Reduced Uterine Indoleamine 2,3-Dioxygenase Versus Increased Th1/Th2 Cytokine Ratios as a Basis for Occult and Clinical Pregnancy Failure in Mice and Humans

Problem

Indoleamine 2,3-dioxygenase (IDO) expression in fetal trophoblast and decidual antigen-presenting cells has been proposed to inactivate maternal T cells and thereby prevent rejection of the 'fetal allograft' in early pregnancy. Psychic stress has been proposed to cause miscarriages as well as infertility, at the same time in pregnancy when blockade of IDO causes loss, but the suggested mechanism of stress-triggered loss has been an increased ratio of pro-rejection Th1-type cytokines to anti-rejection Th2/3 cytokines. Could stress act by reducing IDO expression?

Methods

Using DBA/2-mated A/J mice where stress causes early pregnancy failure, we examined the role of stress in reducing IDO versus increasing Th1/Th2 ratio in deciduas. IDO loss was also examined in human decidua associated with pregnancy failure.

Results

A post-implantation sonic stress increased the pregnancy failure rate, increased the Th1/Th2 ratio, but did not reduce IDO. IDO was reduced, and Th1/Th2 ratios increased in A/J mice pre-immunized against paternal DBA/2 antigens, and concomitant stress increased these effects. The rate of pregnancy failure was not further increased consistent with recent discoveries of factors that limit the impact of Th1 cytokines at the feto-maternal interface. In deciduas from spontaneous miscarriage patients, IDO⁺ cell frequencies were low in only 30% of patients. CD3⁺ T-cell numbers and percentage terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end-labelling (TUNEL)⁺ apoptotic T cells were increased, but the level of IDO did not correlate with likelihood of apoptosis.

Conclusions

Loss of an allogeneic embryo in early pregnancy is more likely to be due to a high Th1/Th2 ratio than loss of putative protection by IDO.