IL-6, the "good cytokines." Substituting the values to determine the Th1-and-Th2 ratio, where a higher ratio shows stronger Th1 bias, there was a dramatic switch in the Th1-Th2 ratio in the presence of Duphaston. Also, the discovery of progesterone-induced blocking factor (PIBF) showed that it helps reverse the abortion rate by suppressing specific CMI responses. Normally produced by lymphocytes upon induction with progesterone, PIBF could be induced by dydrogesterone in a dose-dependent manner, as shown in rodent models. Conversely, PIBF production can be reversed with the progesterone antagonist RU-486. "In other words, [it was] shown that when you add Duphaston to lymphocytes, you produce PIBF, and that this production is via the progesterone receptor," explained Raghupathy.
Concluded Raghupathy: "Duphaston redirects or modulates cytokine production in such a way that it shifts the balance from a Th1 towards a Th2 bias, leading us to suggest that Duphaston may have a great potential in shifting harmful maternal immune reactivity towards a more conducive immunologic environment in pregnancy. We know that dydrogesterone as an orally administered drug has a proven efficacy in a variety of gynecological conditions, a very good safety record, and extensive worldwide use."
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