Human Tregs at the materno-fetal interface show site-specific adaptation reminiscent of tumor Tregs.

Tregs are crucial for maintaining maternal immunotolerance against the semiallogeneic fetus. We investigated the elusive transcriptional profile and functional adaptation of human uterine Tregs (uTregs) during pregnancy. Uterine biopsies, from placental bed (materno-fetal interface) and incision site (control) and blood were obtained from women with uncomplicated pregnancies undergoing cesarean section. Tregs and CD4+ non-Tregs were isolated for transcriptomic profiling by Cel-Seq2. Results were validated on protein and single cell levels by flow cytometry. Placental bed uTregs showed elevated expression of Treg signature markers, including FOXP3, CTLA-4, and TIGIT. Their transcriptional profile was indicative of late-stage effector Treg differentiation and chronic activation, with increased expression of immune checkpoints GITR, TNFR2, OX-40, and 4-1BB; genes associated with suppressive capacity (HAVCR2, IL10, LAYN, and PDCD1); and transcription factors MAF, PRDM1, BATF, and VDR. uTregs mirrored non-Treg Th1 polarization and tissue residency. The particular transcriptional signature of placental bed uTregs overlapped strongly with that of tumor-infiltrating Tregs and was remarkably pronounced at the placental bed compared with uterine control site. In conclusion, human uTregs acquire a differentiated effector Treg profile similar to tumor-infiltrating Tregs, specifically at the materno-fetal interface. This introduces the concept of site-specific transcriptional adaptation of Tregs within 1 organ.

Efficacy of adalimumab in sarcoidosis patients who developed intolerance to infliximab.

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) inhibitors are regarded as the third-line therapy in sarcoidosis, the first choice generally being infliximab. To date, data regarding response to adalimumab in sarcoidosis patients intolerant to infliximab are lacking. The objective of this retrospective observational study was to establish if adalimumab could achieve stabilization or improvement of the disease in refractory sarcoidosis patients who developed intolerance to infliximab. MATERIAL AND METHODS: Sarcoidosis patients referred to St Antonius Interstitial Lung Diseases Center of Excellence, Nieuwegein, The Netherlands, between January 2008 and April 2015 who switched from infliximab to adalimumab were included. Changes in organ function, inflammatory biomarker levels, and adverse events were retrieved from medical records. RESULTS: Out of 142 infliximab treated patients, 18 (13%) had to discontinue treatment due to antibody formation or severe adverse events and switched to adalimumab therapy. Organ function improved in 7 patients (39%), was stable in 6 patients (33%), and worsened in 5 patients (28%) after 12 months of treatment or after 6 months if evaluation after 12 months was not available (n = 4). In none of the patients biomarker levels of soluble interleukin-2 receptor (sIL-2R) deteriorated. Median decrease in sIL-2R was 3614 pg/mL. Most reported adverse event was infection (n = 10). CONCLUSIONS: Adalimumab is an effective alternative for patients intolerant to infliximab. The switch to adalimumab achieved clinical improvement in 39% and stabilization in 33% of patients intolerant to infliximab. Further research is needed to develop guidelines on how to use adalimumab for sarcoidosis in terms of dosing regimen.