Gordana Laškarin

Cross-Linking of the Mannose Receptor on Monocyte-Derived Dendritic Cells Activates an Anti-Inflammatory Immunosuppressive Program

Immature monocyte-derived dendritic cells (DC) strongly express the endocytic mannose receptor (MR). Addition of a specific anti-MR mAb (clone PAM-1) for 24 h to cultures of immature DC induced phenotypical and functional maturation of the cells, assessed as up-regulation of costimulatory molecules and CD83, and chemotactic response to CCL19. A different isotype-matched anti-MR mAb (clone 19.2) had no significant effect. Engagement of MR with mAb PAM-1 induced the production of the anti-inflammatory cytokines IL-10, IL-1R antagonist, and of the nonsignaling IL-1R type II. In contrast IL-1β, TNF, and IL-12 were not produced. PAM-1-treated DC were unable to polarize Th1 effector cells and did not secrete the chemokines CXCL10 and CCL19; in turn, they produced large amounts of CCL22 and CCL17, thus favoring the amplification of Th2 circuits. T cells cocultured with PAM-1-matured DC initially proliferated but later became anergic and behaved as suppressor/regulatory cells. Natural ligands binding to MR had differential effects. MUC III (a partially purified mucin), biglycan (a purified complex proteoglycan), and mannosylated lipoarabinomannan from Mycobacterium tuberculosis affected cytokine production with high IL-10, IL-1R antagonist, IL-1R type II, and inhibition of IL-12. In contrast, mannan, dextran, and thyroglobulin had no significant effect. In conclusion, the appropriate engagement of the MR by mAb PAM-1 and selected natural ligands elicit a secretory program in mono-derived DC characterized by a distinct profile of cytokines/chemokines with the ability to dampen inflammation and to inhibit the generation of Th1-polarized immune responses.

Antigen-presenting cells and materno-fetal tolerance: an emerging role for dendritic cells

During pregnancy, a delicate balance of innate and adaptive immune responses at the maternal–fetal interface promotes survival of the semi‐allogeneic embryo and, at the same time, allows effective immunity to protect the mother from environmental pathogens. As in other tissues, antigen handling and processing in the decidualized endometrium constitutes a primary event in the onset of immune responses and is therefore likely to determine their stimulatory or tolerogenic nature. Maternal antigen‐presenting cells [macrophages and dendritic cells (DCs)] are scattered throughout the decidualized endometrium during all stages of pregnancy and appear to be important players in this feto‐maternal immune adjustment. This review focuses on the characterization of decidual macrophages and DCs, as well as their involvement in cell–cell interactions within the decidual leukocyte network, which are likely to influence uterine and placental homeostasis as well as the local maternal immune responses to the fetus during pregnancy.

Progesterone-induced blocking factor inhibits degranulation of natural killer cells

PROBLEM: During the first trimester of pregnancy, nonclassical (CD3—, CD56+, CD16—, perforin [P]bright +) natural killer (NK) cells comprise the major decidual lymphocyte population. These cells, in spite of their high perforin content, exert a low cytolytic activity. Peripheral blood lymphocytes of healthy pregnant women produce progesterone‐induced blocking factor (PIBF), which inhibits NK activity. PIBF‐producing cells are likely to be present in decidua and might contribute to low decidual NK activity.

Engagement of the mannose receptor by tumoral mucins activates an immune suppressive phenotype in human tumor-associated macrophages

Tumor-Associated Macrophages (TAMs) are abundantly present in the stroma of solid tumors and modulate several important biological processes, such as neoangiogenesis, cancer cell proliferation and invasion, and suppression of adaptive immune responses. Myeloid C-type lectin receptors (CLRs) constitute a large family of transmembrane carbohydrate-binding receptors that recognize pathogens as well as endogenous glycoproteins. Several lines of evidence demonstrate that some CLRs can inhibit the immune response. In this study we investigated TAM-associated molecules potentially involved in their immune suppressive activity. We found that TAMs isolated from human ovarian carcinoma samples predominantly express the CLRs Dectin-1, MDL-1, MGL, DCIR, and most abundantly the Mannose Receptor (MR). Components of carcinomatous ascites and purified tumoral mucins (CA125 and TAG-72) bound the MR and induced its internalization. MR engagement by tumoral mucins and by an agonist anti-MR antibody modulated cytokine production by TAM toward an immune-suppressive profile: increase of IL-10, absence of IL-12, and decrease of the Th1-attracting chemokine CCL3. This study highlights that tumoral mucin-mediated ligation of the MR on infiltrating TAM may contribute to their immune suppressive phenotype.

Progesterone Induced Blocking Factor (PIBF) Mediates Progesterone Induced Suppression of Decidual Lymphocyte Cytotoxicity

Laškarin G, Tokmadžić VS, Štrbo N, Bogović T, Szekeres‐Bartho J, Randić L, Podack ER, Rukavina D. Progesterone induced blocking factor (PIBF) mediates progesterone induced suppression of decidual lymphocyte cytotoxicity. AJRI 2002; 48:201–209

Progesterone directly and indirectly affects perforin expression in cytolytic cells

Laskarin G, Faust Zs, Štrbo N, SotoŠek V, Szekeres‐Bartho J, Podack ER, Rukavina D. Progesterone directly and indirectly affects perforin expression in cytolytic cells. AJRI 1999; 42:312–320

Decidual natural killer cell tuning by autologous dendritic cells.

Problem  Dendritic cells (DC)/natural killer (NK) cells interactions in the deciduas of early human pregnancies were analyzed in vitro.

An insight into the dendritic cells at the maternal-fetal interface.

The conditions that permit the genetically distinct fetus to survive and develop within the mother are among the most fascinating immunologic puzzles. The presence of dendritic cells in the maternal decidua pointed to a biologic role of antigen‐presenting cells in maternal–fetal interaction. The method of study included recent findings on the lineage, maturity, phenotype and function of dendritic cells at the maternal–fetal interface. The increment of uterine dendritic cells occurs simultaneously with the decisive phase of gestation, when implantation takes place. Decidual dendritic cells of the first trimester pregnancy, with a phenotype characteristic of the mature myeloid lineage, express MHC class II, co‐stimulatory and adhesion molecules, control Th1/Th2 balance and activate the proliferative response of autologous NK cells. Dentritic cells are specifically equipped to control immunity, to trigger immune response and also to maintain tolerance, avoiding the rejection of the conceptus by the maternal immune system.

Early pregnancy decidual lymphocytes beside perforin use Fas ligand (FasL) mediated cytotoxicity.

Decidual natural killer (NK) cells are the predominant lymphocytes at the maternal-fetal interface. They are involved in defense against virally infected, parasitized and transformed cells and may contribute to the control of trophoblast invasion. The presence of perforin and other possible cytolytic mediators suggests these functions. Cytolytic mechanisms of unstimulated and Th1 cytokine stimulated decidual lymphocytes (DL), as well as purified decidual CD56(+) cells, were analyzed against NK sensitive and resistant targets. DL were isolated from decidual mononuclear cells (DMC) cultured in the medium only or in the presence of Th1 cytokines: IL-2, IL-12, IL-15, IL-18 and their combinations (IL-12/IL-18 or IL-15/IL-18). Fas ligand (FasL), perforin and granzyme B mRNAs expression and cytotoxicity were analyzed by flow cytometry and/or RT-PCR. DL (containing 72.19+/-7.53% of CD56(+) cells), obtained from 18h-cultured DMC in the medium only, expressed perforin, FasL and granzyme B mRNAs and lysed the NK-sensitive K-562 cell line, and also the NK-resistant P815 and P815-Fas transfected cell lines. Concanamycin A, a blocker of granule exocytosis, decreased significantly K-562 lysis, but not P815 lysis. However, the addition of anti-FasL antibody diminished significantly P815 lysis as well. IL-2 and IL-15, known inducers of perforin and FasL mRNAs and protein expression, could not additionally increase P 815 cell lysis by DL cultured within DMC. These results suggest that DL cultured in DMC for 18h, have the characteristics of lymphokine-activated killer (LAK) cells and are able to use efficiently both the perforin and the FasL cytolytic pathways.

IL-18 is present at the maternal-fetal interface and enhances cytotoxic activity of decidual lymphocytes

Tokmadz̆ić VS, Tsuji Y, Bogović T, Laškarin G, Cupurdija K, Štrbo N, Koyama K, Okamura H, Podack ER, Rukavina D. IL‐18 is present at the maternal‐fetal interface and enhances cytotoxic activity of decidual lymphocytes. AJRI 2002; 48:191–200