In vivo manipulation of dendritic cells to induce therapeutic immunity

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1676-1682 ◽  
Author(s):  
Miriam Merad ◽  
Tomoharu Sugie ◽  
Edgar G. Engleman ◽  
Lawrence Fong
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Antitumor Immunity ◽  
Flt3 Ligand ◽  
Essential Components ◽  
Tumor Protection ◽  
Immunostimulatory Dna

Efficient antigen presentation and T-cell priming are essential components of effective antitumor immunity. Dendritic cells are critical to both of these functions but to date no method has been devised that both targets antigen to these cells and activates them, in situ, in a manner that induces systemic immunity. In this study we combined a dendritic cell growth factor, Flt3 ligand, with a dendritic cell activator, immunostimulatory DNA, and a tumor antigen to activate and load dendritic cells in vivo. Initial studies showed that immunostimulatory DNA not only activates dendritic cells but also prolongs their survival in vivo and in vitro. Following treatment of mice with Flt3 ligand, coadministration of immunostimulatory DNA and antigen induced potent antitumor immunity, resulting in both tumor prevention and regression of existing tumors. CD8 cytotoxic T lymphocytes but not CD4 T cells were required for tumor protection. Natural killer cells also contributed to tumor protection. These results show that dendritic cells can be loaded with antigen and activated, in situ, and provide the basis for dendritic cell- targeted clinical strategies.

In Vitro Human Tissues via Multi-material 3-D Bioprinting

2018 ◽  
Vol 46 (4) ◽  
pp. 209-215 ◽  
Author(s):  
David B. Kolesky ◽  
Kimberly A. Homan ◽  
Mark Skylar-Scott ◽  
Jennifer A. Lewis
Keyword(s):  
Kidney Tissue ◽  
Harvard University ◽  
Human Tissues ◽  
Osteogenic Lineage ◽  
Rapid Fabrication ◽  
Essential Components ◽  
Foundational Research

This paper highlights the foundational research on multi-material 3-D bioprinting of human tissues, for which the Lewis Bioprinting team at Harvard University was awarded the 2017 Lush Science Prize. The team's bioprinting platform enables the rapid fabrication of 3-D human tissues that contain all of the essential components found in their in vivo counterparts: cells, vasculature (or other tubular features) and extracellular matrix. The printed 3-D tissues are housed within a customised perfusion system and are subjected to controlled microphysiological environments over long durations (days to months). As exemplars, the team created a thick, stem cell-laden vascularised tissue that was controllably differentiated toward an osteogenic lineage in situ, and a 3-D kidney tissue that recapitulated the proximal tubule, a sub-unit of the nephron responsible for solute reabsorption. This highly versatile platform for manufacturing 3D human tissue in vitro opens new avenues for replacing animal models used to develop next-generation therapies, test toxicity and study disease pathology.

scholarly journals Mature Dendritic Cells Infiltrate the T Cell-Rich Region of Oral Mucosa in Chronic Periodontitis: In Situ, In Vivo, and In Vitro Studies

2001 ◽  
Vol 167 (8) ◽  
pp. 4693-4700 ◽  
Author(s):  
Ravi Jotwani ◽  
Anna Karolina Palucka ◽  
Montasr Al-Quotub ◽  
Mahyar Nouri-Shirazi ◽  
Jay Kim ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Oral Mucosa ◽  
Chronic Periodontitis ◽  
In Vitro Studies ◽  
Rich Region

scholarly journals Leishmania major Promastigotes Inhibit Dendritic Cell Motility In Vitro

2002 ◽  
Vol 70 (2) ◽  
pp. 1023-1026 ◽  
Author(s):  
Heather Jebbari ◽  
Andrew J. Stagg ◽  
Robert N. Davidson ◽  
Stella C. Knight
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Cell Motility ◽  
Leishmania Major ◽  
Protective Role ◽  
Transwell Migration Assay ◽  
Migration Assay ◽  
Dose Dependent

ABSTRACT Using an in vitro transwell migration assay, we have demonstrated that products secreted by Leishmania major promastigotes inhibit the motility of dendritic cells (DC) by up to 93%. Inhibition was dose dependent and reversible. By inhibiting DC migration in vivo, L. major may therefore subvert DC from their potentially protective role during leishmaniasis.

scholarly journals Vimentin provides target search efficiency and mechanical resilience for dendritic cell migration

2020 ◽  
Author(s):  
Luiza Da Cunha Stankevicins ◽  
M. Reza Shaebani ◽  
Doriane Vesperini ◽  
Marta Urbanska ◽  
Daniel A. D. Flormann ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Cell Migration ◽  
Dendritic Cell ◽  
Cell Stiffness ◽  
Search Efficiency ◽  
Mechanical Stiffness ◽  
Target Search ◽  
Dendritic Cell Migration

AbstractDendritic cells use amoeboid migration to pass through confined tissues to reach the lymph nodes, and this homing function is crucial for immune responses. The underlying mechanisms for this type of migration remain unknown. As vimentin intermediate filaments regulate adhesion-dependent migration, we analyzed whether they have a similar effect on amoeboid migration. We show that lack of vimentin impairs amoeboid migration in vitro in confined environments, and blocks lymph-node homing in mice in vivo. Importantly, we show that vimentin-deficient dendritic cells have a lower coupling factor between cell speed and persistence and reduced target search efficiency (e.g., finding a pathogen, or another cell). These data show that the characteristics of vimentin in its dynamic regulation of cell stiffness and load-bearing, and also elastic capacity, appear to explain the coupling between their migratory ability and search efficiency. Taken together, these data show that vimentin provides the specific mechano-dynamics required for dendritic cell migration and for efficient target searching.Summary statementVimentin contributes to the mechanical stiffness of cells required for amoeboid cell migration through confined spaces, and improves cell-search efficiency. Vimentin-deficient cells migrate more slowly and their migration speed is less coupled to persistence compared to control cells.

The concerted action of GM-CSF and Flt3-ligand on in vivo dendritic cell homeostasis

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 835-843 ◽  
Author(s):  
Dior Kingston ◽  
Michael A. Schmid ◽  
Nobuyuki Onai ◽  
Aya Obata-Onai ◽  
Dirk Baumjohann ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Lymphoid Organ ◽  
Receptor Expression ◽  
Antigen Delivery ◽  
Flt3 Ligand ◽  
Concerted Action ◽  
Gm Csf ◽  
Deficient Mice

Abstract Dendritic cell (DC) development is efficiently supported by Flt3-ligand or GM-CSF in vitro, and lymphoid-organ DC maintenance in vivo is critically dependent on Flt3-ligand. However, the relevance of GM-CSF for lymphoid-tissue DC maintenance and the importance of both cytokines for nonlymphoid organ DC homeostasis are not defined. Here, we show that, although Gm-csfr and Flt3 are both expressed in DC progenitors, Gm-csfr is expressed predominantly in monocytes, classical DCs (cDCs), and skin DCs, whereas Flt3 is expressed in both cDCs and plasmacytoid DCs (pDCs). In accordance with the respective cytokine receptor expression, DC progenitor and pDC numbers are primarily affected by Flt3-ligand deficiency, whereas both splenic and lymph node cDCs and dermal DCs are reduced in the absence of either GM-CSF or Flt3-ligand. Combined lack of GM-CSF and Flt3-ligand in newly generated double-deficient mice leads to further significant reductions of DC progenitors and dermal DCs. In line with the decrease of respective DC subsets, T-cell and antigen-specific IgG responses decline progressively, from wild-type to GM-CSF– to Flt3-ligand– to double-deficient mice, upon subcutaneous antigen delivery. These data thus show the concerted action of GM-CSF and Flt3-ligand on DC homeostasis in vivo.

Dendritic cell potentials of early lymphoid and myeloid progenitors

Blood ◽  
2001 ◽  
Vol 97 (11) ◽  
pp. 3333-3341 ◽  
Author(s):  
Markus G. Manz ◽  
David Traver ◽  
Toshihiro Miyamoto ◽  
Irving L. Weissman ◽  
Koichi Akashi
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Steady State ◽  
Dendritic Cell ◽  
Developmental Potential ◽  
Lymphoid Lineage ◽  
B Lymphoid ◽  
Myeloid Progenitors

It has been proposed that there are at least 2 classes of dendritic cells (DCs), CD8α+ DCs derived from the lymphoid lineage and CD8α− DCs derived from the myeloid lineage. Here, the abilities of lymphoid- and myeloid-restricted progenitors to generate DCs are compared, and their overall contributions to the DC compartment are evaluated. It has previously been shown that primitive myeloid-committed progenitors (common myeloid progenitors [CMPs]) are efficient precursors of both CD8α+ and CD8α− DCs in vivo. Here it is shown that the earliest lymphoid-committed progenitors (common lymphoid progenitors [CLPs]) and CMPs and their progeny granulocyte-macrophage progenitors (GMPs) can give rise to functional DCs in vitro and in vivo. CLPs are more efficient in generating DCs than their T-lineage descendants, the early thymocyte progenitors and pro-T cells, and CMPs are more efficient DC precursors than the descendant GMPs, whereas pro-B cells and megakaryocyte-erythrocyte progenitors are incapable of generating DCs. Thus, DC developmental potential is preserved during T- but not B-lymphoid differentiation from CLP and during granulocyte-macrophage but not megakaryocyte-erythrocyte development from CMP. In vivo reconstitution experiments show that CLPs and CMPs can reconstitute CD8α+ and CD8α− DCs with similar efficiency on a per cell basis. However, CMPs are 10-fold more numerous than CLPs, suggesting that at steady state, CLPs provide only a minority of splenic DCs and approximately half the DCs in thymus, whereas most DCs, including CD8α+ and CD8α− subtypes, are of myeloid origin.

5-lipoxygenase expression in dendritic cells generated from CD34+ hematopoietic progenitors and in lymphoid organs

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3857-3865
Author(s):  
Rainer Spanbroek ◽  
Markus Hildner ◽  
Dieter Steinhilber ◽  
Norbert Fusenig ◽  
Kozo Yoneda ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocyte ◽  
Transforming Growth Factor ◽  
Leukotriene B4 ◽  
Lymphoid Tissues ◽  
Ionophore A23187 ◽  
In Cells

The 5-lipoxygenase (5-LO) pathway in human CD34+ hematopoietic progenitor cells, which were induced to differentiate into dendritic cells (DCs) by cytokines in vitro and in DCs of lymphoid tissues in situ, was examined. Extracts prepared from HPCs contained low levels of 5-LO or 5-LO–activating protein. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plus tumor necrosis factor–α (TNF-α) promoted DC differentiation and induced a strong rise in 5-LO and FLAP expression. Fluorescence-activated cell sorter (FACS) analyses identified a major DC population coexpressing human leukocyte antigen (HLA)-DR/CD80 and monocytic or Langerhans cell markers. Transforming growth factor–β1 (TGF-β–1), added to support DC maturation, strongly promoted the appearance of CD1a+/Lag+ Langerhans-type cells as well as mature CD83+ DCs. TGF-β–1 further increased 5-LO and FLAP expression, recruited additional cells into the 5-LO+DC population, and promoted production of 5-hydroxyeicosatetraenoic acid and leukotriene B4 in response to calcium (Ca++) ionophore A23187. These in vitro findings were corroborated by 5-LO expression in distinct DC phenotypes in vivo. Scattered 5-LO and FLAP in situ hybridization signals were recorded in cells of paracortical T-lymphocyte–rich areas and germinal centers (GCs) of lymph nodes (LNs) and tonsil and in cells of mucosae overlying the Waldeyer tonsillar ring. 5-LO protein localized to both CD1a+ immature DCs and to CD83+ mature interdigitating DCs of T-lymphocyte–rich areas of LNs and tonsil. As DCs have the unique ability to initiate naive lymphocyte activation, our data support the hypothesis that leukotrienes act at proximal steps of adaptive immune responses.

5-lipoxygenase expression in dendritic cells generated from CD34+ hematopoietic progenitors and in lymphoid organs

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3857-3865 ◽  
Author(s):  
Rainer Spanbroek ◽  
Markus Hildner ◽  
Dieter Steinhilber ◽  
Norbert Fusenig ◽  
Kozo Yoneda ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocyte ◽  
Transforming Growth Factor ◽  
Leukotriene B4 ◽  
Lymphoid Tissues ◽  
Ionophore A23187 ◽  
In Cells

Abstract The 5-lipoxygenase (5-LO) pathway in human CD34+ hematopoietic progenitor cells, which were induced to differentiate into dendritic cells (DCs) by cytokines in vitro and in DCs of lymphoid tissues in situ, was examined. Extracts prepared from HPCs contained low levels of 5-LO or 5-LO–activating protein. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plus tumor necrosis factor–α (TNF-α) promoted DC differentiation and induced a strong rise in 5-LO and FLAP expression. Fluorescence-activated cell sorter (FACS) analyses identified a major DC population coexpressing human leukocyte antigen (HLA)-DR/CD80 and monocytic or Langerhans cell markers. Transforming growth factor–β1 (TGF-β–1), added to support DC maturation, strongly promoted the appearance of CD1a+/Lag+ Langerhans-type cells as well as mature CD83+ DCs. TGF-β–1 further increased 5-LO and FLAP expression, recruited additional cells into the 5-LO+DC population, and promoted production of 5-hydroxyeicosatetraenoic acid and leukotriene B4 in response to calcium (Ca++) ionophore A23187. These in vitro findings were corroborated by 5-LO expression in distinct DC phenotypes in vivo. Scattered 5-LO and FLAP in situ hybridization signals were recorded in cells of paracortical T-lymphocyte–rich areas and germinal centers (GCs) of lymph nodes (LNs) and tonsil and in cells of mucosae overlying the Waldeyer tonsillar ring. 5-LO protein localized to both CD1a+ immature DCs and to CD83+ mature interdigitating DCs of T-lymphocyte–rich areas of LNs and tonsil. As DCs have the unique ability to initiate naive lymphocyte activation, our data support the hypothesis that leukotrienes act at proximal steps of adaptive immune responses.

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