IRX-2 is a cytokine-based biologic agent that has the potential to enhance antitumor immune responses. We investigated whether IRX-2 can protect T cells from tumor-induced apoptosis. Tumor-derived microvesicles (MV) expressing FasL were purified from supernatants of tumor cells and incubated with activated CD8+ T cells. MV induced significant CD8+ T-cell apoptosis, as evidenced by Annexin binding (64.4±6.4%), caspase activation (58.1±7.6%), a loss of mitochondrial membrane potential (82.9±3.9%) and DNA fragmentation. T-cell pretreatment with IRX-2 prevented apoptosis. IRX-2-mediated cytoprotection was dose and time dependent and was comparable to effects of IL-2, IL-7 or IL-15. IRX-2 prevented MV-induced downregulation of JAK3 and TCRζ chain and induced STAT5 activation in T cells. IRX-2 prevented MV-induced Bax and Bim upregulation (P<0.005–0.05), prevented cytochrome c release and Bid cleavage, and concurrently restored the expression of Bcl-2, Bcl-xL, FLIP and Mcl-1 (P<0.005–0.01) in T cells. In addition, IRX-2 reversed MV-induced inhibition of the PI3K/Akt pathway. An Akt inhibitor (Akti-1/2) abrogated protective effects of IRX-2, suggesting that Akt is a downstream target of IRX-2 signaling. Thus, ex vivo pretreatment of CD8+ T cells with IRX-2 provided potent protection from tumor-induced apoptosis. IRX-2 application to future cancer biotherapies could improve their effectiveness by bolstering T-cell resistance to tumor-induced immunosuppression.
Long term treatment with antiepileptic drugs (AEDs) is the standard therapeutic approach to eradicate seizures. However, a small but significant number of patients fail AED treatment. Intrinsic drug resistance may depend on two main and not necessarily mutually exclusive mechanisms: 1) Loss of pharmacological target (e.g., GABAA receptors); 2) poor penetration of the drug into the central nervous system (CNS). The latter is due to the action of multiple drug resistance proteins capable of active CNS extrusion of drugs. These include MDR1 (P-glycoprotein, PgP), the multidrug resistance related proteins MRP1-5, and lung-resistance protein (LRP). Overexpression of MDR1 occurs in human epileptic brain. It has therefore been proposed that MDR1/PgP may contribute to multiple drug resistance in epilepsy. In addition to MDR1/PgP, other genes such as MRP2, MRP5, and human cisplatin resistance-associated protein are also overexpressed in drug-resistant epilepsy. In normal brain tissue MDR1/PgP is expressed almost exclusively by endothelial cells (EC), while in epileptic cortex both EC and perivascular astrocytes express MDR1/PgP. The underlying causes for tissue differences may be genomic (i.e., at the DNA level), or MDR1/PgP could be induced by seizures, previous drug treatment, or a combination of the above. We will present evidence showing that expression of multiple drug resistance genes in epilepsy is a complex phenomenon and that glial cells are involved. This second line of defense for xenobiotics may have profound implications for the pharmacokinetic properties of antiepileptic drugs and their capacity to reach neuronal targets.
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