The investigators next sought to determine whether antiphospholipid antibodies directly activate the mTORC pathway. They compared immunoglobulin G antibodies from 12 patients with antiphospholipid syndrome with antibodies from 14 healthy control patients. They found that both groups had anti-human leukocyte antigen (HLA) antibodies, which suggested that these antibodies were not the ones responsible for mTORC activation in patients with antiphospholipid syndrome.
Sirolimus
The researchers then used an in vitro assay to evaluate the molecular pathway through which antiphospholipid antibodies modulate mTORC. They administered antiphospholipid antibodies from patients to cultured vascular epithelial cells and found that the antibodies were able to stimulate mTORC via the phosphatidyl-inositol 3-kinase (PI3K)-AKT pathway.
The investigators next tested the ability of sirolimus, a pharmacologic inhibitor of the mTORC pathway, to modulate the effect of the antiphospholipid antibodies. They found that one hour of exposure to sirolimus completely inhibited activation of the epithelial cells by antiphospholipid antibodies.
The team then examined the medical records of patients with antiphospholipid syndrome nephropathy who required transplantation to determine if those patients who received treatment with sirolimus had better outcomes than those who did not. They found that sirolimus treatment appeared to protect the kidney transplants from loss of function. A Kaplan-Meier survival analysis revealed that at 82 ± 35 months patients with antiphospholipid antibodies who were receiving sirolimus had a clear improvement in allograft survival in comparison with patients who were not receiving sirolimus.
Individuals with antiphospholipid antibodies who received sirolimus were also less likely to develop subsequent lesions. Specifically, 70% of patients treated with sirolimus had a functioning renal allograft at 144 months compared to 11% of untreated patients. Moreover, biopsies performed at three and 12 months post-transplantation revealed increased phosphorylation of S6RP and AKT (Ser473) in vascular endothelial cells from transplant recipients who were not receiving sirolimus in comparison to those who were receiving sirolimus.
An examination of autopsy specimens from patients who had died from catastrophic antiphospholipid syndrome revealed activated mTORC pathways, not only in the kidney, but also in both the carotid and left anterior descending arteries. These results suggest that the vascular pathology characterized in the kidney may be generalizable throughout the body of these patients and may likewise respond to treatment with sirolimus.
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
Reference
Note
Read a letter, Inhibition of the mTORC Pathway in the Antiphospholipid Syndrome, on the topic in the N Engl J Med. 2014;371:1553-1555.
