Abstract 26: Anti-TIM-1 Monoclonal Antibody Therapy Expands Atheroprotective B1a B Cells in vivo and Attenuates Development and Progression of Atherosclerosis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Tin Kyaw ◽  
Hamid Hosseini ◽  
Peter Kanellakis ◽  
Christopher Tay ◽  
Anh Cao ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Apoptotic Cell ◽  
Antibody Therapy ◽  
Atherosclerosis Progression ◽  
Atherosclerosis Development ◽  
Deficient Mice

Background: B1a B cells attenuate atherosclerosis by secreting natural IgM, but their therapeutic application is limited by lack of availability. Regulatory B cells identified by Tim-1 expression and expanded through Tim-1 ligation by anti-TIM-1 low affinity monoclonal antibody (RMT1-10 mAb) induced tolerance. Here, we examined the capacity of this mAb to expand B1a B cells to inhibit atherosclerosis development and progression of established atherosclerosis. Methods and Results: Six-week old male ApoE-deficient mice were treated with RMT1-10 mAb and fed a high-fat diet (HFD) for 8 weeks. B1a TIM-1+IgM+ B cells and B1a TIM-1+IgM+IL-10+ B cells were selectively expanded. These effects reduced lesion size, markedly increased plasma and lesion IgM and decreased lesion oxidatively modified LDL. Lesion CD4+ and CD8+ T cells, macrophages and MCP-1, VCAM-1, proinflammatory cytokine expression, apoptotic cell numbers and necrotic cores were reduced. Splenectomy indicated that these effects were B1a B cell-dependent. B1a B cell stimulation in vitro with RMT1-10 mAb promoted dose-response B1a B cell proliferation and B1a-derived IgM production. To determine whether treatment attenuated developed atherosclerosis progression, 6 week-old male ApoE-deficient mice were fed a HFD for 6 weeks, and treated with anti-TIM-1 mAb for another 6 weeks while continuing the HFD. Treatment also increased B1a TIM-1+IgM+ B cells, B1a TIM-1+IgM+IL-10+ B cells and IgM levels and greatly attenuated atherosclerosis progression. Conclusions: Anti-TIM-1 treatment attenuates atherosclerosis development and progression by selectively expanding atheroprotective B1a B cells and modulating its immunoinflammatory component. TIM-1 mAb therapy could be an attractive approach for treating atherosclerosis.

scholarly journals Inhibition of murine B and T lymphopoiesis in vivo by an anti-interleukin 7 monoclonal antibody.

1993 ◽  
Vol 178 (1) ◽  
pp. 257-264 ◽  
Author(s):  
K H Grabstein ◽  
T J Waldschmidt ◽  
F D Finkelman ◽  
B W Hess ◽  
A R Alpert ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
B Cell ◽  
Culture Methods ◽  
Cell Stage ◽  
Interleukin 7 ◽  
Slow Turnover

The effects of interleukin 7 (IL-7) on the growth and differentiation of murine B cell progenitors has been well characterized using in vitro culture methods. We have investigated the role of IL-7 in vivo using a monoclonal antibody that neutralizes IL-7. We find that treatment of mice with this antibody completely inhibits the development of B cell progenitors from the pro-B cell stage forward. We also provide evidence that all peripheral B cells, including those of the B-1 and conventional lineages, are derived from IL-7-dependent precursors. The results are consistent with the rapid turnover of B cell progenitors in the marrow, but a slow turnover of mature B cells in the periphery. In addition to effects on B cell development, anti-IL-7 treatment substantially reduced thymus cellularity, affecting all major thymic subpopulations.

scholarly journals TACI-BLyS signaling via B-cell–dendritic cell cooperation is required for naive CD8+ T-cell priming in vivo

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 594-601 ◽  
Author(s):  
Yaiza Diaz-de-Durana ◽  
George T. Mantchev ◽  
Richard J. Bram ◽  
Alessandra Franco
Keyword(s):  
B Cells ◽  
Dendritic Cell ◽  
B Cell ◽  
B Lymphocyte ◽  
Costimulatory Molecule ◽  
Early Signal ◽  
Maturation In Vitro ◽  
Deficient Mice

AbstractWe demonstrated that B-cell–dendritic cell (DC) interactions via transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) and B-lymphocyte stimulator (BLyS) provide an early signal critical to generate adequate numbers of mature antigen presenting cells (APCs) to prime naive CD8+ T cells (CTLs) in vivo. Evidence that B cells are required for efficient CTL generation in mice and that reconstitution with wild-type but not TACI-knockout B cells restored normal CTL responses support our conclusion. Moreover, low doses of a TACI fusion protein (TACI-Fc) that express the extracellular domain of TACI (amino acid [aa] 1-126) restored CTL priming in B-cell–deficient mice in vivo and induced DC maturation in vitro. In fact, following interactions with B cells, splenic DCs rapidly express the CD86 costimulatory molecule, to an extent comparable to the exposure to antigenic stimuli. BLyShigh peptide-pulsed bone marrow–derived DCs, used as vaccines in vivo, cannot generate CTLs in B-cell–deficient and TACI-deficient mice, strongly supporting a need for B-cell–DC cooperation through TACI-BLyS during CTL first encounter with antigens in vivo.

Stat5a/b contribute to interleukin 7–induced B-cell precursor expansion, but abl- andbcr/abl-induced transformation are independent of Stat5

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2277-2283 ◽  
Author(s):  
Veronika Sexl ◽  
Roland Piekorz ◽  
Richard Moriggl ◽  
Juerg Rohrer ◽  
Michael P. Brown ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
Target Cells ◽  
Interleukin 7 ◽  
And Function ◽  
Deficient Mice

Abstract The cytokines interleukin 7 (IL-7) and interleukin 4 (IL-4) regulate lymphoid differentiation and function and activate the transcription factor Stat5. Using mice deficient for the 2 highly related transcription factors, Stat5a and Stat5b (Stat5a/b−/−), we investigated the role of Stat5 for B-cell differentiation, expansion, and function. Peripheral blood B cells of Stat5-deficient mice are significantly reduced, but no proliferation defects in response to various mitogenic stimuli are found. Also, IgM and IgG1 antibody production and immunoglobulin class switching are not affected. Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7. Pro- and pre-B cells are the target cells of the abloncogene and numerous studies have suggested that Stat5a/b is essential for transformation by derivatives of the Abelson(abl) gene. To assess the role of Stat5a/b in transformation, we have evaluated the ability of variousabl derivatives to transform cells from Stat5a/b-deficient mice in vitro or in vivo. We demonstrate that the absence of Stat5a/b is not essential for the induction of lymphoid or myeloid tumors in vivo or on the ability to transform bone marrow cells in vitro.

scholarly journals Successful T cell priming in B cell-deficient mice.

1995 ◽  
Vol 182 (4) ◽  
pp. 915-922 ◽  
Author(s):  
M M Epstein ◽  
F Di Rosa ◽  
D Jankovic ◽  
A Sher ◽  
P Matzinger
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Protein Antigens ◽  
Capture Process ◽  
T Cell Priming ◽  
Deficient Mice

B cells are an abundant population of lymphocytes that can efficiently capture, process, and present antigen for recognition by activated or memory T cells. Controversial experiments and arguments exist, however, as to whether B cells are or should be involved in the priming of virgin T cells in vivo. Using B cell-deficient mice, we have studied the role of B cells as antigen-presenting cells in a wide variety of tests, including assays of T cell proliferation and cytokine production in responses to protein antigens, T cell killing to minor and major histocompatibility antigens, skin graft rejection, and the in vitro and in vivo responses to shistosome eggs. We found that B cells are not critical for either CD4 or CD8 T cell priming in any of these systems. This finding lends support to the notion that the priming of T cells is reserved for specialized cells such as dendritic cells and that antigen presentation by B cells serves distinct immunological functions.

Stat5a/b contribute to interleukin 7–induced B-cell precursor expansion, but abl- andbcr/abl-induced transformation are independent of Stat5

Blood ◽  
2000 ◽  
Vol 96 (6) ◽  
pp. 2277-2283 ◽  
Author(s):  
Veronika Sexl ◽  
Roland Piekorz ◽  
Richard Moriggl ◽  
Juerg Rohrer ◽  
Michael P. Brown ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Interleukin 4 ◽  
Target Cells ◽  
Interleukin 7 ◽  
And Function ◽  
Deficient Mice

The cytokines interleukin 7 (IL-7) and interleukin 4 (IL-4) regulate lymphoid differentiation and function and activate the transcription factor Stat5. Using mice deficient for the 2 highly related transcription factors, Stat5a and Stat5b (Stat5a/b−/−), we investigated the role of Stat5 for B-cell differentiation, expansion, and function. Peripheral blood B cells of Stat5-deficient mice are significantly reduced, but no proliferation defects in response to various mitogenic stimuli are found. Also, IgM and IgG1 antibody production and immunoglobulin class switching are not affected. Pre- and pro-B cells of Stat5-deficient animals were found to have reduced responses to IL-7. Pro- and pre-B cells are the target cells of the abloncogene and numerous studies have suggested that Stat5a/b is essential for transformation by derivatives of the Abelson(abl) gene. To assess the role of Stat5a/b in transformation, we have evaluated the ability of variousabl derivatives to transform cells from Stat5a/b-deficient mice in vitro or in vivo. We demonstrate that the absence of Stat5a/b is not essential for the induction of lymphoid or myeloid tumors in vivo or on the ability to transform bone marrow cells in vitro.

scholarly journals Differential Regulation of Mouse B Cell Development by Transforming Growth Factor β1

2002 ◽  
Vol 9 (2) ◽  
pp. 86-95 ◽  
Author(s):  
Denise A. Kaminski ◽  
John J. Letterio ◽  
Peter D. Burrows
Keyword(s):  
B Cells ◽  
Growth Factor ◽  
B Cell ◽  
Transforming Growth Factor ◽  
Plasma Cells ◽  
Population Analysis ◽  
Cell Development ◽  
B Cell Development

Transforming growth factor β (TGFβ) can inhibit thein vitroproliferation, survival and differentiation of B cell progenitors, mature B lymphocytes and plasma cells. Here we demonstrate unexpected, age-dependent reductions in the bone marrow (BM) B cell progenitors and immature B cells in TGFβ1-/-mice. To evaluate TGFβ responsiveness during normal B lineage development, cells were cultured in interleukin 7 (IL7)±TGFβ. Picomolar doses of TGFβ1 reduced pro-B cell recoveries at every timepoint. By contrast, the pre-B cells were initially reduced in number, but subsequently increased compared to IL7 alone, resulting in a 4-fold increase in the growth rate for the pre-B cell population. Analysis of purified BM sub-populations indicated that pro-B cells and the earliest BP1-pre-B cells were sensitive to the inhibitory effects of TGFβ1. However, the large BP1+pre-B cells, although initially reduced, were increased in number at days 5 and 7 of culture. These results indicate that TGFβ1 is important for normal B cell developmentin vivo, and that B cell progenitors are differentially affected by the cytokine according to their stage of differentiation.

CD40 inhibits B cell apoptosis by upregulating bcl-xL expression and blocking oxidant accumulation

1997 ◽  
Vol 272 (3) ◽  
pp. C950-C956 ◽  
Author(s):  
W. Fang ◽  
K. A. Nath ◽  
M. F. Mackey ◽  
R. J. Noelle ◽  
D. L. Mueller ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cd40 Ligand ◽  
Antioxidant Response ◽  
Immunoglobulin M ◽  
Inhibitory Protein ◽  
Wehi 231 ◽  
Immature Mouse

Signaling through the CD40 receptor on human and murine B lymphocytes is necessary for germinal center formation and immunoglobulin class switching in vivo and rescues B cells from apoptosis triggered by cross-linking of surface immunoglobulin M in vitro. Ligation of CD40 on the immature mouse B cell line WEHI-231 with recombinant CD40 ligand (CD40L) was found to protect cells from apoptosis after gamma irradiation, as well as that following treatment with the sphingomyelin ceramide or compounds that deplete intracellular glutathione. CD40 signaling led to a rapid increase in the expression of the apoptosis inhibitory protein Bcl-xL. In addition, the apoptosis-induced accumulation of intracellular oxidants in WEHI-231 B cells was rapidly diminished by CD40 crosslinking. This antioxidant response was observed within 1 h and coincided with a preservation of intracellular thiols. These findings indicate that CD40 signaling induces a generalized cellular resistance to apoptosis characterized by an upregulation of Bcl-xL and changes in the intracellular redox potential.

scholarly journals Epstein-Barr Virus LMP2A Alters In Vivo and In Vitro Models of B-Cell Anergy, but Not Deletion, in Response to Autoantigen

2005 ◽  
Vol 79 (12) ◽  
pp. 7355-7362 ◽  
Author(s):  
Michelle A. Swanson-Mungerson ◽  
Robert G. Caldwell ◽  
Rebecca Bultema ◽  
Richard Longnecker
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Nuclear Translocation ◽  
Cell Receptor ◽  
Barr Virus ◽  
Low Levels ◽  
Epstein Barr

ABSTRACT A significant percentage of the population latently harbors Epstein-Barr virus (EBV) in B cells. One EBV-encoded protein, latent membrane protein 2A (LMP2A), is expressed in tissue culture models of EBV latent infection, in human infections, and in many of the EBV-associated proliferative disorders. LMP2A constitutively activates proteins involved in the B-cell receptor (BCR) signal transduction cascade and inhibits the antigen-induced activation of these proteins. In the present study, we investigated whether LMP2A alters B-cell receptor signaling in primary B cells in vivo and in vitro. LMP2A does not inhibit antigen-induced tolerance in response to strong stimuli in an in vivo tolerance model in which B cells are reactive to self-antigen. In contrast, LMP2A bypasses anergy induction in response to low levels of soluble hen egg lysozyme (HEL) both in vivo and in vitro as determined by the ability of LMP2A-expressing HEL-specific B cells to proliferate and induce NF-κB nuclear translocation after exposure to low levels of antigen. Furthermore, LMP2A induces NF-κB nuclear translocation independent of BCR cross-linking. Since NF-κB is required to bypass tolerance induction, this LMP2A-dependent NF-κB activation may complete the tolerogenic signal induced by low levels of soluble HEL. Overall, the findings suggest that LMP2A may not inhibit BCR-induced signals under all conditions as previously suggested by studies with EBV immortalized B cells.

scholarly journals Identification of an Essential Cytoplasmic Region of Interleukin-7 Receptor α Subunit in B-Cell Development

2018 ◽  
Vol 19 (9) ◽  
pp. 2522 ◽  
Author(s):  
Hirotake Kasai ◽  
Taku Kuwabara ◽  
Yukihide Matsui ◽  
Koichi Nakajima ◽  
Motonari Kondo
Keyword(s):  
B Cells ◽  
B Cell ◽  
Myeloid Cell ◽  
Cell Development ◽  
B Cell Development ◽  
Α Subunit ◽  
Interleukin 7 ◽  
In Cells

Interleukin-7 (IL-7) is essential for lymphocyte development. To identify the functional subdomains in the cytoplasmic tail of the IL-7 receptor (IL-7R) α chain, here, we constructed a series of IL-7Rα deletion mutants. We found that IL-7Rα-deficient hematopoietic progenitor cells (HPCs) gave rise to B cells both in vitro and in vivo when a wild-type (WT) IL-7Rα chain was introduced; however, no B cells were observed under the same conditions from IL-7Rα-deficient HPCs with introduction of the exogenous IL-7Rα subunit, which lacked the amino acid region at positions 414–441 (d414–441 mutant). Signal transducer and activator of transcription 5 (STAT5) was phosphorylated in cells with the d414–441 mutant, similar to that in WT cells, in response to IL-7 stimulation. In contrast, more truncated STAT5 (tSTAT5) was generated in cells with the d414–441 mutant than in WT cells. Additionally, the introduction of exogenous tSTAT5 blocked B lymphopoiesis but not myeloid cell development from WT HPCs in vivo. These results suggested that amino acids 414–441 in the IL-7Rα chain formed a critical subdomain necessary for the supportive roles of IL-7 in B-cell development.

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