Depletion of MHC class II invariant chain peptide or γ-δ T-cells ameliorates experimental preeclampsia.

Excessive innate immune system activation and inflammation during pregnancy can lead to organ injury and dysfunction and preeclampsia (PE); however, the molecular mechanisms involved are unknown. We tested the hypothesis that Toll-like receptor (TLR) activation induces major histocompatibility complex (MHC) class II invariant chain peptide (CLIP) expression on immune cells, makes them pro-inflammatory, and are necessary to cause PE-like features in mice. Treatment with VG1177, a competitive antagonist peptide for CLIP in the groove of MHC class II, was able to both prevent and treat PE-like features in mice. We then determined that γ-δ T cells are critical for the development of PE-like features in mice since γ-δ T-cell knockout mice, like CLIP deficient mice, are resistant to developing PE-like features. Placentas from women with PE exhibit significantly increased levels of γ-δ T cells. These preclinical data demonstrate that CLIP expression and activated γ-δ T cells are responsible for the development of immunologic PE-like features and that temporarily antagonizing CLIP and/or γ-δ T cells may be a therapeutic strategy for PE.

Cotreatment with interleukin 4 and interleukin 10 modulates immune cells and prevents hypertension in pregnant mice.

BACKGROUND: Excessive maternal immune system activation plays a central role in the development of the hypertensive disorder of pregnancy preeclampsia (PE). The immunomodulatory cytokines interleukin 4 (IL-4) and interleukin 10 (IL-10) are dysregulated during PE; therefore we hypothesized that treatment with both recombinant IL-4 and IL-10 during pregnancy could prevent the development of PE in mice. METHODS: Using our mouse model of PE in which immune system activation is induced by the double-stranded RNA receptor agonist poly I:C, we gave daily injections of IL-4, IL-10, or both on days 13-17 of pregnancy. Mice were then killed on day 18. RESULTS: Poly I:C caused a significant increase in systolic blood pressure in pregnant (P-PIC) mice compared with vehicle-treated pregnant (P) mice. All 3 treatments significantly decreased blood pressure in P-PIC mice to P levels, ameliorated the endothelial dysfunction, and decreased placental TLR3 levels in P-PIC mice. However, only IL-4/IL-10 cotreatment prevented the proteinuria and increased incidence of fetal demise in P-PIC mice; IL-4 or IL-10 alone had no effect. Additionally, only IL-4/IL-10 cotreatment prevented the significant increase in CD3(+)/γδ(+) T cells and CD11c(+) dendritic cells and significant decrease in CD11b(+)/CD14(-) suppressor monocytes, as well as completely prevented placental necrosis, in P-PIC mice. Importantly, IL-4/IL-10 cotreatment in P mice had no detrimental effects. CONCLUSIONS: Taken together, these data demonstrate that exogenous IL-4 and IL-10 administration concurrently during pregnancy can normalize immune cell subsets and prevent PE induced by maternal immune system activation.

A Rare Case of Subarachnoid Hemorrhage due to Rupture of Isolated Anterior Spinal Artery Aneurysm in a Patient with Polycystic Kidney Disease.

Only a very few cases of subarachnoid hemorrhage due to isolated anterior spinal artery aneurysms have been reported in the literature. We report a case of subarachnoid hemorrhage due to anterior spinal artery aneurysm rupture in a renal transplant patient at our institution. A 47-year-old male had abrupt onset of left lower extremity weakness with bowel and bladder disturbances which prompted emergent surgical evacuation of the clot and hence immediate diagnostic angiography was not performed. However, follow-up serial intracranial arterial ultrasound studies showed only vasospasm of the basilar artery. Repeat MRI of the thoracic spine showed persistence of subarachnoid blood products, but no larger foci compared to previous imaging. When spinal subarachnoid hemorrhage is present in the appropriate clinical setting, isolated anterior spinal artery aneurysm should be considered as a possible, treatable cause.