Purpose: Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained pro-inflammatory signals provided by intra-lesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as pro-inflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Experimental Design: Three MC lines were used to assess permissivity to infection and to evaluate MC activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by immunohistochemistry for the presence of MCs in KS lesions, assessment of activation state, and KSHV infection. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. Results: In culture, MCs supported KSHV infection and infection induced MC degranulation. Within KS lesions MCs were closely associated with spindle cells. MC activation was extensive within KS patients, reflected by elevated circulating levels of tryptase and N-methylhistamine. One patient with clinical signs of extensive MC activation was treated with antagonists of MC-derived pro-inflammatory mediators, which resulted in rapid and durable regression of AIDS-KS lesions. Conclusions: Using complimentary in vitro and in vivo studies we identify MCs as a potential long-lived reservoir for KSHV and a source of pro-inflammatory mediators within the lesion microenvironment. Additionally, we identify MC antagonists as a promising novel therapeutic approach for KS.
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