Chimeric antigen receptor (CAR) T-cell therapy has yielded impressive outcomes and transformed treatment algorithms for hematological malignancies. To date, five CAR T-cell products have been approved by the US Food and Drug Administration (FDA). Nevertheless, some significant toxicities pose great challenges to the development of CAR T-cell therapy, most notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Understanding the mechanisms underlying these toxicities and establishing prevention and treatment strategies are important. In this review, we summarize the mechanisms underlying CRS and ICANS and provide potential treatment and prevention strategies.

Mechanisms of cytokine release syndrome and neurotoxicity of CAR T-cell therapy and associated prevention and management strategies.

The neurovascular unit (NVU) is a relatively recent concept that clearly describes the relationship between brain cells and their blood vessels. The components of the NVU, comprising different types of cells, are so interrelated and associated with each other that they are considered as a single functioning unit. For this reason, even slight disturbances in the NVU could severely affect brain homeostasis and health. In this review, we aim to describe the current state of knowledge concerning the role of oxidative stress on the neurovascular unit and the role of a single cell type in the NVU crosstalk.

Oxidative Stress and the Neurovascular Unit.

Pericytes are a component of the blood–brain barrier (BBB) neurovascular unit, in which they play a crucial role in BBB integrity and are also implicated in neuroinflammation. The association between pericytes, BBB dysfunction, and the pathophysiology of epilepsy has been investigated, and links between epilepsy and pericytes have been identified. Here, we review current knowledge about the role of pericytes in epilepsy. Clinical evidence has shown an accumulation of pericytes with altered morphology in the cerebral vascular territories of patients with intractable epilepsy. In vitro, proinflammatory cytokines, including IL-1β, TNFα, and IL-6, cause morphological changes in human-derived pericytes, where IL-6 leads to cell damage. Experimental studies using epileptic animal models have shown that cerebrovascular pericytes undergo redistribution and remodeling, potentially contributing to BBB permeability. These series of pericyte-related modifications are promoted by proinflammatory cytokines, of which the most pronounced alterations are caused by IL-1β, a cytokine involved in the pathogenesis of epilepsy. Furthermore, the pericyte-glial scarring process in leaky capillaries was detected in the hippocampus during seizure progression. In addition, pericytes respond more sensitively to proinflammatory cytokines than microglia and can also activate microglia. Thus, pericytes may function as sensors of the inflammatory response. Finally, both in vitro and in vivo studies have highlighted the potential of pericytes as a therapeutic target for seizure disorders.

https://www.mdpi.com/2227-9059/9/7/759/pdf

The Neuroinflammatory Role of Pericytes in Epilepsy

Factors influencing the blood-brain barrier permeability

In recent decades, research scientists, molecular biologists, and pharmacologists have placed a strong emphasis on cutting-edge nanostructured materials technologies to increase medicine delivery to the central nervous system (CNS). The application of nanoscience for the treatment of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), Huntington’s disease (HD), brain cancer, and hemorrhage has the potential to transform care. Multiple studies have indicated that nanomaterials can be used to successfully treat CNS disorders in the case of neurodegeneration. Nanomedicine development for the cure of degenerative and inflammatory diseases of the nervous system is critical. Nanoparticles may act as a drug transporter that can precisely target sick brain sub-regions, boosting therapy success. It is important to develop strategies that can penetrate the blood–brain barrier (BBB) and improve the effectiveness of medications. One of the probable tactics is the use of different nanoscale materials. These nano-based pharmaceuticals offer low toxicity, tailored delivery, high stability, and drug loading capacity. They may also increase therapeutic effectiveness. A few examples of the many different kinds and forms of nanomaterials that have been widely employed to treat neurological diseases include quantum dots, dendrimers, metallic nanoparticles, polymeric nanoparticles, carbon nanotubes, liposomes, and micelles. These unique qualities, including sensitivity, selectivity, and ability to traverse the BBB when employed in nano-sized particles, make these nanoparticles useful for imaging studies and treatment of NDs. Multifunctional nanoparticles carrying pharmacological medications serve two purposes: they improve medication distribution while also enabling cell dynamics imaging and pharmacokinetic study. However, because of the potential for wide-ranging clinical implications, safety concerns persist, limiting any potential for translation. The evidence for using nanotechnology to create drug delivery systems that could pass across the BBB and deliver therapeutic chemicals to CNS was examined in this study.

Exploring the role of nanomedicines for the therapeutic approach of central nervous system dysfunction: At a glance

Pericytes are contractile cells that extend along the vasculature to mediate key homeostatic functions of endothelial barriers within the body. In the central nervous system (CNS), pericytes are important contributors to the structure and function of the neurovascular unit, which includes endothelial cells, astrocytes and neurons. The understanding of pericytes has been marred by an inability to accurately distinguish pericytes from other stromal cells with similar expression of identifying markers. Evidence is now growing in favor of pericytes being actively involved in both CNS homeostasis and pathology of neurological diseases, including multiple sclerosis, spinal cord injury, and Alzheimer's disease among others. In this review, we discuss the current understanding on the characterization of pericytes, their roles in maintaining the integrity of the blood-brain barrier, and their contributions to neuroinflammation and neurorepair. Owing to its plethora of surface receptors, pericytes respond to inflammatory mediators such as CCL2 (monocyte chemoattractant protein-1) and tumor necrosis factor-α, in turn secreting CCL2, nitric oxide, and several cytokines. Pericytes can therefore act as promoters of both the innate and adaptive arms of the immune system. Much like professional phagocytes, pericytes also have the ability to clear up cellular debris and macromolecular plaques. Moreover, pericytes promote the activities of CNS glia, including in maturation of oligodendrocyte lineage cells for myelination. Conversely, pericytes can impair regenerative processes by contributing to scar formation. A better characterization of CNS pericytes and their functions would bode well for therapeutics aimed at alleviating their undesirable properties and enhancing their benefits.

Anindita Bhattacharya

Papers

Beyond barrier functions: Roles of pericytes in homeostasis and regulation of neuroinflammation.