Human Bone Marrow Hosts Polyfunctional Memory CD4+ and CD8+ T Cells with Close Contact to IL-15–Producing Cells

Herndler‐Brandstetter, Dietmar; Landgraf, Katja; Jenewein, Brigitte; Tzankov, Alexandar; Brunauer, Regina; Brunner, Stefan M.; Parson, Walther; Kloss, Frank; Gaßner, Robert; Lepperdinger, Günter; Grubeck‐Loebenstein, Beatrix

doi:10.4049/jimmunol.1100243

Cited by 95 publications

(122 citation statements)

References 54 publications

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“…27,28 A recent study suggests that this may also occur in humans. 29 Thus, BM is potentially a major source of these cells mobilized to the blood by plerixafor.…”

Section: Discussionmentioning

confidence: 99%

The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

McDermott

Liu

Ulrick

et al. 2011

Blood

128

111

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WHIM syndrome is a rare congenital immunodeficiency disorder characterized by warts, hypogammaglobulinemia, infections, and myelokathexis (neutropenia because of impaired egress from the BM); most patients also have severe panleukopenia. Because WHIM syndrome is caused by mutations in the chemokine receptor CXCR4 that result in increased agonist-dependent signaling, we hypothesized that the CXCR4 antagonist plerixafor (Mozobil [Genyzme Corporation], AMD3100), might be an effective treatment. To test this, we enrolled 3 unrelated adult patients with the most common WHIM mutation, CXCR4 R334X , in a phase 1 dose-escalation study. Plerixafor increased absolute lymphocyte, monocyte, and neutrophil counts in blood to normal without significant side effects in all 3 patients. Peak responses occurred at 3-12 hours after injection and waned by 24 hours after injection which tracked the drug's pharmacokinetics. All 3 cell types increased in a dose-dependent manner with the rank order of responsiveness absolute lymphocyte > monocyte > neutrophil. These data provide the first pharmacologic evidence that panleukopenia in WHIM syndrome is caused by CXCL12-CXCR4 signalingdependent leukocyte sequestration, and support continued study of plerixafor as mechanism-based therapy in this disease. This study is registered at http:// www.clinicaltrials.gov as NCT00967785.

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“…27,28 A recent study suggests that this may also occur in humans. 29 Thus, BM is potentially a major source of these cells mobilized to the blood by plerixafor.…”

Section: Discussionmentioning

confidence: 99%

The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

McDermott

Liu

Ulrick

et al. 2011

Blood

128

111

View full text Add to dashboard Cite

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“…30,31 Vaccination studies have identified effector memory T cells in mouse bone marrow that may serve as a reservoir, 32,33 and this may also be true in humans. 34 Thus, bone marrow is potentially a major source of all the major cell types mobilized to the blood by plerixafor. However, our serial biopsy/ aspirate data were most consistent with bone marrow being a source for neutrophil and B-cell mobilization, since the frequency of these 2 cell types declined from baseline after 6 months of plerixafor treatment.…”

Section: Discussionmentioning

confidence: 99%

A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor

McDermott

Liu

Velez

et al. 2014

Blood

118

119

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• Plerixafor can be given safely to WHIM syndrome patients twice daily for a 6-month period and appears promising as a treatment.Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare immunodeficiency disorder caused by gain-of-function mutations in the G proteincoupled chemokine receptor CXCR4. The CXCR4 antagonist plerixafor, which is approved by the US Food and Drug Administration (FDA) for stem cell mobilization in cancer and administered for that indication at 0.24 mg/kg, has been shown in short-term (1-to 2-week) phase 1 dose-escalation studies to correct neutropenia and other cytopenias in WHIM syndrome. However, long-term safety and long-term hematologic and clinical efficacy data are lacking. Here we report results from the first long-term clinical trial of plerixafor in any disease, in which 3 adults with WHIM syndrome self-injected 0.01 to 0.02 mg/kg (4% to 8% of the FDA-approved dose) subcutaneously twice daily for 6 months. Circulating leukocytes were durably increased throughout the trial in all patients, and this was associated with fewer infections and improvement in warts in combination with imiquimod; however, immunoglobulin levels and specific vaccine responses were not fully restored. No drug-associated side effects were observed. These results provide preliminary evidence for the safety and clinical efficacy of long-term, low-dose plerixafor in WHIM syndrome and support its continued study as mechanism-based therapy in this disease. The ClinicalTrials.gov identifier for this study is NCT00967785. (Blood. 2014;123(15):2308-2316

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“…In mice, 30%‐40% of bone marrow CD8 + memory T cells express CD69,117 and about 40%‐50% of bone marrow CD4 + memory T cells 137. Expression of CD69 is induced upon activation of T cells138 and therefore has been conceived as a marker of activation, also for bone marrow memory T cells 133, 139. However, in murine bone marrow, neither CD69 + nor CD69 − memory CD4 + T cells are cycling according to Ki‐67 expression 137.…”

Section: The Lifestyle Of Bone Marrow Memory T Lymphocytesmentioning

confidence: 99%

Immunological memories of the bone marrow

Chang

Tokoyoda

Radbruch

2018

Immunological Reviews

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SummaryMemory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic “half‐lives”, but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.

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Human Bone Marrow Hosts Polyfunctional Memory CD4+ and CD8+ T Cells with Close Contact to IL-15–Producing Cells

Cited by 95 publications

References 54 publications

The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

The CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome

A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor

Immunological memories of the bone marrow

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