Reconstructive surgery for urethral defects employing tissue‐engineered scaffolds represents an alternative treatment for urethroplasty. The aim of this study was to compare the therapeutic efficacy of the bilayer poly‐D,L‐lactide/poly‐ε‐caprolactone (PL‐PC) scaffold seeded with allogenic mesenchymal stem cells (MSCs) for urethra reconstruction in a rabbit model with conventional urethroplasty employing an autologous buccal mucosa graft (BG). The inner layer of the scaffold based on poly‐D,L‐lactic acid (PL) was seeded with MSCs, while the outer layer, prepared from poly‐ε‐caprolactone, protected the surrounding tissues from urine. To track the MSCs in vivo, the latter were labeled with superparamagnetic iron oxide nanoparticles. In rabbits, a dorsal penile defect was reconstructed employing a BG or a PL‐PC graft seeded with nanoparticle‐labeled MSCs. In the 12‐week follow‐up period, no complications were detected. Subsequent histological analysis demonstrated biointegration of the PL‐PC graft with surrounding urethral tissues. Less fibrosis and inflammatory cell infiltration were observed in the experimental group as compared with the BG group. Nanoparticle‐labeled MSCs were detected in the urothelium and muscular layer, co‐localizing with the urothelium cytokeratin marker AE1/AE3, indicating the possibility of MSC differentiation into neo‐urothelium. Our results suggest that a bilayer MSCs‐seeded scaffold could be efficiently employed for urethroplasty.

In recent years, the application of mesenchymal stem cells (MSCs) has been recognized as a promising method for treatment of different diseases associated with inflammation and sclerosis, which include nephrotuberculosis. The aim of our study is to investigate the effectiveness of MSCs in the complex therapy of experimental rabbit kidney tuberculosis and to evaluate the effect of cell therapy on the reparative processes. Methods: To simulate kidney tuberculosis, a suspension of the standard strain Mycobacterium tuberculosis H37Rv (106 CFU) was used, which was injected into the cortical layer of the lower pole parenchyma of the left kidney under ultrasound control in rabbits. Anti-tuberculosis therapy (aTBT) was started on the 18th day after infection. MSCs (5 × 107 cells) were transplanted intravenously after the start of aTBT. Results: 2.5 months after infection, all animals showed renal failure. Conducted aTBT significantly reduced the level of albumin, ceruloplasmin, elastase and the severity of disorders in the proteinase/inhibitor system and increased the productive nature of inflammation. A month after MSC transplantation, the level of inflammatory reaction activity proteins decreased, the area of specific and destructive inflammation in kidneys decreased and the formation of mature connective tissue was noted, which indicates the reparative reaction activation.

Treatment of bladder cancer has evolved over time to include the traditional modalities of chemotherapy and surgery, and it has been greatly impacted by the use of immunotherapy. Modern immunotherapy focuses on checkpoint protein inhibitors, which are molecules impeding immune function, thereby allowing unregulated tumor cell growth and proliferation. Several immune checkpoint targets (programmed death ligand-1 [PD-L1], programmed cell death protein-1 [PD-1], and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]) have received the most attention in the treatment of bladder cancer, whereas inhibitor agents have either been approved or are in late-stage development. This review describes the most recent data on PD-L1-inhibiting agents, found on the surface of tumor cells, and PD-1, found on activated T and B cells and macrophages. Aim. A review of modern PD-1 and PD-L1 inhibitors as target immunotherapeutic agents for the treatment of bladder cancer. Materials and methods. We performed a comprehensive literature review using MEDLINE/PubMed and EMBASE. Results. The PD-1/PD-L1 pathway is possibly manipulated by cancer cells to suppress the immune system. PD-1/PD-L1 blockade has been tested in clinical trials for various malignancies, including metastatic urothelial carcinoma, with significant response rates and limited adverse effects. PD-L1 expression has mixed results as a prognostic marker for bladder cancer. Conclusions. PD-1 is a key receptor mediating immune escape, and agents targeting its ligand, PD-L1, have already been successful in patients with metastatic urothelial cancer. Further research is warranted to standardize the criteria for PD-L1 positivity and to optimize its use in the treatment of bladder cancer. (For citation: Gorelov AI, Simbirtsev AS, Zhuravskiy DA, Gorelova AA. A review of the PD-1/PD-l1 checkpoint in bladder cancer: from mediator of immune escape to target for treatment. Urologicheskie vedomosti. 2018;8(2):64-72. doi: 10.17816/uroved8264-72).