Case Report: Splenic Irradiation for the Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Allograft Recipients With De Novo Donor-Specific Antibodies

Chronic active antibody-mediated rejection (AMR) in renal transplantation is usually refractory to current conventional treatment with rituximab, plasmapheresis (PP), and intravenous immunoglobulins (IVIG). Splenic irradiation has been reported to be effective in the rescue of early severe acute AMR after kidney transplantation; however, its effect in chronic active AMR has not been reported to date. In order to reduce donor-specific antibody (DSA) and prevent the progression of chronic AMR, we used repetitive low-dose splenic irradiation, together with rituximab and PP/IVIG, in two living-related kidney transplant recipients with pathologically diagnosed chronic active AMR and the presence of long-term class II-de novo DSA. DSA monitoring and repeated renal biopsy revealed significantly reduced DSA levels as well as alleviated glomerulitis and peritubular capillaritis in both patients after treatment, and these therapies may have played a role in delaying the progression of chronic AMR. Although DSA levels in both patients eventually rebounded to some extent after treatment, serum creatinine increased slowly in one patient during the 16-month follow-up period and remained stable in the other during the 12-month follow-up period. Given the poor efficacy of conventional treatment at present, splenic irradiation may still be one of the treatment options for chronic active AMR.

Ultra high dose rate (35 Gy/sec) radiation does not spare the normal tissue in cardiac and splenic models of lymphopenia and gastrointestinal syndrome

Recent reports have shown that very high dose rate radiation (35–100 Gy/second) referred to as FLASH tends to spare the normal tissues while retaining the therapeutic effect on tumor. We undertook a series of experiments to assess if ultra-high dose rate of 35 Gy/second can spare the immune system in models of radiation induced lymphopenia. We compared the tumoricidal potency of ultra-high dose rate and conventional dose rate radiation using a classical clonogenic assay in murine pancreatic cancer cell lines. We also assessed the lymphocyte sparing potential in cardiac and splenic irradiation models of lymphopenia and assessed the severity of radiation-induced gastrointestinal toxicity triggered by the two dose rate regimes in vivo. Ultra-high dose rate irradiation more potently induces clonogenic cell death than conventional dose rate irradiation with a dose enhancement factor at 10% survival (DEF10) of 1.310 and 1.365 for KPC and Panc02 cell lines, respectively. Ultra-high dose rate was equally potent in depleting CD3, CD4, CD8, and CD19 lymphocyte populations in both cardiac and splenic irradiation models of lymphopenia. Radiation-induced gastrointestinal toxicity was more pronounced and mouse survival (7 days vs. 15 days, p = 0.0001) was inferior in the ultra-high dose rate arm compared to conventional dose rate arm. These results suggest that, contrary to published data in other models of radiation-induced acute and chronic toxicity, dose rates of 35 Gy/s do not protect mice from the detrimental side effects of irradiation in our models of cardiac and splenic radiation-induced lymphopenia or gastrointestinal mucosal injury.