B-cell kinetics in humans: rapid turnover of peripheral blood memory cells

Macallan, Derek C.; Wallace, Diana L.; Zhang, Yan; Ghattas, Hala; Asquith, Becca; Lara, Catherine de; Worth, Andrew; Panayiotakopoulos, George; Griffin, George E.; Tough, David F.; Beverley, Peter C. L.

doi:10.1182/blood-2004-09-3740

Cited by 162 publications

(140 citation statements)

References 54 publications

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“…In the spleen, increases in GFP marking over time were seen for CD19 1 and Gr-1 1 cells, suggesting an influx of modified cells derived from HSPCs in the BM, rather than initial transduction or expansion of the cells in the spleen. The fact that the CD19 1 cells turnover is less than 4 weeks 21,22 and that modified cells are detected at much later time points, support this hypothesis. Notably, changes in the levels of BM CD19 1 and Gr-1 1 cells were observed after in vivo transduction, independent of animals' mobilization status.…”

Section: Resultssupporting

confidence: 69%

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

Richter

Saydaminova

Yumul

et al. 2016

Blood

145

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• Mobilized hematopoietic stem cells transduced with IV injected HD-Ad5/35 11 vectors home to the BM persist long term.• Our approach allows for the stable genetic modification of primitive, long-term persisting HSPCs.Current protocols for hematopoietic stem/progenitor cell (HSPC) gene therapy, involving the transplantation of ex vivo genetically modified HSPCs are complex and not without risk for the patient. We developed a new approach for in vivo HSPC transduction that does not require myeloablation and transplantation. It involves subcutaneous injections of granulocyte-colony-stimulating factor/AMD3100 to mobilize HSPCs from the bone marrow (BM) into the peripheral blood stream and the IV injection of an integrating, helper-dependent adenovirus (HD-Ad5/35 11 ) vector system. These vectors target CD46, a receptor that is uniformly expressed on HSPCs. We demonstrated in human CD46 transgenic mice and immunodeficient mice with engrafted human CD34 1 cells that HSPCs transduced in the periphery home back to the BM where they stably express the transgene. In hCD46 transgenic mice, we showed that our in vivo HSPC transduction approach allows for the stable transduction of primitive HSPCs. Twenty weeks after in vivo transduction, green fluorescent protein (GFP) marking in BM HSPCs (Lin 2 Sca1 1 Kit 2 cells) in most of the mice was in the range of 5% to 10%. The percentage of GFP-expressing primitive HSPCs capable of forming multilineage progenitor colonies (colony-forming units [CFUs]) increased from 4% of all CFUs at week 4 to 16% at week 12, indicating transduction and expansion of long-term surviving HSPCs. Our approach was well tolerated, did not result in significant transduction of nonhematopoietic tissues, and was not associated with genotoxicty. The ability to stably genetically modify HSPCs without the need of myeloablative conditioning is relevant for a broader clinical application of gene therapy. (Blood. 2016;128(18):2206-2217

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Section: Resultssupporting

confidence: 69%

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

Richter

Saydaminova

Yumul

et al. 2016

Blood

145

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“…Using in vivo labeling of dividing cells, cell sorting, and gas chromatography-mass spectrometry, the authors showed that naive B cells divide slowly (0.46% per day), whereas memory B cells proliferate more rapidly (2.66% per day). This supports the view that B cell memory may be maintained independently of Ag by clones of spontaneously proliferating B cells (47).…”

Section: Menc-specific Memory B Cell Immune Responses Postboostersupporting

confidence: 77%

“…Consequently, this theory suggests that memory B cells continuously recirculate through the blood and secondary lymphoid organs (27), and therefore circulating levels of Ab are in proportion to the total Ag-specific memory B cell pool that is reflected by the frequency of circulating Ag-specific B cells. This theory is supported by a B cell kinetic study in humans (47). Using in vivo labeling of dividing cells, cell sorting, and gas chromatography-mass spectrometry, the authors showed that naive B cells divide slowly (0.46% per day), whereas memory B cells proliferate more rapidly (2.66% per day).…”

Section: Menc-specific Memory B Cell Immune Responses Postboostersupporting

confidence: 54%

B Cell Memory to a Serogroup C Meningococcal Conjugate Vaccine in Childhood and Response to Booster: Little Association with Serum IgG Antibody

Perrett

Jin

Clutterbuck

et al. 2012

The Journal of Immunology

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The maintenance of adequate serum Ab levels following immunization has been identified as the most important mechanism for individual long-term protection against rapidly invading encapsulated bacteria. The mechanisms for maintaining adequate serum Ab levels and the relationship between Ag-specific memory B cells and Ab at steady state are poorly understood. We measured the frequency of circulating serogroup C meningococcal (MenC)-specific memory B cells in 250 healthy 6- to 12-y-old children 6 y following MenC conjugate vaccine priming, before a booster of a combined Haemophilus influenzae type b–MenC conjugate vaccine and then 1 wk, 1 mo, and 1 y after the booster. We investigated the relationship between circulating MenC-specific memory B cell frequencies and Ab at baseline and following the booster vaccine. We found very low frequencies of circulating MenC-specific memory B cells at steady state in primary school-aged children and little association with MenC IgG Ab levels. Following vaccination, there were robust memory B cell booster responses that, unlike Ab levels, were not dependent on age at priming with MenC. Measurement of B cell memory in peripheral blood does not predict steady state Ab levels nor the capacity to respond to a booster dose of MenC Ag.

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“…This is consistent with the idea that antigen persistence and continuous stimulation are necessary to maintain memory B-cells [25]. However, to date, polysaccharides were not thought to be able to elicit a memory B cell response [26].…”

Section: Microanatomic Site Of Splenic Immune Reaction Towards Polysasupporting

confidence: 85%

The role of complement in the success of vaccination with conjugated vs. unconjugated polysaccharide antigen

Salehen¹,

Stover²

2008

Vaccine

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The complement system, a well-characterised arm of the innate immune system, significantly influences the adaptive immune response via direct cell-cell interaction and maintenance of lymphoid organ architecture. Development of vaccines is a major advance in modern health care. In this review, we highlight the importance of the marginal zone in response to both, polysaccharide and conjugated vaccines, and discuss the relevance of complement herein, based on findings obtained from animal models with specific deletions of certain complement components and from vaccination reports of complement-deficient individuals. We conclude that both, intactness of the complement system and maturity of expression of its components, are relatively more important to aid in the immune response to polysaccharide vaccine than to conjugated vaccines. keywords (3): complement vaccine polysaccharide running titleComplement essential for polysaccharide vaccines 2 The importance of complement activation in adaptive immunityThe complement system is part of the innate immune defence, because it partakes in first-line, pattern-mediated recognition via its germ-line encoded serum proteins and receptors. It has evolved from a primordial fluid-phase system that "simply" tags and mediates uptake of micro-organisms by cells of early chordates. Large-scale gene duplications, exon shuffling and transposition events are the main evolutionary mechanisms that have generated a wide range of diversified molecules, which we now ascribe to innate and adaptive immune defences Importantly, after subcutaneous administration of T-independent or T-dependent antigens in mice, it is the spleen that reacts with formation of antibody forming cells before the draining lymphnodes, especially in response to T-independent antigen [32].Germinal centers are formed during an immune response elicited with a so-called Tindependent antigen. This reaction is, however, of short duration. It is possible that the absence of somatic hypermutation of the immunoglobulin V genes is due to both, the curtailed germinal center reaction -as somatic hypermutation is a relatively late event -6 and the lack of T-cell help [33]. Of note, marginal zone B-cells are incapable of participating in the process of somatic hypermutation due to the lack of expression of activation-induced cytidine deaminase, an enzyme essential for this process [34].The involvement of T-cells is not strictly excluded in the antibody response against polysaccharides, as B7 ligand dependent costimulation of B-cells (by T-cells) is needed, however, the interaction in this early response is short and T-cell receptor unspecific [35].The absence of somatic hypermutation does, however, explain the low affinity binding of anti-polysaccharide antibodies.

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B-cell kinetics in humans: rapid turnover of peripheral blood memory cells

Cited by 162 publications

References 54 publications

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors

B Cell Memory to a Serogroup C Meningococcal Conjugate Vaccine in Childhood and Response to Booster: Little Association with Serum IgG Antibody

The role of complement in the success of vaccination with conjugated vs. unconjugated polysaccharide antigen

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