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98The Immune System in Pregnancy: Friend or Foe?June 2009Fig. 1: The possible influences of maternal Th1 and Th2 immunereactivity on pregnancy. Th1-type cytokines acting directly andvia effector cells such as activated macrophages, activated natural(NK) cells and lymphokine-activated killer (LAK) cells may lead topregnancy complications and pregnancy loss. On the other hand,Th2 cytokines, progesterone, progesterone-induced blockingfactor (PIBF), cytokines such as IL-3, GM-CSF and CSF-1 that haveplacental growth-promoting properties help prevent Th1-mediateddeleterious effects on the conceptus.manipulating the cytokine balance so as to downregulatepro-inflammatory cytokines such as IFNγand TNFα; this is expected to create an environmentthat is more conducive to the success of pregnancy.One approach would be to use a hormone suchas progesterone, which has been shown to haveanti-inflammatory and immunosuppressiveproperties [62] . Piccinni and colleagues demonstratedthat progesterone induces the development ofhuman T cells producing Th2 cytokines [20] . Theypropose that as the Th1 cytokines IFNγ and TNFαmay compromise pregnancy, the production of Th1-inibitory Th2-type cytokines may allow allografttolerance and fetus survival and that progesteronemediatedimmunosuppression is needed for the“natural” maintenance of normal gestation.These observations inspired us to investigatedydrogesterone (6-dehydro-9β, 10α-progesterone)for potential immunomodulatory properties.Dydrogesterone is a potent orally-administeredprogestogen, similar to endogenous progesterone inits molecular structure and pharmacological effects,with a high affinity for the progesterone receptor.We exposed lymphocytes from women with RSM orwith PTD to the progestogens, dydrogesterone andprogesterone, and observed that dydrogesteronebrings about a significantly reduced secretionof the Th1 cytokines IFN-γ and TNF-α, as doesprogesterone. On the contrary, levels of IL-4 and IL-6,both Th2 cytokines, are significantly elevated in thepresence of dydrogesterone or progesterone. Thus,the levels of Th1 cytokines decreased significantlywhile levels of Th2 cytokines increased significantlywhen cells were exposed to dydrogesterone orprogesterone [23] . We found a marked reductionin the ratios of Th1 to Th2 cytokines indicating adecrease in Th1 cytokine bias in lymphocytes fromboth women with RSM [23] and with PTD [24] .In order to ascertain whether dydrogesterone andprogesterone mediate their cytokine-modulatingeffects via the progesterone receptor, we tested theinfluence of the progesterone-receptor antagonist,RU486 on cytokine modulation by dydrogesteroneand progesterone. Since RU486 competes withprogesterone (and dydrogesterone) for theprogesterone-receptor, if the addition of RU486reverses the effects of these substances, it wouldindicate that dydrogesterone and progesterone haveto interact with the progesterone-receptor in orderto affect cytokine production. When PBMC fromsubjects with unexplained RSM were cultured withdydrogesterone or progesterone in the presence orabsence of RU486, we observed increased levels ofIFN-γ and TNF-α which are otherwise suppressedby dydrogesterone and progesterone, and decreasedlevels of IL-4 and IL-6 which are otherwiseupregulated by dydrogesterone and progesterone.Thus RU486 reverses the effects of dydrogesteroneindicating that the effect of dydrogesterone andprogesterone is mediated via the progesteronereceptor [23] .Our data based on laboratory studies indicatethat significantly lower levels of the Th1-typecytokines IFN-γ and TNF-α are produced bylymphocytes exposed to dydrogesterone. Thesetwo cytokines have been shown to deter embryodevelopment, implantation events and proliferationof the trophoblast [54] and to have apoptotic effectson human trophoblast cells [36] . In animals, thesecytokines bring about fetal demise when injectedduring gestation [34] . Furthermore, IFN-γ and TNF-αmay mediate placental / fetal damage via activationof NK activity and macrophages [52] , both of whichin their activated states have been shown to havedeleterious effects on the embryo. Thus, studiesdemonstrating an association between high levelsof these Th1 cytokines and unexplained RSMindicate a potential benefit in down-regulating theirproduction.We found that IL-4 and IL-6, both Th2 cytokines, areupregulated in the presence of dydrogesterone [23,24] .Increased production of IL-4 has been shown to favorfurther Th2 bias which would affect the eventualoutcome of Th1/Th2 dichotomy [3,4] . It is relevant tonote that progesterone has been shown to promotethe differentiation of T cells into Th2 effectors and is