Introducing a mouse model for pre‐eclampsia: adoptive transfer of activated Th1 cells leads to pre‐eclampsia‐like symptoms exclusively in pregnant mice

Abstract

Pre-eclampsia (PE) is the most severe pregnancy-related disease, leading to high maternal and fetal morbidity/mortality. Immunological imbalances associated with endothelial cell dysfunction have been hypothesized as a cause for the onset and perpetuation of PE. Valid and reliable animal models are urgently required to test this hypothesis and to better understand the mechanisms underlying PE. We developed a novel PE-model by adoptively transferring activated BALB/c Th1-like splenocytes into allogeneically pregnant BALB/c female mice during late gestation; the model mimicked the symptoms of PE, i.e. increased blood pressure and glomerulonephritis accompanied by proteinuria. Interestingly, these PE-like symptoms were not detectable in non-pregnant recipients of activated Th1-like cells. Adoptive cell transfer adversely affected the outcome of pregnancy by increasing fetal rejection, with uterine immune cells showing an inflammatory profile. In conclusion, we have established a valid and reliable PE mouse model, which opens vast opportunities for therapeutic interventions.

Alloantigen-enhanced accumulation of CCR5+‘effector’ regulatory T cells in the gravid uterus

“…In analogy one might expect a similar directed accumulation of CCR5 ϩ effector T R cells to the sites where their action is required. In the case of pregnancy, the site of implantation poses clearly a main target of effector T H cells (35). Similarly, we have shown that significant number of T R cells can be detected in the gravid uterus at the maternal-fetal interface (6).…”

“…Upon activation, naïve CD4 ϩ T cells start to express CD25, a subpopulation of which also expresses CCR5. The conversion from CCR5 Ϫ to CCR5 ϩ T H cell is enhanced in the presence of proinflammatory cytokines, in particular IL-12 (35). Similarly, expression of CCR5 can be induced in CCR5 Ϫ CD4 ϩ CD25 ϩ T R cells by activation, in particular in the presence of IL-2 (33).…”

Regulatory T cells induce a privileged tolerant microenvironment at the fetal‐maternal interface

“…On the contrary, a slight augmentation in the number of CD4 + CD25 + cells could be observed, which may indicate activated cells. In fact, CD25 is used in the Immunomodulation decidua as an activation marker rather than a marker for Treg [28,33]. For having a more confidential marker of Treg activity, we analyzed the foxp3 and neuropilin-1 [34] mRNA levels in whole tissue by real-time RT-PCR (decidua and placenta, respectively).…”

“…We confirm that the transfer of pregnancy-induced Treg expanded the CD4 + CD25 + Treg population in DBA/2J-mated CBA/J females systemically (spleen) and in thymus. When analyzing the decidual Treg population, we were not able to find an expansion of this population in decidua, probably due to the fact that the measurement of CD4 + CD25 + cells is not a good choice for determining the Treg subpopulation and may indicate the presence of activated cells [24,28,33]. We therefore analyzed the protein and mRNA levels for foxp3 and neuropilin-1 as more accurate Treg activity markers.…”

Disturbances in placental immunology: ready for therapeutic interventions?

“…In humans, the presence of IFN-γ or TNFα in the placenta in the case of malarial infection during pregnancy is strongly associated with poor pregnancy outcome [60]. Recent studies with a murine model have indicated that the adoptive transfer of activated Th1 lymphocytes leads to preeclampsia-like symptoms exclusively in pregnant mice [61]. In our own analyses, we observed that there was a reduction in the activation levels, as measured by the expression of CD69, in both CD8+ and CD4+ T cells in late pregnancy (Schatt et al, in preparation).…”