Many investigations have identified similarities between cytokine networks in
progressive malignant processes and successful pregnancy. In addition, large
similarities have been found between cytokine networks in malignant processes in
regression and unsuccessful pregnancy. Elevated levels of cytokines such as IL-4, IL-
6, IL-10 and TGF-β (Th2 and Th3 cytokines) are labels of both progressive malignant
disease and successful pregnancy. Similarly, decreased levels of IL-2, IL-12, IL-18,
IFN-γ and TNF-α (Th1 cytokines) are specific for progressive malignant disease and
successful pregnancy (reviewed in Bubanovic, 2003a; Raghupathy
et al., 2000;
Wegmann
et al., 1993).
Many other non-cytokine factors are included in the mechanisms of tumor and
trophoblast escape. The most important factors are prostaglandine, sex hormones,
chorionic gonadotropins, oncofetal and cancer-testis antigens, extrathymic lymphocyte
maturation processes, co-stimulatory molecule expression etc. Each of them has immunoregulatory and/or immunosuppressive effects on the immune system
contributing to the protection of proliferative tissue. Cytokines and other factors are
very important for the type and density of expressed MHC/lmp/TAP molecules on
tumor cells, trophoblast cells and Antigen Presenting Cells (APCs). Consequently, the
microenvironmental network of the regulatory factors and MHC/lmp/TAP molecule
expression defines the type and intensity of anti-tumor and anti-trophoblast immune
response (reviewed in Bubanovic, 2003a, b, c and d; Chaux et al., 1996). For example,
absence of classical class I molecules expression and enhanced expression of nonclassical
class I molecules like HLA-G, can mediate up-regulation of tumor protective
cytokines like TGF-β and IL-10, as well as down-regulate CTL and NK cells mediated
cytotoxicity (Guerra et al., 1999).
In pregnancy one such mechanism is that placental syncytio-trophoblasts at the
maternal-fetal interface do not express the classic MHC class I and class II molecules
except for HLA-C, HLA-E and HLA-G (Kovats et al., 1990). When trophoblasts
express MHC molecules the pregnancy is unsuccessful, but a high expression of
HLA-G is an important precondition for a successful pregnancy. Anti-tumor responses
are commonly triggered by the presentation of tumor antigen to T cells by host antigen
presenting cells. If APCs are not coordinated in their function, anti-tumor immunity
will be strongly affected. APCs in the infiltrates of human carcinoma are MHC class II
positive but essentially fail to express the co-stimulatory molecules CD80 or CD86
(Chaux et al., 1996). Trophoblast cells also do not express costimulatory molecules.
At the same time, most of the decidual immunocompetent cells express very low
levels of costimulatory molecules like CD80, CD86 and CD40. Rarely do early
decidual cells express HLA-DR and CD86 but term decidual cells do not express these
molecules (Oliver et al., 1999). Decidual dendritic cells in recurrent spontaneous
abortion (RSA) patients express a high level of costimulatory molecules, so that
successful immunotherapy of RSA based on immunization with paternal white blood
cells down-regulates the decidual mononuclear cells expression of CD80 molecules,
and down-regulates the decidual production of Th1 cytokines (Gafter et al., 1997).
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