Antibody synthesis by bone marrow cells in vitro following primary and booster tetanus toxoid immunization in humans.

Kodo, Hideki; Gale, Robert Peter; Saxon, Andrew

doi:10.1172/jci111341

Cited by 31 publications

(9 citation statements)

References 24 publications

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“…Vaccinations were separated by at least 1.5 y, and blood was drawn for analysis 6 d after each challenge, at which time point the circulating Ab-secreting cells specific for TT are known to peak (16,17). Using the Symplex technology (5), Ab repertoires were prepared from circulating plasma blasts separately after each challenge.…”

Section: Statistical Analysesmentioning

confidence: 99%

Limits for Antibody Affinity Maturation and Repertoire Diversification in Hypervaccinated Humans

Poulsen

Jensen

Haurum

et al. 2011

The Journal of Immunology

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The immune system is known to generate a diverse panel of high-affinity Abs by adaptively improving the recognition of pathogens during ongoing immune responses. In this study, we report the biological limits for Ag-driven affinity maturation and repertoire diversification by analyzing Ab repertoires in two adult volunteers after each of three consecutive booster vaccinations with tetanus toxoid. Maturation of on-rates and off-rates occurred independently, indicating a kinetically controlled affinity maturation process. The third vaccination induced no significant changes in the distribution of somatic mutations and binding rate constants implying that the limits for affinity maturation and repertoire diversification had been reached. These fully matured Ab repertoires remained similar in size, genetically diverse, and dynamic. Somatic mutations and kinetic rate constants showed normal and log-normal distribution profiles, respectively. Mean values can therefore be considered as biological constants defining the observed boundaries. At physiological temperature, affinity maturation peaked at kon = 1.6 × 104 M−1 s−1 and koff = 1.7 × 10−4 s−1 leading to a maximum mean affinity of KD = 1.0 × 10−9 M. At ambient temperature, the average affinity increased to KD = 3.4 × 10−10 M mainly due to slower off-rates. This experimentally determined set of constants can be used as a benchmark for analysis of the maturation level of human Abs and Ab responses.

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Section: Statistical Analysesmentioning

confidence: 99%

Limits for Antibody Affinity Maturation and Repertoire Diversification in Hypervaccinated Humans

Poulsen

Jensen

Haurum

et al. 2011

The Journal of Immunology

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“…23,24,[29][30][31] These tet-specific circulating PCs exhibit features of intermediate maturity between early PCs and PCs present in deposit organs such as the BM, 23,28,31 and the occurrence of these PCs is temporarily and functionally associated with the high-rate phase of serum anti-tet Ab formation and, accordingly, with the establishment of the BM pool of anti-tet Ab-producing PCs. [29][30][31][32][33] Therefore, blood tet-specific PCs may be an appropriate model for exploring the factors involved in the selection of the BM PC compartment. In this regard, it is well established that long-lived BM PCs predominantly synthesize Ab with high-affinity for the Ag.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, IGVH3 sequences obtained from tetC HIGH PCs exhibited R/R ϩ S ratios clearly higher than those from tetC INT PCs, a possible indication of a more precise Ag selection process and, in consequence, of higher affinity. It is well established that tet, as well as tetC, is a complex multiepitopic Ag that elicits an extensively polyclonal humoral response 32,36,49 (data not shown). The present findings imply that tet booster generated not only PCs secreting a variety of high-affinity Abs, but also induced a considerable number of PCs whose Abs exhibited a certain range of intermediate affinity for this Ag.…”

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confidence: 99%

Increased survival is a selective feature of human circulating antigen-induced plasma cells synthesizing high-affinity antibodies

González-Garcı́a

Rodríguez‐Bayona

Mora-López

et al. 2008

Blood

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The present study shows that tetanus toxoid (tet) booster releases to the human circulation 2 subsets of specific plasma cells (PCs), as defined by phenotype and morphology, which clearly differed in the staining capacity of their cytoplasmic antibodies (Abs) with fluorescein isothiocyanate (FITC)-labeled tet-fragment C (tetC). These cells, called tetC HIGH IntroductionPlasma cells (PCs) represent the final and effector phase of the B lymphocyte differentiation process. There is accumulating evidence to support the view that in mammals, the PC compartment comprises a biologically complex variety of cell stages. In systemic humoral responses, specific PCs initially appear in antigen (Ag)-induced extrafollicular foci of secondary lymphoid tissues. In the presence of sufficient Ag, PCs are subsequently generated in the follicular germinal centers. [1][2][3][4][5] Most of the early-generated PCs die within a few days by apoptosis. [5][6][7] Later, some of the recently generated PCs migrate through the circulation and home into specialized survival niches present mainly in the bone marrow (BM) 5,[8][9][10][11][12][13][14][15] and, less commonly, in the spleen and probably in other lymphoid organs, [16][17][18] as well as in inflamed tissues. 19 In these locations, PCs are thought to produce antibodies (Abs) for prolonged periods of time. Thus, it is well established that the BM PC pool is responsible for the generation of long-lasting serum Ab levels. 5,[9][10][11][12]20 The mechanisms involved in the arrival and retention of PCs into the BM niches are beginning to be known. In this respect, the interaction between the chemokine receptor CXCR4 expressed on PCs and its ligand CXCL12 is required for the establishment of the BM PC compartment in mice, 21 and probably in humans. [22][23][24] Although the auxiliary cellular components of the BM PC niches still remain poorly defined, [13][14][15]25 they are believed to convey the necessary signals to support the prolonged survival of immigrant PCs. Some of the molecular mechanisms that participate in this process have been identified, including IL-6, APRIL, and certain ligands of PC adhesion molecules. [13][14][15]25,26 In spite of these findings, it remains uncertain whether occupancy of BM PC niches is merely a random phenomenon, or whether intrinsic factors of PCs are involved in the generation of the BM PC compartment.It is now clear that, a few days after booster immunization, Ag-specific PCs are transiently observed in the blood, and this circulating PC subset appears to contain the precursors of BM PCs. 27,28 In humans, a conventional booster immunization with tetanus-toxoid (tet) induces the temporary appearance in the blood of tet-specific PCs. 23,24,[29][30][31] These tet-specific circulating PCs exhibit features of intermediate maturity between early PCs and PCs present in deposit organs such as the BM, 23,28,31 and the occurrence of these PCs is temporarily and functionally associated with the high-rate phase of serum anti-tet Ab formation and, accordingly, ...

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“…A second and any further exposure to the same Ag evoke "secondaries" or "memory" responses that involve mainly IgG with a higher affinity for the Ag. Although study ofthe human antibody response to some Ags, e.g., tetanus toxoid (TT) and keyhole limpet hemocyanin, has been attempted (9)(10)(11)(12)(13), the enormous difficulty in generating human mAbs (14,15) has hindered the definition of the clonal basis of such responses.…”

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confidence: 99%

Clonal analysis of a human antibody response. Quantitation of precursors of antibody-producing cells and generation and characterization of monoclonal IgM, IgG, and IgA to rabies virus.

Ueki

Goldfarb

Harindranath

et al. 1990

The Journal of Experimental Medicine

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The maturation of the specific antibody response to foreign antigens (Ags)' has been thoroughly investigated in experimental animals (1-8). A first in vivo exposure to Ag induces a "primary" antibody response constituted mainly of IgM with relatively low affinity for the inducing Ag. A second and any further exposure to the same Ag evoke "secondaries" or "memory" responses that involve mainly IgG with a higher affinity for the Ag. Although study ofthe human antibody response to some Ags, e.g., tetanus toxoid (TT) and keyhole limpet hemocyanin, has been attempted (9-13), the enormous difficulty in generating human mAbs (14, 15) has hindered the definition of the clonal basis of such responses.The recent progress made in the generation of human mAb-producing cell lines (14-21) and in the characterization of novel B cell subsets (22, 23) allowed us to investigate the human antibody response to self and exogenous Ags at the clonal level (16)(17)(18)(19). In the present studies, we quantitated the circulating B cells committed to the production of antibodies to rabies virus and determined their phenotype in healthy humans before and after multiple administrations of inactivated rabies virus vaccine. Moreover, using EBV transformation and somatic cell hybridization techniques, we constructed 10 cell hybrids secreting IgM, IgG, and IgA mAbs to the virus. We found that in the preimmune B cell repertoire, circulating lymphocytes committed to the production ofvirus-binding IgM, but not IgG or IgA antibodies, are present in high number. These cells are surface CD5+ and the antibodies they produce are polyreactive and low affinity. After vaccination with inactivated rabies virus, B lymphocytes producing monoreactive high affinity IgG and IgA antibodies to the virus consistently appear in the circulating. Most ofthese cells are surface CD5-and account for >10% of the total IgG-and IgA-producing cell precursors, respectively.

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Antibody synthesis by bone marrow cells in vitro following primary and booster tetanus toxoid immunization in humans.

Abstract: Kodo's present address is

Cited by 31 publications

References 24 publications

Limits for Antibody Affinity Maturation and Repertoire Diversification in Hypervaccinated Humans

Limits for Antibody Affinity Maturation and Repertoire Diversification in Hypervaccinated Humans

Increased survival is a selective feature of human circulating antigen-induced plasma cells synthesizing high-affinity antibodies

Clonal analysis of a human antibody response. Quantitation of precursors of antibody-producing cells and generation and characterization of monoclonal IgM, IgG, and IgA to rabies virus.

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