Role of immunoregulator factors in the modulation of maternal-alloresponse to fetal antigens: implications in recurrent pregnancy failures.

R. RAMHORST 1, G. GUTIERREZ, V.E. GARCÍA, GIL MOR, D. SCHUST, G.A. RABINOVICH AND L. FAINBOIM

Mangueritiba, Angras Do Reis, Brazil

Conferencia; First Satellite Symposium on Reproductive Immunology; 2007

Chemokines and cytokines are required to preserve immune privileged sites. For example,  it has been widely demonstrated in murine models that RANTES is implicated in the induction of tolerance: antigens injected into the eye induced RANTES production by CD1d-stimulated murine NKT cells and the recruitment of immune effector cells involved in a tolerogenic response. Therefore, we investigated whether RANTES might contribute to feto-maternal tolerance, allowing a succesfull implantation and fetal survival. Moreover, we studied the modulation of RANTES by immunoregulators factors present during/after implantation (progesterone and paternal allontigens). We observed that progesterone significantly increased intracellular RANTES expression in CD4+ and CD8+ endometrial T-cells from fertile women. Furthermore, RANTES secretion levels from alloreactive lymphocytes to paternal antigens from patients with recurrent spontaneous abortions (RSA) were significantly lower than the levels produced by control women.  These results might suggest the existence of natural maternal immunologic deficiencies and/or potential breaks into maternal tolerance. At the local level, edometrial cells treated with recombinant RANTES induced a decrease in CCR5 and CXCR4 mRNA, that correlated with an increase in T-bet expression. In addition, although pre-implantation endometrium-cells from fertile women and RSA patients produced RANTES, RSA patients showed a differential autocrine response to RANTES, demonstrated by a differential expression of its receptors (CCR1, CCR3 and CCR5). Studies performed in co-cultures of PBMCs from RSA patients and the trophoblast cell line (Swan-71) showed a differential kinetic of RANTES production by troblastic cells compared to fertile women, and a correlation with the generation of a cytokine-proinflammatory microenvironment. Moreover, in RSA patients co-cultures systems, RANTES induced apoptosis of trophoblastic cells but not CD3+ T cells. Interestingly, RANTES displayed the opposite effect in fertile co-cultures. Then, our results suggest that RANTES is implicated in the control of alloreactive-lymphocytes. RANTES can be also related with pro-inflammatory effects. Since high levels of fetal losses of CBA/J x DBA/2 abortion murine model are associated to an exacerbated inflammatory response, we evaluated RANTES sera levels at local and systemic compartment and its modulation by alloantigens and progesterone in this high-resortion-model. Our results showed deficient RANTES sera levels in nulliparous CBA/J females, whereas pregnancies with male BALB/c or DBA/2 increased RANTES production.  Primiparous CBA/J females were high producers of progesterone that could induced high levels of RANTES at feto-maternal interface, correlating with a strong Th1 response. This deleterious effect was abrogated after multiple pregnancies. Hence, under the asumption that during the early phase of pregnancy, a successful implantation occurs followed by a local proinflammatory and Th1-type of response, subsequently controlled by a Th2-type, high levels of progesterone and alloantigens might induce an increase production of RANTES in endometrial T lymphocytes, promoting a Th1 cytokine response at the local compartment, which may be essential for implantation, however and exacerbated placental expression could be associated to high resorption rate. Therefore, the altered response to RANTES evidenciated in RSA patients could be responsible for poor pregnancy outcome and the RANTES-beneficial effect on feto-maternal interface might require an optimal concentration range modulated by progesterone.