T11 target structure exerts effector function by activating immune cells in CNS against glioma where cytokine modulation provide favorable microenvironment

Abstract

Glycoprotein T 11 target structure (T11TS), derived from sheep erythrocyte membrane, directly interacts with T cells to activate them to enter in the brain. When untreated, glioma exerts an immune-suppressive environment in its vicinity by secreting prostaglandin E2 (PGE₂), IL-10, tumor growth factor <img src='/image/spc_char/beta.gif' border=0>, gangliosides etc. to dampen the immune attack. But exogenous administration of T11TS reverses the situation to pro-inflammatory immune active state by expressing enhanced IL-12 and tumor necrosis factor <img src='/image/spc_char/alpha.gif' border=0> (TNF-<img src='/image/spc_char/alpha.gif' border=0>) production and suppression of IL-4 and IL-10 levels. The T11TS activated lymphocytic accumulation along the capillary endothelium in brain and their penetration in the matrix was evident from histological sections. IL-6 with TNF-<img src='/image/spc_char/alpha.gif' border=0> facilitates leukocyte migration to glioma site to exert cytotoxic effector function. Brain infiltrated lymphocytes offer cytotoxic proximity to neoplastic glial cells, which lead them to apoptosis. In the Th1 dominated microenvironment microglial cells was found with enhanced phagocytic functions. Initially infiltrated lymphocytes with microglia showed increased production of TNF-<img src='/image/spc_char/alpha.gif' border=0>, interferon <img src='/image/spc_char/gamma2.gif' border=0> (IFN-<img src='/image/spc_char/gamma2.gif' border=0>) to facilitate their effector actions. Repeated dosing of T11TS shows glioma abrogation in rat model, but also a resurgence of anti-inflammatory cytokine environment found with increased IL-4, IL-10 and decreased IL-12, IL-6, TNF-<img src='/image/spc_char/alpha.gif' border=0>. This is a unique homeostatic regulation of total immune system after T11TS mediated carnage of glioma. The resultant balance of cytokines between interacting glioma cells, T cells and microglia in T11TS induced condition determines the success of its immunotherapeutic effect in glioma.