Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile

TY - JOUR

T1 - Depletion of CD8+ cells abolishes the pregnancy protective effect of progesterone substitution with dydrogesterone in mice by altering the Th1/Th2 cytokine profile

AU - Blois, Sandra M

AU - Joachim, Ricarda

AU - Kandil, Judith

AU - Margni, Ricardo

AU - Tometten, Mareike

AU - Klapp, Burghard F

AU - Arck, Petra C

PY - 2004/5/15

Y1 - 2004/5/15

N2 - 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.

AB - 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.

KW - Abortion, Spontaneous/immunology

KW - Animals

KW - CD8-Positive T-Lymphocytes/immunology

KW - Cytokines/biosynthesis

KW - Dydrogesterone/antagonists & inhibitors

KW - Female

KW - Injections, Subcutaneous

KW - Lymphocyte Count

KW - Lymphocyte Depletion

KW - Mice

KW - Mice, Inbred CBA

KW - Mice, Inbred DBA

KW - Pregnancy

KW - Pregnancy Maintenance/drug effects

KW - Progesterone/analogs & derivatives

KW - Stress, Physiological/drug therapy

KW - Th1 Cells/immunology

KW - Th2 Cells/immunology

KW - Uterus/cytology

U2 - 10.4049/jimmunol.172.10.5893

DO - 10.4049/jimmunol.172.10.5893

M3 - SCORING: Journal article

C2 - 15128769

VL - 172

SP - 5893

EP - 5899

JO - J IMMUNOL

JF - J IMMUNOL

SN - 0022-1767

IS - 10

ER -