It is therefore important that experiments examining BBB behavior account for the function of the entire NVU

It is therefore important that experiments examining BBB behavior account for the function of the entire NVU. The BBB in patients with GBM appears to be compromised. this review, we first discuss recent advances in the CNS and CNS tumor immunology, with particular attention to factors that may promote immune escape of gliomas. We also review advances in passive and active immunotherapy strategies for glioma, as well as novel immunotherapy strategies that have been recently tested in non-CNS tumors with great potential to treat gliomas. Finally, we discuss how each of these promising strategies can be combined to achieve clinical benefits for patients with glioma. II. TUMOR IMMUNOLOGY AND THE CENTRAL NERVOUS SYSTEM A. CNS-Immune System Interactions For many decades, the brain has been referred to as an immune-privileged site (1) because it has been thought to lack dendritic cells (DCs) and lymphatics, (2) because of the presence of a blood brain barrier (BBB), and (3) on the basis of studies claiming a lack of allograft rejection in the brain.8 At the time, it remained a mystery as to whether immunosurveillance,9 the Rabbit Polyclonal to OR idea that thymus-dependent T cells constantly survey tissues for transformed cells, occurs Decloxizine in the brain. More recent work has described the CNS as immune specialized,10 after strong evidence of immune-CNS interactions in diseases such as multiple sclerosis (MS), experimental autoimmune encephalitis (EAE), and brain tumors. This section focuses on three key issues of CNS immunology, including how immune cells (1) are restricted from the brain, (2) can be activated against CNS antigens, and (3) traffic to and enter the brain. This discussion provides a framework to understand current treatment strategies harnessing Decloxizine the immune system to treat brain tumors. 1. How Immune Cells Are Restricted from Decloxizine the Brain CNS cells are known to be extremely sensitive to the toxic effects of exogenous substances, making regulation of homeostasis and proper restriction of entry to the CNS crucial. To this end, the neurovasculature has evolved specialized mechanisms to control both molecular and cellular migration into (and out of) the CNS parenchyma and cerebral spinal fluid (CSF). The CNS capillary endothelial cells are termed the BBB due to their ability to restrict passive diffusion and maintain low pinocytotic activity.11 Neuroimmunologists synonymously use the term BBB to describe both the capillary and postcapillary vessels, the latter of which is the site of T-cell migration into the brain. Restricting passive diffusion is accomplished through close cell-cell interactions known as tight junctions (TJs).10 The lack of fenestrations and the tight junctions prevent paracellular transport of large hydrophilic molecules (i.e., peptides and proteins) and cells.12 Under low magnification electron microscopy (EM), TJs appear to be fusions between the plasma membrane of juxtaposed cells, demonstrating how close these cell interactions are. However, high magnification reveals that in reality, TJs are the very close contact of cell membranes13 stabilized by specific proteins. Many extracellular proteins have been Decloxizine studied as TJ proteins, primarily the occludin, claudin, and junctional adhesion molecule (JAM) families. Experimental characterization of each shows that mice carrying a null mutation in the occludin gene develop normal TJs, whereas claudins have been shown to be independently sufficient for Decloxizine TJ formation, 14 suggesting the importance of claudins in TJ formation and regulation. Additionally, i.v. injection of monoclonal antibodies (MAbs) blocking JAM into mice has been shown to inhibit leukocyte accumulation in CSF and brain parenchyma,14 presumably by blocking leukocyte transmigration at the BBB. The BBB does not function in isolation, and current research focuses on the BBB in the context of the neurovascular unit (NVU), which is composed of the BBB, pericytes, parenchymal membrane, and astrocytic feet.15 We know that of these NVU cells, astrocytic feet cover greater than 80% of the abluminal side of the CNS vessels.14 One study demonstrated astrocytic feet as the specific site of water entry to the brain during edema, presumably through aquaporin-4 channels. 16 These astrocytes also contribute to the glia limitans, creating an added layer of protection for the brain or a barrier for immune cells. A more recent study has demonstrated that during cerebral ischemia, astrocytic swelling and detachment from the NVU results in increased permeability at the BBB.17 Thus, it seems that the BBB is just one layer of CNS capillary protection and that the capillaries are bound by a system rather than.