Transforming the understanding of brain immunity

Abstract

Contemporary studies have completely changed the view of brain immunity from envisioning the brain as isolated and inaccessible to peripheral immune cells to an organ in close physical and functional communication with the immune system for its maintenance, function, and repair. Circulating immune cells reside in special niches in the brain’s borders, the choroid plexus, meninges, and perivascular spaces, from which they patrol and sense the brain in a remote manner. These niches, together with the meningeal lymphatic system and skull microchannels, provide multiple routes of interaction between the brain and the immune system, in addition to the blood vasculature. In this Review, we describe current ideas about brain immunity and their implications for brain aging, diseases, and immune-based therapeutic approaches.

Enhancing Glioblastoma Immunotherapy with Integrated Chimeric Antigen Receptor T Cells through the Re-Education of Tumor-Associated Microglia and Macrophages

“…29,30 However, the discovery of lymphatic vessels lining the dural sinuses has challenged the perception of the brain as an immune-privileged organ. 31,32 These vessels exchange fluid with the cerebral spinal fluid (CSF) surrounding the brain parenchyma, facilitating the trafficking of effector T cells into and out of the brain. 33 Numerous clinical practices have also reported the infiltration of CAR-T cells into the glioma site, confirming that CAR-T cells could penetrate the BBB and target GBM.…”

“…The BBB, which consists of continuous tight and adherent junctions between brain capillary endothelial cells, distinguishes the brain from other organs and protects it from inflammation and toxic substances. , At the same time, most therapeutic agents, even immune cells, are excluded from brain parenchyma due to the existence of BBB. Thus, the BBB is the main drug delivery bottleneck in the treatment of GBM. , However, the discovery of lymphatic vessels lining the dural sinuses has challenged the perception of the brain as an immune-privileged organ. , These vessels exchange fluid with the cerebral spinal fluid (CSF) surrounding the brain parenchyma, facilitating the trafficking of effector T cells into and out of the brain . Numerous clinical practices have also reported the infiltration of CAR-T cells into the glioma site, confirming that CAR-T cells could penetrate the BBB and target GBM. , However, we needed to determine whether the PLX-Lip/AZO-T cells also had these capabilities.…”

“…45 Moreover, the discovery of lymphatic vessels in the brain and the overturned understanding of brain immunity revealed that T cells could penetrate the BBB and infiltrate the brain in a diffuse manner. [31][32][33]41 Considerable CAR-T cell infiltration into the glioma site and decreased expression of target antigen were observed in phase I clinical trials of CAR-T cells (NCT02209376, NCT03170141), indicating that CAR-T cells could cross the BBB and target GBM. 9,34 However, despite demonstrating a suitable safety profile and promising antitumor activity, these CAR-T cells failed to achieve the expected therapeutic outcome.…”

“…However, the pathologic condition of GBM can disrupt the integrity of the BBB to some extent . Moreover, the discovery of lymphatic vessels in the brain and the overturned understanding of brain immunity revealed that T cells could penetrate the BBB and infiltrate the brain in a diffuse manner. − , Considerable CAR-T cell infiltration into the glioma site and decreased expression of target antigen were observed in phase I clinical trials of CAR-T cells (NCT02209376, NCT03170141), indicating that CAR-T cells could cross the BBB and target GBM. , However, despite demonstrating a suitable safety profile and promising antitumor activity, these CAR-T cells failed to achieve the expected therapeutic outcome . Moreover, numerous preclinical studies have shown that although GBM-targeting CAR-T cells exhibited some therapeutic effects, they did not eradicate the tumor completely and therefore could not be effective in the long term. ,,, To overcome this limitation of conventional CAR-T cells and improve their therapeutic efficacy against GBM, researchers have attempted to combine them with other drugs.…”

The Ever-Evolving Concept of the Neurovascular Unit

“…In addition to the well-established bidirectional interactions between NVU and peripheral immune cells, recent evidence indicates that immune cells reside at the brain border in the choroid plexus, meninges, circumventricular organs, perivascular spaces, and skull bone marrow. 8 These local immune compartments complement the meningeal lymphatic system and the peripheral immune and stand ready to respond to signals of neurovascular injury neuroinflammatory and neoplastic diseases. 9 In stroke, infiltrating peripheral immune cells exacerbate ischemic neuronal injury in the acute phase but are now recognized to contribute to functional recovery and repair in the chronic phase of stroke.…”