For decades, it was believed that due to its unique structure, the brain functions best as an autonomous tissue behind barriers, equipped with mechanisms of homeostasis and repair. Since immune cells are the body’s champions of repair, it was assumed that the brain-resident innate immune cells, the microglia, mediate this function. The microglia enter the CNS during early development , and their maturation occurs step-wise, in synchrony with the needs of the developing brain . Yet, most of the body’s other tissues, while containing resident immune cells, require additional systemic immune support for their repair. In contrast, it was believed that the brain escapes from such help, relying solely on its resident immune population. This dogma prevailed for decades. Below, I briefly summarize milestones that paved the way to changes in this commonly accepted view.
Almost all brain pathologies are associated with local inflammation , the etiology of which has only recently started to be deciphered. Nevertheless, based on the long-held dogma that the brain is an immune privileged site, attempts were made to use anti-inflammatory drugs to treat brain pathologies in which local inflammation was observed, almost regardless of the primary disease etiology; this approach mostly failed, resulting in much confusion within the research community .
Studies initiated by my team over almost two decades have demonstrated that the CNS and the immune system engage in bi-directional communication, and that the brain is dependent on systemic immunity, and not only on the local innate immune-resident cells. The dependence of the brain on systemic immune support was shown with respect to formation of new neurons, cognitive ability [5-7], coping with stress , and recently, in social behavior .
Independent studies, some of which preceded those demonstrating the effect on healthy brain function, revealed that the process of recovery from acute injuries is highly dependent on circulating monocytes and T cells [10-12], through a well-orchestrated immune network, which is initiated within the brain, continues in the periphery and culminates back in the CNS [13-15]. Nevertheless, it was not clear how such communication could take place if circulating immune cells are excluded from the CNS parenchyma, and possible aberrations in these pathways in neurodegenerative diseases and brain aging were not characterized. A turning point in addressing this question was reached when the research focus shifted to understanding the immunological properties of the borders between the brain and the circulation [13, 16, 17].
The CNS barrier system includes the blood–brain barrier (BBB), the meningeal barrier, and the blood–cerebrospinal fluid barrier (BCSFB). These three barriers are distinct in their structure, and recently were also found to differ with respect to their functions in relation to immune cells . Both the meningeal barrier and the BCSFB barrier are continuously populated by adaptive immune cells and by dendritic cells [14,16,17]. However, in contrast to the other barriers, the BCSFB, which is an epithelial rather endothelial barrier, created by the choroid plexus epithelium (CP), was found to serve as an interface that allows trafficking of immune cells under physiological conditions for surveillance and for repair [13,14,19,20].
The understanding that adaptive immune cells populate the CP within the BCSFB and can orchestrate trafficking though this barrier has led to the hypothesis that its mode of operation and its fate under different brain pathologies could be critical to determining its ability to cope with disease conditions. It was found that T cells that reside in the CP via local production of IFN-γ control expression of leukocyte trafficking molecules, thereby allowing trafficking of leukocytes into the CNS parenchyma when needed. Moreover, a synergy was found between IFN-γ and danger signals coming from the injured CNS, which augments trafficking through this interface upon signaling from the brain .
Almost paradoxically, in aging and neurodegenerative diseases, the CP was shown to be suppressed with respect to its ability to support expression of leukocyte trafficking molecules, apparently due to limited availability of IFN-γ at the CP [20–22]. Transient reduction of regulatory T cell levels resulted in elevation of IFN-γ availability, activation of the CP, infiltration of monocytes and regulatory T cells to the brain, and reduced burden of disease pathology, including reversal of cognitive loss [20, 21]. Such results led us to test a treatment based on de-repressing the immune system by blocking inhibitory pathways. Specifically, we used antibodies directed at inhibitory immune checkpoints, known to tightly control effector memory T cells.
Specifically, to release suppression of cells that could potential produce IFN-γ, we tested the effects of an antibody directed against the inhibitory immune checkpoint PD-1. We treated 5XFAD mice, a mouse model of Alzheimer’s disease (AD), which expresses most features of human AD, including the accumulation of intracellular and extracellular misfolded amyloid-beta, loss of synapses, local inflammation, gliosis and neuronal loss . In response to a single systemic treatment, the animals showed reversal of cognitive loss, and a dramatic decrease in plaque burden and gliosis. The effect was maintained for at least 4 weeks after a single treatment . Further studies are needed before translating this therapy into the clinic, to correspond to the current understanding of the mechanism of action needed for allowing circulating leukocytes to traffic into the brain and display their consequential local disease-modifying activity in AD. The studies will aim to determine the type of the antibody, the dose and the regimen, which will differ from the current immunotherapy for cancer. This approach in AD may signal a major transition in the search for AD-modifying therapy, as it targets the immune system, rather than a specific pathological factor within the diseased brain.
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This work was supported by the EU Seventh Framework Program HEALTH-2011 (grant no. 279017) and the ISF-Legacy Heritage Biomedical Science Partnership-research (grant no. 1354/15). M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology.
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