Feline Interleukin 10

The potent immunosuppression induced by glioblastoma (GBM) is one of the primary obstacles to finding effective immunotherapies. One hallmark of the GBM-associated immunosuppressive landscape is the massive infiltration of myeloid-derived suppressor cells (MDSC) and, to a lesser extent, regulatory T cells (Treg) within the tumor microenvironment. Here, we showed that regulatory B cells (Breg) are a prominent feature of the GBM microenvironment in both preclinical models and clinical samples. Forty percent of GBM patients (n = 60) scored positive for B-cell tumor infiltration. Human and mouse GBM-associated Bregs were characterized by immunosuppressive activity toward activated CD8(+) T cells, the overexpression of inhibitory molecules PD-L1 and CD155, and production of immunosuppressive cytokines TGF beta and IL10. Local delivery of B cell-depleting anti-CD20 immunotherapy improved overall survival of animals (IgG vs. anti-CD20 mean survival: 18.5 vs. 33 days, P = 0.0001), suggesting a potential role of Bregs in GBM progression. We unveiled that GBM-associated MDSCs promoted regulatory B-cell function by delivering microvesicles transporting membrane-bound PD-L1, able to be up-taken by tumoral B cells. The transfer of functional PD-L1 via microvesicles conferred Bregs the potential to suppress CD8(+) T-cell activation and acquisition of an effector phenotype. This work uncovered the role of B cells in GBM physiopathology and provides a mechanism by which the GBM microenvironment controls B cell-mediated immunosuppression.

Background: Emerging evidence suggests retroviruses play a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Specifically, activation of ancient viral genes embedded in the human genome is theorized to lead to motor neuron degeneration. We explore whether connections exist between ALS and retroviruses through protein interaction networks (PIN) and pathway analysis, and consider the potential roles in drug target discovery. Protein database and pathway/network analytical software including Ingenuity Pathway BioProfiler, STRING, and CytoScape were utilized to identify overlapping protein interaction networks and extract core cluster (s) of retroviruses and ALS. Results: Topological and statistical analysis of the ALS-PIN and retrovirus-PIN identified a shared, essential protein network and a core cluster with significant connections with both networks. The identified core cluster has three interleukin molecules IL10, Il-6 and IL-1B, a central apoptosis regulator TP53, and several major transcription regulators including MAPK1, ANXA5, SQSTM1, SREBF2, and FADD. Pathway enrichment analysis showed that this core cluster is associated with the glucocorticoid receptor singling and neuroinflammation signaling pathways. For confirmation purposes, we applied the same methodology to the West Nile and Polio virus, which demonstrated trivial connectivity with ALS, supporting the unique connection between ALS and retroviruses. Conclusions: Bioinformatics analysis provides evidence to support pathological links between ALS and retroviral activation. The neuroinflammation and apoptotic regulation pathways are specifically implicated. The continuation and further analysis of large scale genome studies may prove useful in exploring genes important in retroviral activation and ALS, which may help discover new drug targets.