Antigen Presenting Cells: Detection and Quantification of a Cytochrome c Determinant Important for Activation of T-Cells on Bone Marrow Derived Macrophages by using Specific Anti Cytochrome c Monoclonal Antibody

1987 ◽  
pp. 129-145
Author(s):  
Stéphane Demotz ◽  
Claudio Vita ◽  
Giampietro Corradin
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
T Cells ◽  
Cytochrome C ◽  
Antigen Presenting Cells ◽  
Antigen Presenting ◽  
Detection And Quantification

scholarly journals CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages

2020 ◽  
Vol 4 (12) ◽  
pp. 2595-2605 ◽  
Author(s):  
Ole Audun W. Haabeth ◽  
Kjartan Hennig ◽  
Marte Fauskanger ◽  
Geir Åge Løset ◽  
Bjarne Bogen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Antigen Presenting Cells ◽  
Bone Marrow Microenvironment ◽  
Cd4 T Cell ◽  
Myeloma Cells ◽  
Antigen Presenting

Abstract CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.

scholarly journals Gas6 deficiency in recipient mice of allogeneic transplantation alleviates hepatic graft-versus-host disease

Blood ◽  
2010 ◽  
Vol 115 (16) ◽  
pp. 3390-3397 ◽  
Author(s):  
Laurent Burnier ◽  
François Saller ◽  
Linda Kadi ◽  
Anne C. Brisset ◽  
Rocco Sugamele ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Antigen Presenting Cells ◽  
Allogeneic Bone ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Antigen Presenting

Abstract Growth arrest-specific gene 6 (Gas6) is expressed in antigen-presenting cells and endothelial cells (ECs) but not in T cells. When wild-type (WT) or Gas6−/− mice received allogeneic non–T cell–depleted bone marrow cells, hepatic graft-versus-host disease (GVHD) was alleviated in Gas6−/− recipients regardless of donor genotype, but not in WT recipients. T-cell infiltration was more prominent and diffuse in WT than in Gas6−/− recipients' liver. When mice received 0.5 × 106 allogeneic T cells with T cell–depleted allogeneic bone marrow, clinical signs indicated that GVHD was less severe in Gas6−/− than in WT recipients, as shown by a significant improvement of the survival and reduced liver GVHD. These data demonstrate that donor cells were not involved in the protection mechanism. In addition, lack of Gas6 in antigen-presenting cells did not affect WT or Gas6−/− T-cell proliferation. We therefore assessed the response of WT or Gas6−/− ECs to tumor necrosis factor-α. Lymphocyte transmigration was less extensive through Gas6−/− than WT ECs and was not accompanied by increases in adhesion molecule levels. Thus, the lack of Gas6 in ECs impaired donor T-cell transmigration into the liver, providing a rationale for considering Gas6 pathway as a potential nonimmunosuppressive target to minimize GVHD in patients receiving allogeneic hematopoietic stem cell transplantation.

Abstract 44: Interleukin-27 Signaling is a Critical Regulator of Inflammation in Atherosclerosis

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Ekaterina Koltsova ◽  
Gisen Kim ◽  
Sibylle von Vietinghoff ◽  
Mitchell Kronenberg ◽  
Klaus Ley
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Inflammatory Cytokines ◽  
Arterial Wall ◽  
Antigen Presenting Cells ◽  
Cytokine Signaling ◽  
Interleukin 27 ◽  
Anti Inflammatory ◽  
Antigen Presenting

Atherosclerosis is chronic inflammatory disease, which affects blood vessels. While the pro-atherogenic role of various inflammatory cytokines was broadly investigated, less is known about contribution of anti-inflammatory cytokines with regard to their ability to control inflammation in vivo. Interleukin 27 (IL-27) was shown to play immunosuppressive function via multiple mechanisms. We tested whether IL-27 signaling is important to restrain inflammation in mouse models of atherosclerosis. We transplanted bone marrow from Il27ra -/- or Il27ra +/+ mice into atherosclerosis prone Ldlr -/- littermates. Recipients of Il27ra -/- marrow showed significantly larger atherosclerotic lesions in aortic roots, aortic arches and, most strikingly, in the abdominal aorta. Aortas contained more CD45 + leukocytes and CD4 + T cells, which produced pro-atherogenic cytokines IL-17A and TNF-α. Concomitantly, the levels of IL-17A and IL-6 were significantly elevated in aortic tissue. These cytokines normally suppressed by IL-27, regulated the expression of CCL2 and other chemokines, which in turn led to accumulation of myeloid CD11b + and CD11c + cells in aortas, atherosclerotic plaque growth and disease progression. Moreover, using our recently developed live imaging by two-photon microscopy, we found enhanced interaction between antigen presenting cells and T cells in the arterial wall of Il27ra deficient mice. Overall, IL-27 signaling in bone marrow-derived cells regulates atherosclerosis by controlling interaction of antigen presenting cells and T cells in the arterial wall and therefore curbing Th17 and Th1 lineage differentiation, TNF and IL-17 dependent chemokine expression and subsequent myeloid cell accumulation. Thus, our work establishes the importance of anti-inflammatory cytokine signaling in atherosclerosis and demonstrates novel anti-atherogenic role of IL-27.

Efficient Binding, but Moderate Modulation, of Human Dendritic Cell Functions by Milatuzumab, a Humanized Anti-CD74 Monoclonal Antibody

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2649-2649 ◽  
Author(s):  
Xiaochuan Chen ◽  
Chien-Hsing Chang ◽  
David Goldenberg
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Cell Viability ◽  
Antigen Presenting Cells ◽  
Lymphocytic Leukemia ◽  
Dependent Manner ◽  
Immune Functions ◽  
Cell Functions ◽  
Antigen Presenting

Abstract Milatuzumab (hLL1, Immunomedics, Inc.), a humanized anti-CD74 immunoglobulin-G monoclonal antibody (MAb), has been shown to have therapeutic activity against CD74-expressing B-cell malignancies in vitro and in xenografts models, and is in clinical evaluation as a therapeutic MAb for non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma. Since it is unclear whether this MAb has any effects on human antigen-presenting cells that express CD74, we investigated the binding efficiency, viability, and functional modulation of human dendritic cells (DC), the professional and most potent antigen-presenting cells, exposed to milatuzumab. We found that milatuzumab bound efficiently with B cells, monocytes, and different subsets of blood DCs including myeloid DC1 (BDCA-1+), myeloid DC2 (BDCA-3+) and plasmacytoid DC (BDCA-2+) in human PBMC, as well as with monocyte-derived immature DCs, but not LPS-matured DCs. The side-by-side comparative cytotoxicity assay showed that milatuzumab, in the presence of a second antibody for cross-linking (GAH, the F(ab′)2 of goat anti-human IgG Fcgamma-specific), dramatically reduced the cell viability of Daudi B-lymphoma cells, but did not influence the cell viability or induce apoptosis in monocyte-derived DCs, even at high concentations up to 50 μg/ml. At the concentrations ranging from 0.05 to 5 μg/ml, milatuzumab upregulated the expression of the antigen-presenting molecule, HLA-DR, and costimulatory molecules, CD54 and CD86, in human monocyte-derived DCs in a moderate, but dose-dependent manner, suggesting that milatuzumab could enhance DC constitutive maturation. Although this effect was not reflected by an enhanced T-cell expansion, as shown by unaltered CFSE-low, -medium, and –high peaks in total and CD4+ and CD4− T cells, milatuzumab-treated DCs could moderately promote the differentiation of CD4+ naïve T cells toward more Th1 effector cells, suggesting that milatuzumab can modulate DC functions, inducing the polarization and differentiation of functional Th cells. These data highlight the prospects of milatuzumab as a novel immunotherapeutic agent that possesses not only direct anti-proliferative effects against CD74+ hematological malignancies, but also some regulatory effects on DC-mediated immune functions, and no cytotoxic effect on DCs.

scholarly journals TGF-β1 pretreatment impairs the allostimulatory function of human bone marrow-derived antigen-presenting cells for both naive and primed T cells

1996 ◽  
Vol 4 (3) ◽  
pp. 186-191 ◽  
Author(s):  
C Andrew Bonham ◽  
Lina Lu ◽  
Richard A Banas ◽  
Paulo Fontes ◽  
Abdul S Rao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Antigen Presenting Cells ◽  
Human Bone ◽  
Human Bone Marrow ◽  
Antigen Presenting ◽  
Tgf Β1

scholarly journals CTLA-4 on alloreactive CD4 T cells interacts with recipient CD80/86 to promote tolerance

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3475-3484 ◽  
Author(s):  
Josef Kurtz ◽  
Forum Raval ◽  
Casey Vallot ◽  
Jayden Der ◽  
Megan Sykes
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Bone Marrow Cells ◽  
Antigen Presenting Cells ◽  
Cd4 T Cell ◽  
Cell Tolerance ◽  
Antigen Presenting ◽  
Marrow Cells

Abstract Although the inhibitory receptor CTLA-4 (CD152) has been implicated in peripheral CD4 T-cell tolerance, its mechanism of action remains poorly defined. We analyzed mechanisms of CD4 cell tolerance in a model of tolerance induction involving establishment of mixed hematopoietic chimerism in recipients of fully MHC-mismatched allogeneic bone marrow cells with anti-CD154 mAb. Animals lacking CD80 and CD86 failed to achieve chimerism. We detected no T cell–intrinsic requirement for CD28 for chimerism induction. However, a CD4 T cell–intrinsic signal through CTLA-4 was shown to be essential within the first 48 hours of exposure to alloantigen for the establishment of tolerance and mixed chimerism. This signal must be provided by a recipient CD80/86+ non–T-cell population. Donor CD80/86 expression was insufficient to achieve tolerance. Together, our findings demonstrate a surprising role for interactions of CTLA-4 expressed by alloreactive peripheral CD4 T cells with CD80/86 on recipient antigen-presenting cells (APCs) in the induction of early tolerance, suggesting a 3-cell tolerance model involving directly alloreactive CD4 cells, donor antigen-expressing bone marrow cells, and recipient antigen-presenting cells. This tolerance is independent of regulatory T cells and culminates in the deletion of directly alloreactive CD4 T cells.

scholarly journals Ex Vivo Generation of Human Anti–Pre-B Leukemia-Specific Autologous Cytolytic T Cells

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 549-561 ◽  
Author(s):  
Angelo A. Cardoso ◽  
Mark J. Seamon ◽  
Hernani M. Afonso ◽  
Paolo Ghia ◽  
Vassiliki A. Boussiotis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
B Cell ◽  
Tumor Cells ◽  
Antigen Presenting Cells ◽  
Cell Leukemia ◽  
B Cell Leukemia ◽  
Antigen Presenting

Abstract In contrast to other neoplasms, antigen-specific autologous cytolytic T cells have not been detected in patients with human pre-B–cell leukemias. The absence of efficient B7 family (B7-1/CD80; B7-2/CD86) -mediated costimulation has been shown to be a major defect in tumor cells' capacity to function as antigen-presenting cells. We show here the generation of autologous anti–pre-B–cell leukemia-specific cytolytic T-cell lines from the marrows of 10 of 15 patients with pre-B–cell malignancies. T-cell costimulation via CD28 is an absolute requirement for the generation of these autologous cytolytic T cells (CTL). Although costimulation could be delivered by either bystander B7 transfectants or professional antigen-presenting cells (indirect costimulation), optimal priming and CTL expansion required that the costimulatory signal was expressed by the tumor cell (direct costimulation). These anti–pre-B–cell leukemia-specific CTL lysed both unstimulated and CD40-stimulated tumor cells from each patient studied but did not lyse either K562 or CD40-stimulated allogeneic B cells. Cytolysis was mediated by the induction of tumor cell apoptosis by CD8+ T cells via the perforin-granzyme pathway. Although we were able to generate anti–leukemia-specific CTL from the bone marrow, we were unable to generate such CTL from the peripheral blood of these patients. These studies show that antigen-specific CTL can be generated from the bone marrow of patients with pre-B–cell leukemias and these findings should facilitate the design of adoptive T-cell–mediated immunotherapy trials for the treatment of patients with B-cell precursor malignancies.

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