Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view

Cserr, Helen F.; Knopf, Paul M.

doi:10.1016/0167-5699(92)90027-5

Cited by 612 publications

(319 citation statements)

References 23 publications

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“…43,44 Unlike peripheral tissues, the CNS is protected by the BBB, 45,46 possesses a unique non-classical lymphatic drainage system, 47 and contains distinct tissue-resident cells that T cells inevitably interact with including neurons, astrocytes, and microglia. 48 Since the CNS has limited abilities to regenerate or accommodate large volume changes in a skull-confined space (cellular infiltrates and/or edema), these specialized cellular and anatomic structures serve to protect the host from the fatal consequences of excessive neuro-inflammation.…”

Section: Discussionmentioning

confidence: 99%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

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Section: Discussionmentioning

confidence: 99%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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“…Interaction between the brain and the secondary lymphoid organs allows regulation of immune responses in the brain [48]. This is exemplified by the crucial role of CLN in brain lesion expansion in cryolesion-enhanced EAE in rats [20] and by the presence of myelin antigens in APC in CLN of MS patients and EAE-affected rhesus monkeys and common marmoset monkeys [21,22].…”

Section: Discussionmentioning

confidence: 99%

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in J Mol Med (2009) human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked.

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“…The central nervous system (CNS) has been considered immune privileged because of its inability to mount an immune response and process antigens (1) . However, we now know that the CNS, when challenged by injury and systemic infections, has the ability to mount a wellorganized immune response (2) .…”

Section: Immune Privilege and The Spinal Cordmentioning

confidence: 99%

Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes

Trivedi

Olivas

Noble-Haeusslein

2006

Clinical Neuroscience Research

195

138

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The immune response that accompanies spinal cord injury contributes to both injury and reparative processes. It is this duality that is the focus of this review. Here we consider the complex cellular and molecular immune responses that lead to the infiltration of leukocytes and glial activation, promote oxidative stress and tissue damage, influence wound healing, and subsequently modulate locomotor recovery. Immunomodulatory strategies to improve outcomes are gaining momentum as ongoing research carefully dissects those pathways, which likely mediate cell injury from those, which favor recovery processes. Current therapeutic strategies address divergent approaches including early immunoblockade and vaccination with immune cells to prevent early tissue damage and support a wound-healing environment that favors plasticity. Despite these advances, there remain basic questions regarding how inflammatory cells interact in the injured spinal cord. Such questions likely arise as a result of our limited understanding of immune cell/neural interactions in a dynamic environment that culminates in progressive cell injury, demyelination, and regenerative failure.

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Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: a new view

Cited by 612 publications

References 23 publications

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

Inflammation and spinal cord injury: Infiltrating leukocytes as determinants of injury and repair processes

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