Human donor bone marrow cells (DBMC) trigger A suppressed B cell function via autologous “T cell suppressor cells” in vitro

Abstract Background The role of myeloid-derived suppressor cells (MDSCs) in severe tuberculosis patients who suffer from uncontrolled pulmonary inflammation caused by hypervirulent mycobacterial infection remains unclear. Methods This issue was addressed using C57BL/6 mice infected with highly virulent Mycobacterium bovis strain MP287/03. Results CD11b +GR1 int population increased in the bone marrow, blood and lungs during advanced disease. Pulmonary CD11b +GR1 int (Ly6G intLy6C int) cells showed granularity similar to neutrophils and expressed immature myeloid cell markers. These immature neutrophils harbored intracellular bacilli and were preferentially located in the alveoli. T cell suppression occurred concomitantly with CD11b +GR1 int cell accumulation in the lungs. Furthermore, lung and bone-marrow GR1 + cells suppressed both T cell proliferation and IFN-γ production in vitro. Anti-GR1 therapy given when MDSCs infiltrated the lungs prevented expansion and fusion of primary pulmonary lesions and the development of intragranulomatous caseous necrosis, along with increased mouse survival and partial recovery of T cell function. Lung bacterial load was reduced by anti-GR1 treatment, but mycobacteria released from the depleted cells proliferated extracellularly in the alveoli, forming cords and clumps. Conclusions Granulocytic MDSCs massively infiltrate the lungs during infection with hypervirulent mycobacteria, promoting bacterial growth and the development of inflammatory and necrotic lesions, and are promising targets for host-directed therapies.

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In vitro regulation of immunoglobulin synthesis after marrow transplantation. I. T-cell and B-cell deficiencies in patients with and without chronic graft-versus-host disease

Blood ◽

10.1182/blood.v58.3.431.431 ◽

1981 ◽

Vol 58 (3) ◽

pp. 431-439 ◽

Cited By ~ 65

Author(s):

LG Lum ◽

MC Seigneuret ◽

RF Storb ◽

RP Witherspoon ◽

ED Thomas

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Graft Versus Host Disease ◽

Marrow Transplantation ◽

Cell Function ◽

Cell Activity ◽

Graft Versus Host ◽

B Cell Function

Abstract Twenty-four patients with aplastic anemia or acute leukemia were treated by marrow grafts from HLA-identical donors after conditioning with high doses of cyclophosphamide and/or today body irradiation. They were studied between 4 and 63 mo (median 14.2) after transplantation. Seventeen patients had chronic graft-versus-host disease (C-GVHD) and 7 were healthy. They were studied for defects in their T- and B-cell function using and indirect hemolytic plaque assay for Ig production after 6 days of culture in the presence of pokeweek mitogen. T or B cells from the patients with or without C-GVHD were cocultured with T or B cells from their HLA-identical marrow donors or unrelated normal controls. Intrinsic B-cell defects, lack of helper T-cell activity, and suppressor T-cell activity were more frequently found in patients with C-GVHD than in healthy patients. Fifteen of the 17 patients with C-GVHD showed on or more defects in their T-and B-cell function compared to only 3 of the 7 patients without C-GVHD. None of the healthy controls, including the marrow donors, showed defects in their T- and B-cell functions. These in vitro findings may be helpful in assessing the process of immune reconstitution and the immunologic aberration found after human marrow transplantation.

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In vitro regulation of immunoglobulin synthesis after marrow transplantation. I. T-cell and B-cell deficiencies in patients with and without chronic graft-versus-host disease

Blood ◽

10.1182/blood.v58.3.431.bloodjournal583431 ◽

1981 ◽

Vol 58 (3) ◽

pp. 431-439 ◽

Cited By ~ 1

Author(s):

LG Lum ◽

MC Seigneuret ◽

RF Storb ◽

RP Witherspoon ◽

ED Thomas

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Graft Versus Host Disease ◽

Marrow Transplantation ◽

Cell Function ◽

Cell Activity ◽

Graft Versus Host ◽

B Cell Function

Twenty-four patients with aplastic anemia or acute leukemia were treated by marrow grafts from HLA-identical donors after conditioning with high doses of cyclophosphamide and/or today body irradiation. They were studied between 4 and 63 mo (median 14.2) after transplantation. Seventeen patients had chronic graft-versus-host disease (C-GVHD) and 7 were healthy. They were studied for defects in their T- and B-cell function using and indirect hemolytic plaque assay for Ig production after 6 days of culture in the presence of pokeweek mitogen. T or B cells from the patients with or without C-GVHD were cocultured with T or B cells from their HLA-identical marrow donors or unrelated normal controls. Intrinsic B-cell defects, lack of helper T-cell activity, and suppressor T-cell activity were more frequently found in patients with C-GVHD than in healthy patients. Fifteen of the 17 patients with C-GVHD showed on or more defects in their T-and B-cell function compared to only 3 of the 7 patients without C-GVHD. None of the healthy controls, including the marrow donors, showed defects in their T- and B-cell functions. These in vitro findings may be helpful in assessing the process of immune reconstitution and the immunologic aberration found after human marrow transplantation.

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Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted haplocompatible bone marrow transplantation

Blood ◽

10.1182/blood.v81.8.2021.2021 ◽

1993 ◽

Vol 81 (8) ◽

pp. 2021-2030 ◽

Cited By ~ 80

Author(s):

Y Dror ◽

R Gallagher ◽

DW Wara ◽

BW Colombe ◽

A Merino ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

B Cell ◽

Cell Function ◽

Severe Combined Immunodeficiency ◽

Combined Immunodeficiency ◽

Cell Numbers ◽

B Cell Function ◽

Immunodeficiency Disease ◽

Severe Combined Immunodeficiency Disease

Abstract We describe our 9-year experience with lectin-treated T-cell-depleted haplocompatible parental bone marrow transplantation (BMT) for 24 patients with severe combined immunodeficiency disease (SCID). Nineteen of 21 evaluable patients had T-cell engraftment; 2 of 11 patients tested had B-cell and monocyte engraftment. Fourteen of 24 (58%) patients are alive 7 months to 9.8 years post-BMT. Seventeen of 24 patients received pretransplant conditioning with chemotherapy and/or total body irradiation, and 8 of 24 received more than one transplant. Patients who received conditioning had a survival rate of 61% versus 57% for those who received no conditioning. None received graft-versus- host disease (GVHD) prophylaxis and no patient had acute or chronic GVHD greater than grade I. Kinetics and follow-up of immune recovery were analyzed in 14 patients who are greater than 1 year from transplant. Half of the patients showed evidence of T-cell function by 3 months and normal T-cell function by 4 to 7 months post-BMT. On average, T-cell numbers and subsets became normal 10 to 12 months posttransplant. Recovery of B-cell function was more delayed, although in most patients B-cell numbers and IgM levels were normal by 12 months post-BMT. B-cell function, as determined by isohemagglutinin titers or specific antibodies to pneumococcal polysaccharide, keyhole limpet hemocyanin, or tetanus toxoid, became normal in 10 of 14 patients 2 to 8 years post-BMT. Seven of the 14 are off gammaglobulin therapy. Production of isohemagglutinins tended to predict recovery of antibody response to pneumococcal polysaccharide (P < .064). Based on these results, we believe that haplocompatible BMT is an effective, curative treatment for patients with SCID who lack an HLA-matched related donor.

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Human donor bone marrow cells induce in vitro “suppressor T cells” that functionally suppress autologous B cells

Human Immunology ◽

10.1016/s0198-8859(02)00774-7 ◽

2003 ◽

Vol 64 (1) ◽

pp. 21-30 ◽

Cited By ~ 5

Author(s):

Manuel R Carreno ◽

Laphalle Fuller ◽

James M Mathew ◽

Gaetano Ciancio ◽

George W Burke ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

B Cells ◽

Bone Marrow Cells ◽

Suppressor T Cells ◽

Human Donor ◽

Donor Bone Marrow ◽

Marrow Cells

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Effects of L-canavanine on immune function in normal and autoimmune mice: disordered B-cell function by a dietary amino acid in the immunoregulation of autoimmune disease

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y85-139 ◽

1985 ◽

Vol 63 (7) ◽

pp. 843-854 ◽

Cited By ~ 20

Author(s):

Pamela E. Prete

Keyword(s):

New Zealand ◽

Amino Acid ◽

T Cell ◽

B Cell ◽

Immune Function ◽

Cell Function ◽

Cell Functions ◽

B Cell Function ◽

Dietary Amino Acid

This study reports the effects in vitro and in vivo of L-canavanine (LCN), an amino acid found in commonly consumed legumes, on immune function in normal and autoimmune mice. L-Canavanine in high doses effectively blocks all DNA synthesis in vitro within 24 h. At lower doses, LCN affects B-cell function of autoimmune New Zealand Black/New Zealand White (NZB/NZW)F1 mice, inhibiting [3H]thymidine incorporation in response to B-cell mitogens, and pokeweed-induced intracytoplasmic immunoglobulin synthesis. LCN stimulates intracytoplasmic immunoglobulin (IgG > IgM). T-cell functions such as lymphoproliferation in response to concanavalin A or phytohemagglutinin and T-cell cytotoxicity are not affected. Suppression of the lipopolysaccharide response by LCN is removed by the addition of fresh B cells. Addition of the amino acid to mouse diet resulted in a decrease in the life-span of the autoimmune NZB and (NZB × NZW)F1 mice and abolished the protective effect of male sex on their survival. The decrease in survival in LCN-treated autoimmune mice correlated with an increase in spontaneous immnunoglobulin-secreting cells (IgG > IgM) and antinuclear and double-stranded DNA antibodies. The histopathological analyses revealed increased glomerular damage and immunoglobulin deposition in the kidneys of the LCN-treated autoimmune and normal (DBA/2) mice. Ten percent of normal mice developed high titers of autoantibodies after 24 weeks of the diet. These data suggest a dietary amino acid, L-canavanine, affects B-cell function resulting in autoimmune phenomena and providing a new animal model of autoimmunity, a diet-induced systemic lupus erythematosus.

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In Vitro 3D Staphylococcus aureus Abscess Communities Induce Bone Marrow Cells to Expand into Myeloid-Derived Suppressor Cells

Pathogens ◽

10.3390/pathogens10111446 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1446

Author(s):

Marloes I. Hofstee ◽

Anja Heider ◽

Sonja Häckel ◽

Caroline Constant ◽

Martijn Riool ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Bone Marrow ◽

T Cell ◽

Bone Marrow Cells ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Cell Numbers ◽

Biomarker Analysis ◽

Marrow Cells

Staphylococcus aureus is the main causative pathogen of subcutaneous, bone, and implant-related infections, forming structures known as staphylococcal abscess communities (SACs) within tissues that also contain immunosuppressive myeloid-derived suppressor cells (MDSCs). Although both SACs and MDSCs are present in chronic S. aureus infections, it remains unknown whether SACs directly trigger MDSC expansion. To investigate this, a previously developed 3D in vitro SAC model was co-cultured with murine and human bone marrow cells. Subsequently, it was shown that SAC-exposed human CD11blow/− myeloid cells or SAC-exposed murine CD11b+ Gr-1+ cells were immunosuppressive mainly by reducing absolute CD4+ and CD8α+ T cell numbers, as shown in T cell proliferation assays and with flow cytometry. Monocytic MDSCs from mice with an S. aureus bone infection also strongly reduced CD4+ and CD8α+ T cell numbers. Using protein biomarker analysis and an immunoassay, we detected in SAC–bone marrow co-cultures high levels of GM-CSF, IL-6, VEGF, IL-1β, TNFα, IL-10, and TGF-β. Furthermore, SAC-exposed neutrophils expressed Arg-1 and SAC-exposed monocytes expressed Arg-1 and iNOS, as shown via immunofluorescent stains. Overall, this study showed that SACs cause MDSC expansion from bone marrow cells and identified possible mediators to target as an additional strategy for treating chronic S. aureus infections.

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B Cell Receptor Signaling and Protein Kinase D2 Support Regulatory B Cell Function in Pancreatic Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2021.745873 ◽

2022 ◽

Vol 12 ◽

Author(s):

Daniel Michaud ◽

Bhalchandra Mirlekar ◽

Colleen Steward ◽

Gail Bishop ◽

Yuliya Pylayeva-Gupta

Keyword(s):

Pancreatic Cancer ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Function ◽

Cell Receptor ◽

Regulatory B Cell ◽

B Cell Function ◽

T Cell Function

B cells can act as potent suppressors of anti-tumor T cell immunity, presenting a mechanism of resistance to immunotherapy. In pancreatic ductal adenocarcinoma, B cells can display a T cell-suppressive or regulatory phenotype centered on the expression of the cytokine Interleukin 35 (IL-35). While B cell-mediated immunosuppression presents a barrier to anti-tumorigenic T cell function, it is not clear how regulatory B cell function could be targeted, and the signals that promote this suppressive phenotype in B cells are not well understood. Here we use a novel IL-35 reporter model to understand which signaling pathways are important for immunosuppressive properties in B cells. In vitro analysis of IL-35 reporter B cells revealed a synergy between the BCR and TLR4 signaling pathways is sufficient to induce IL-35 expression. However, in vivo, B cell receptor activation, as opposed to MyD88 signaling in B cells, is central to B cell-mediated suppression and promotion of pancreatic cancer growth. Further analysis identified protein kinase D2 (PKD2) as being a key downstream regulator of IL-35 expression in B cells. Regulatory B cells with an inactivating mutation in PKD2 failed to produce IL-35 or fully suppress effector T cell function in vitro. Furthermore, inhibition of PKD in B cells decreased tumor growth and promoted effector T cell function upon adoptive transfer into B cell-deficient mice. Collectively, these data provide insight into how regulatory B cell function is promoted in pancreatic cancer and identify potential therapeutic targets to restrain this function.

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Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, T-cell-depleted haplocompatible bone marrow transplantation

Blood ◽

10.1182/blood.v81.8.2021.bloodjournal8182021 ◽

1993 ◽

Vol 81 (8) ◽

pp. 2021-2030 ◽

Cited By ~ 1

Author(s):

Y Dror ◽

R Gallagher ◽

DW Wara ◽

BW Colombe ◽

A Merino ◽

...

Keyword(s):

Bone Marrow ◽

T Cell ◽

B Cell ◽

Cell Function ◽

Severe Combined Immunodeficiency ◽

Combined Immunodeficiency ◽

Cell Numbers ◽

B Cell Function ◽

Immunodeficiency Disease ◽

Severe Combined Immunodeficiency Disease

We describe our 9-year experience with lectin-treated T-cell-depleted haplocompatible parental bone marrow transplantation (BMT) for 24 patients with severe combined immunodeficiency disease (SCID). Nineteen of 21 evaluable patients had T-cell engraftment; 2 of 11 patients tested had B-cell and monocyte engraftment. Fourteen of 24 (58%) patients are alive 7 months to 9.8 years post-BMT. Seventeen of 24 patients received pretransplant conditioning with chemotherapy and/or total body irradiation, and 8 of 24 received more than one transplant. Patients who received conditioning had a survival rate of 61% versus 57% for those who received no conditioning. None received graft-versus- host disease (GVHD) prophylaxis and no patient had acute or chronic GVHD greater than grade I. Kinetics and follow-up of immune recovery were analyzed in 14 patients who are greater than 1 year from transplant. Half of the patients showed evidence of T-cell function by 3 months and normal T-cell function by 4 to 7 months post-BMT. On average, T-cell numbers and subsets became normal 10 to 12 months posttransplant. Recovery of B-cell function was more delayed, although in most patients B-cell numbers and IgM levels were normal by 12 months post-BMT. B-cell function, as determined by isohemagglutinin titers or specific antibodies to pneumococcal polysaccharide, keyhole limpet hemocyanin, or tetanus toxoid, became normal in 10 of 14 patients 2 to 8 years post-BMT. Seven of the 14 are off gammaglobulin therapy. Production of isohemagglutinins tended to predict recovery of antibody response to pneumococcal polysaccharide (P < .064). Based on these results, we believe that haplocompatible BMT is an effective, curative treatment for patients with SCID who lack an HLA-matched related donor.

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B-cell proliferative and differentiative responses after autologous peripheral blood stem cell or bone marrow transplantation

Blood ◽

10.1182/blood.v72.2.672.672 ◽

1988 ◽

Vol 72 (2) ◽

pp. 672-678 ◽

Cited By ~ 22

Author(s):

S Kiesel ◽

A Pezzutto ◽

G Moldenhauer ◽

R Haas ◽

M Korbling ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

B Cells ◽

B Cell ◽

Peripheral Blood ◽

Cell Function ◽

Peripheral Blood Stem Cell ◽

Normal Subjects ◽

B Cell Function

Abstract In this study the authors have evaluated B-cell function after autologous peripheral-blood stem cell transplantation (ABSCT) and autologous bone marrow (ABMT) transplantation. The B-enriched fractions of peripheral blood from ten normal subjects and 22 autografted patients (11 patients after ABMT, eight patients after ABSCT, and three patients after ABSCT followed by ABMT) were investigated. Time postgrafting ranged from 1 to 34 months. Proliferative responses to anti-mu antibody, Staphylococcus aureus Cowan 1 (SAC), and low molecular weight (mol wt) 12-Kd B-cell growth factor (BCGF) were measured. Differentiative responses to the same factors were assessed by quantifying in vitro immunoglobulin (IgG/IgM) production. The authors found no difference in B-cell function between the ABMT and the ABSCT patient groups. Compared to the B cells of normal subjects, only five out of 22 autografted patients showed a normal proliferative response to all agents used, while nine out of 22 did not respond to any signals. Eight out of 22 patients displayed various defects of B- cell response. However, in vitro IgG/IgM secretion of predominantly IgG subclass was normal in 19 out of 22 patients. This in vitro ability to produce Ig was reflected by the patients' normal serum IgG/IgM levels, whereas serum IgA levels were low. The authors speculate that there may be 2 B-cell populations: the normal in vitro Ig production and in vivo serum IgG may come from the stimulation of a small number of re-infused pre-committed memory B cells while, in parallel, immature B cells develop from autografted hematopoietic progenitor cells.

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