The microstructure of secondary lymphoid organs that support immune cell trafficking

Matsuno, Kenjiro; Ueta, Hisashi; Shu, Zhao; Xu, Xuedong; Sawanobori, Yasushi; Kitazawa, Yoshiaki; Yu, Bo; Yamashita, M.; Shi, Changde

doi:10.1679/aohc.73.1

Cited by 30 publications

(31 citation statements)

References 51 publications

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“…It is reported that T cells primarily traffic to the WP via the MZBCs (39,40), which occur intermittently along the outer boundary of the PALS. Consistent with a previous report (39), MZBCs were readily identified as the sites where the marginal sinus, containing nepmucin/CD300g-expressing ECs, and the MZ itself, containing CD169 + macrophages, are both interrupted; and from this region, ER-TR7 + fibroblastic reticular cells (FRCs) extended from the MZ to the PALS (Fig.…”

Section: Pdcs Enter the Splenic Wp Via The Mzbcsmentioning

confidence: 99%

Constitutive Plasmacytoid Dendritic Cell Migration to the Splenic White Pulp Is Cooperatively Regulated by CCR7- and CXCR4-Mediated Signaling

Umemoto

Otani

Ikeno

et al. 2012

The Journal of Immunology

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Although the spleen plays an important role in host defense against infection, the mechanism underlying the migration of the innate immune cells, plasmacytoid dendritic cells (pDCs), into the spleen remains ill defined. In this article, we report that pDCs constitutively migrate into the splenic white pulp (WP) in a manner dependent on the chemokine receptors CCR7 and CXCR4. In CCR7-deficient mice and CCR7 ligand-deficient mice, compared with wild-type (WT) mice, substantially fewer pDCs were found in the periarteriolar lymphoid sheath of the splenic WP under steady-state conditions. In addition, the migration of adoptively transferred CCR7-deficient pDCs into the WP was significantly worse than that of WT pDCs, supporting the idea that pDC trafficking to the splenic WP requires CCR7 signaling. WT pDCs responded to a CCR7 ligand with modest chemotaxis and ICAM-1 binding in vitro, and priming with the CCR7 ligand enabled the pDCs to migrate efficiently toward low concentrations of CXCL12 in a CXCR4-dependent manner, raising the possibility that CCR7 signaling enhances CXCR4-mediated pDC migration. In agreement with this hypothesis, CCL21 and CXCL12 were colocalized on fibroblastic reticular cells in the T cell zone and in the marginal zone bridging channels, through which pDCs appeared to enter the WP. Furthermore, functional blockage of CCR7 and CXCR4 abrogated pDC trafficking into the WP. Collectively, these results strongly suggest that pDCs employ both CCR7 and CXCR4 as critical chemokine receptors to migrate into the WP under steady-state conditions.

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Section: Pdcs Enter the Splenic Wp Via The Mzbcsmentioning

confidence: 99%

Constitutive Plasmacytoid Dendritic Cell Migration to the Splenic White Pulp Is Cooperatively Regulated by CCR7- and CXCR4-Mediated Signaling

Umemoto

Otani

Ikeno

et al. 2012

The Journal of Immunology

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“…DCs are the most potent antigen-presenting cells (APCs), leading to the activation of naive Tcells in secondary lymphoid organs (Matsuno et al 2010; Villablanca et al 2008). In steady-state conditions, DCs are found in low numbers in the meninges, choroid plexus, and CSF (Pashenkov et al 2001), possibly because the BBB limits penetration of immune cells into the brain parenchyma.…”

Section: Dendritic Cells and Cnsmentioning

confidence: 99%

Mechanisms of Dendritic Cell Trafficking Across the Blood–brain Barrier

Sagar

Foss

Baz

et al. 2011

J Neuroimmune Pharmacol

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Although the central nervous system (CNS) is considered to be an immunoprivileged site, it is susceptible to a host of autoimmune as well as neuroinflammatory disorders owing to recruitment of immune cells across the blood–brain barrier into perivascular and parenchymal spaces. Dendritic cells (DCs), which are involved in both primary and secondary immune responses, are the most potent immune cells in terms of antigen uptake and processing as well as presentation to T cells. In light of the emerging importance of DC traficking into the CNS, these cells represent good candidates for targeted immunotherapy against various neuroinflammatory diseases. This review focuses on potential physiological events and receptor interactions between DCs and the microvascular endothelial cells of the brain as they transmigrate into the CNS during degeneration and injury. A clear understanding of the underlying mechanisms involved in DC migration may advance the development of new therapies that manipulate these mechanistic properties via pharmacologic intervention. Furthermore, therapeutic validation should be in concurrence with the molecular imaging techniques that can detect migration of these cells in vivo. Since the use of noninvasive methods to image migration of DCs into CNS has barely been explored, we highlighted potential molecular imaging techniques to achieve this goal. Overall, information provided will bring this important leukocyte population to the forefront as key players in the immune cascade in the light of the emerging contribution of DCs to CNS health and disease.

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“…Supporting this hypothesis, ATL1102 treatment produced a ∼10% reduction in the number of CD19+ (pre) B cells with detectable levels of VLA-4 expression in the blood at 8 weeks 14 (appendix e-2). A small number of leukocytes are known to migrate from the secondary lymphoid tissues via the blood, 19 which may be the source of these VLA-4–negative CD19+ cells in the blood.…”

Section: Discussionmentioning

confidence: 99%

CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS

Limmroth¹,

Barkhof²,

Desem³

et al. 2014

Neurology

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Objective:This study evaluated the efficacy and safety of ATL1102, an antisense oligonucleotide that selectively targets the RNA for human CD49d, the α subunit of very late antigen 4, in patients with relapsing-remitting multiple sclerosis (RRMS).Methods:In a multicenter, double-blind, placebo-controlled randomized phase II trial, 77 patients with RRMS were treated with 200 mg of ATL1102 subcutaneously injected 3 times in the first week and twice weekly for 7 weeks or placebo and monitored for a further 8 weeks. MRI scans were taken at baseline and weeks 4, 8, 12, and 16. The primary endpoint was the cumulative number of new active lesions (either new gadolinium-enhancing T1 lesions or nonenhancing new or enlarging T2 lesions) at weeks 4, 8, and 12.Results:A total of 72 patients completed the study and 74 intention-to-treat patients were assessed. ATL1102 significantly reduced the cumulative number of new active lesions by 54.4% compared to placebo (mean 3.0 [SD 6.12] vs 6.2 [9.89], p = 0.01). The cumulative number of new gadolinium-enhancing T1 lesions was reduced by 67.9% compared to placebo (p = 0.002). Treatment-emergent adverse events included mild to moderate injection site erythema and decrease in platelet counts that returned to within the normal range after dosing.Conclusions:In patients with RRMS, ATL1102 significantly reduced disease activity after 8 weeks of treatment and was generally well-tolerated. This trial provides evidence for the first time that antisense oligonucleotides may be used as a therapeutic approach in neuroimmunologic disorders.Classification:This study provides Class I evidence that for patients with RRMS, the antisense oligonucleotide ATL1102 reduces the number of new active head MRI lesions.

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The microstructure of secondary lymphoid organs that support immune cell trafficking

Cited by 30 publications

References 51 publications

Constitutive Plasmacytoid Dendritic Cell Migration to the Splenic White Pulp Is Cooperatively Regulated by CCR7- and CXCR4-Mediated Signaling

Constitutive Plasmacytoid Dendritic Cell Migration to the Splenic White Pulp Is Cooperatively Regulated by CCR7- and CXCR4-Mediated Signaling

Mechanisms of Dendritic Cell Trafficking Across the Blood–brain Barrier

CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS

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