Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile.
One of the most remarkable immunological regulations is the maternal immune tolerance toward the fetal semiallograft during pregnancy, which has been referred to as immunity's pregnant pause. Rejection of the semiallogeneic trophoblast cells must be selectively inhibited and pathways presumably include Th2 cytokines unopposed by Th1 cytokines. Steroid hormones, including progesterone, have similar effects. Low levels of progesterone and Th2 cytokines and high levels of Th1 cytokines are attributable for increased abortions in mammalians, which may be triggered by psychoemotional stress. Thus, the aim of the present study was to provide experimental evidence for the mechanism involved in the mediation of immune responses by endocrine signals during pregnancy and stress-triggered pregnancy failure. DBA/2J-mated CBA/J female mice were randomized in three groups: 1) control females, 2) mice exposed to stress on gestation day 5.5, and 3) mice exposed to stress and substituted with dydrogesterone, a progestogen with a binding profile highly selective for the progesterone receptor on gestation day 5.5. On gestation days 7.5, 9.5, and 10.5, mice of each group were sacrificed, and the frequency of CD8(+) cells and cytokine expression (IL-4, IL-12, TNF-alpha, IFN-gamma) in blood and uterus cells was evaluated by flow cytometry. Additionally, some mice were depleted of CD8 cells by injection of mAb. We observed that progesterone substitution abrogated the abortogenic effects of stress exposure by decreasing the frequency of abortogenic cytokines. This pathway was exceedingly CD8-dependent, because depletion of CD8 led to a termination of the pregnancy protective effect of progesterone substitution.
Blois
Sandra M
SM
Charité, Department of Internal Medicine, Biomedizinisches Forschungszentrum, Humboldt University of Berlin, Berlin, Germany.
Joachim
Ricarda
R
Kandil
Judith
J
Margni
Ricardo
R
Tometten
Mareike
M
Klapp
Burghard F
BF
Arck
Petra C
PC
D000022:Abortion, Spontaneous / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004394:Dydrogesterone / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D005260:Female; D007279:Injections, Subcutaneous; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D011247:Pregnancy; D011255:Pregnancy Maintenance / Q000187:drug effects* / Q000276:immunology*; D011374:Progesterone / Q000031:analogs & derivatives; D013312:Stress, Physiological / Q000188:drug therapy / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D011374:Progesterone; D004394:Dydrogesterone