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Roles of cytokines and immune cells at the interface-a workshop report (CROSBI ID 738996)

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Rukavina, Daniel ; Vince, Gill Roles of cytokines and immune cells at the interface-a workshop report // Placenta. 2000. str. S97-S98-x

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Rukavina, Daniel ; Vince, Gill

engleski

Roles of cytokines and immune cells at the interface-a workshop report

At the maternal-fetal interface the feto-placental unit (FPU) tissues, primarily various subsets of trophoblast cells, come into direct contact with the maternal decidua which is heavily infiltrated with maternal immunocompetent cells. The FPU is a true semiallogeneic allograft since part of its antigenic structure is inherited from the father, and these antigens are at least partially unknown to the maternal immune system. The FPU allograft in humans survives for nine months in an immunologically hostile environment, essentially without any overt sign of rejection. The interface is also exposed to maternally acquired infectious agents and pathological processes, but as a rule there are no signs that immune functions are compromised. The aim of the workshop was to highlight the main immunological factors and mechanisms acting at the maternal-fetal interface. It is generally thought that the continuous layer of trophoblast cells serves as a physical barrier preventing, although not completely, materno-fetal cell exchange including immunocompetent cells. The precise frequency and extent of leukocyte exchange is still unknown. Dr. Anne Croy's group (Guelph, Canada) showed that, in mice, maternal cell transfer to the fetus is a normal event during pregnancy. Maternal cells cross the placenta and chimerism appears in the bone marrow ; in immune deficient (SCID) fetuses this occurs first at day 12.5 and persists postnatally until 7 weeks, and in immune competent fetuses at day 16.5 and persists 2 weeks postnatally. Persistence of maternal cells in bone marrow suggests their role in hematopoiesis and/or development of bone marrow architecture. Many substances are produced at the interface and contribute to the wellbeing of the FPU such as cytokines, prostaglandins, hormones as well as various proteins of pregnancy with immunosuppressive functions. In physiological conditions, trophoblast are protected against complement attack by the presence of complement regulatory proteins (CD46, CD55 and CD59) (Tedesco et al., 1993). Francesco Tedesco (Trieste, Italy) discussed the contribution of the terminal complex of the complement system to placental damage in patients with pre-eclampsia and with repeated spontaneous abortions, showing subendothelial deposits of this complex on the vessel wall. He also reported data on the local synthesis of complement components by endothelial and trophoblast cells. Decidual large granulated lymphocytes (dLGL) are the most prominent population of lymphoid cells in the first trimester pregnancy decidua, with an NK like phenotype (CD3-CD16-CD56bright). Their numbers peak during the first trimester of pregnancy, where they account for almost 80% of the total leukocyte population. Their role in this phase of the pregnancy could be to contribute to the control of cytotrophoblast invasion of the placental bed (Croy et al. 1997). Ann Croy addressed the question as to whether the murine uterine NK (uNK) cell lineage can self renew within the uterus. Mice (tg 26) whose bone marrow cannot produce either NK cells or T cells were used as recipients of uterine tissue containing immature NK cells. Two different donor strains were used, normal mice with a wildtype genotype and SCID mice that lack T and B cells but have NK cells. Small segments of intact donor uterus were placed into the recipient’ s uterine horn, and a week later the recipients were mated and their uteri were studied at day 10 of gestation. Deciduomata devoid of any NK cells was found. In control, wildtype animals, similarly grafted tissues contained either deciduomata with NK cells or an implantation site with full development of a placenta and aggregations of lymphocytes containing NK cell. Thus peripheral sites and not the uterine tissue itself maintain the progenitor pool for uNK cells. During murine pregnancy uterine NK cells are the main source of interferon-gamma which contributes to normal health of midgestational decidua (Ashkar and Croy, 1999). Ali Ashkar (Guelph, Canada) from Dr. Croy’ s laboratory, examined the contribution of IRF-1 (Interferon regulatory factor - 1), a transcription factor induced by IFN- , to the abnormal morphology of implantation sites seen in mice lacking uNK cells. There was a very close phenotypic parallel between uNK cell deficient mice and IRF-1 null mice: small placental size, failure to modify the spiral arteries and lack of decidual cellularity. In all other studies of IRF-1 null mice, the absence of IL-15 transcription has been implicated as important for the phenotype. However, abundant IL-15 mRNA was demonstrated in the decidua of pregnant IRF-1 null mice, suggesting there may be an unusual, IRF-1 independent form of IL-15 regulation within the pregnant uterus. NK cell cytoxocity towards trophoblast is prevented by expression of HLA-G (nonclassical class I molecule) on the trophoblast and HLA-G specific "killer inhibitory receptors" (KIRs) on decidual NK cells (Lanier, l999). Dr. Bürk (Basel, Switzerland) showed that inhibitory receptor for HLA-E (CD94) is significantly elevated on LGL derived from term placentae (Bürk et al., 1999). CD94/NKG2A responds strongest to HLA-E loaded by the HLA-G leader peptide, which suggests that this molecule could be a major contributor to maternal tolerance of the fetal trophoblast. Previous data regarding the presence of HLA-G on monocytes stimulated with IFN- or IFN- plus GM-CSF had given rise to the question whether macrophages in the decidua, where cells producing these cytokines are present, express HLA-G. Peter Sedlmayr (Graz, Austria) was not able to demonstrate HLA-G on decidual macrophages using flow cytometry and laser scanning microscopy (Sedlmayr et al., 1999). The current dogma in reproductive immunology (first proposed by Wegmann et al., 1993) is that in pregnancy potentially harmful Th1 (cell mediated responses) are suppressed whereas Th2 (antibody mediated) responses are normal. This is believed to be brought about by the release of Th2 cytokines by the placenta which alters the balance of Th1/Th2 cytokines in the mother, leading to suppression of Th1 responses. Ian Sargent (Oxford, UK) discussed new evidence that is emerging which suggests that this concept is an over simplification and that while adaptive immune responses are suppressed in pregnancy innate immune (inflammatory) responses are activated (Sacks et al., 1999). This evidence comes from flow cytometric studies of intracellular cytokine production by peripheral blood cells in pregnancy. While CD4+ lymphocytes and CD56+ NK cells from pregnant women were found to have reduced levels of Th1 cytokine (IFN- ) production compared to non-pregnant women (in agreement with Wegmann’ s hypothesis), their monocytes showed normal levels of production of the pro-inflammatory cytokine TNF- and significantly increased production of IL-12. Further studies of other markers of inflammation showed significantly increased levels of CD11b, CD64 and iROS in the monocytes and granulocytes of pregnant women. The reason for this activation of the innate immune system in normal pregnancy is unknown but it may act as a compensatory mechanism to deal with infections in women whose T cell mediated immunity is suppressed. Daniel Rukavina then outlined the physiological significance of the pleiotropy and redundancy of IL-2 and IL-15, particularly at the interface. There is almost complete absence of IL-2 and high affinity IL-2 receptor at the interface, but IL-15 is present. While IL-2 is predominantly produced by activated T cells, IL-15 appears to be produced by a variety of cells and tissues but not T cells. Cytolytic molecule pore forming protein (Perforin) is present at the interface in much higher quantities than in any other place either in physiological or pathological conditions. Perforin is constitutively expressed in dLGL in high concentrations and the phenotype of these cells is CD3-CD16-CD56bright Pbright (Rukavina et al., 1995). IL-15 upregulates cytolytic machinery (perforin expression) of decidual lymphocytes (DL), but not functional cytolytic potential of these cells against NK sensitive line K562. Cytolytic potential is enhanced by stimulation of NK cells with IL-2, IL-12 and IL-12 + IL-15 (Natasa Strbo, Rijeka, Croatia), all Th1 type cytokines that may prevail during infections and pathological pregnancies (Strbo et al., 1999). Decidual macrophages, probably in a paracrine manner, influence perforin expression and cytolytic activity of DL. Immunocytochemical analyses showed that IL-15+ cells are in the fraction of decidual adherent cells, probably among macrophages (Vlatka Sotosek, Rijeka, Croatia). Progesterone is produced locally, at the maternal-fetal interface, in much higher concentrations than that found in peripheral blood of pregnant women. Immunosuppressive actions of progesterone are mediated by progesterone-induced blocking factor (PIBF), a 34 kDa molecule produced by human pregnancy lymphocytes or activated peripheral blood lymphocytes. Gordana Laskarin (Rijeka, Croatia) presented results showing that CD56+ decidual lymphocytes are mostly PIBF positive as well. Both progesterone and PIBF blocked perforin expression in both decidual and peripheral blood lymphocytes cultured with decidual adherent cells or their supernatant (Laskarin et al., 1999). Discussion suggests a particular importance of controlled HLA class I antigens expression, both classical and nonclassical, on extravillous cytotrophoblastic cells and induction of expression of inhibitory receptors on cytolytic effector cells (both NK and T lymphocytes). Cytolytic cells at the interface are overwhelmed with cytolytic armamentarium and their function is suppressed during normal pregnancy by KIRs, hormones and Th2 type cytokines. If protective barrier is breached by infectious agents (virally infected or otherwise parasitized cells) or abnormal immune activation (pathological pregnancies, malignant transformation) a strong Th1 immune response is required for immune clearence of the invading agents or transformed cells. This response may come at the cost of loss of the fetus. These and other questions raised during discussion are supposed to be the main research interests in the near future.

Pregnancy; Decidua; Cytokines; Progesterone

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Podaci o prilogu

S97-S98-x.

2000.

nije evidentirano

objavljeno

Podaci o matičnoj publikaciji

Placenta

0143-4004

Podaci o skupu

Nepoznat skup

ostalo

29.02.1904-29.02.2096

Povezanost rada

Kliničke medicinske znanosti

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