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Dendritic Cells

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Dendritic cells (DC) are present in the blood. and in the majority of peripheral tissues ... Dendritic Cells as Therapeutic Vaccines: Original Concept (circa 1992) ... – PowerPoint PPT presentation

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Title: Dendritic Cells


1
Dendritic Cells
  • Edgar G. Engleman, M.D.

2
Dendritic cells (DC) are present in the blood
and in the majority of peripheral tissues
Skin Langerhans cells
Blood DC
Heart DC
Kidney DC
D
C
A
B
Rat Tracheal DC
Human Bronchiole DC
Murine Tracheal DC
G
F
E
3
Dendritic Cells
Center of the Immuniverse
Lymph node
Bone Marrow
Stem cell CD34
CD4
NK
B
Antibodies
Lymphatics
Epidermis
Dermis
Skin
4
Dendritic Cells as Therapeutic Vaccines Original
Concept (circa 1992)
  • Goal Induce antitumor (or antiviral) immunity
    using autologous DC pulsed with tumor Ag
  • Methods
  • Generate DC in vitro from circulating precursors
  • Load DC with Ag
  • Return DC to patients

5
Dendritic Cell Based Vaccines in Cancer Treatment
Tumor Antigen
DC Generation (GM-CSF, IL-4)
DC Maturation (TNF, CD40-L)
Vaccination (Intratumoral)
Antigen-Pulsed DC
Vaccination (systemic)
Immune Clinical Monitoring
6
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7
Problems with Customized DC Vaccines
  • Poor efficacy -- most tumor bearing patients do
    not respond
  • Best tumor Ags, DC activation method, route of
    delivery all unknown
  • Cost and complexity are high

8
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9
The Future of Immunotherapy Drugs that Target
and Activate DC or T Cells, in situ
  • Toll-like receptor agonists that activate DC are
    currently in clinical trials for the treatment of
    cancer.
  • Antibodies (e.g., anti-CTLA-4) that block
    physiologic inhibition of T cell inactivation are
    also in clinical trials for the treatment of
    cancer.

10
NK-Monocyte-DC-T Cell Crosstalk How the innate
and adaptive immune arms regulate each other
11
Regulation of DC differentiation from monocytes
  • myDC are derived from myeloid progenitors in bone
    marrow.
  • myDC are generated in vitro from monocytes in the
    presence of exogenous GM-CSF and IL-4.
  • The factors that regulate monocyte
    differentiation into DC in situ are not known.

What regulates DC differentiation in vivo?
DC
GM-CSFIL-4
Monocyte
12
Role of natural killer (NK) cells in immunity
  • NK cells constitute about 5-10 of peripheral
    blood lymphocytes in humans.
  • NK cells kill target cells such as transformed or
    aberrant cells.
  • NK cells produce cytokines including IFN?, TNF?,
    GM-CSF, M-CSF, IL-5, IL-6, IL-10, IL-13, etc.
  • NK cells serve as immunoregulators and can affect
    hematopoiesis.

13
Hypothesis
  • NK cells regulate monocyte differentiation into
    DC

14
DC are generated in co-culture with activated NK
cells
15
DCNK phenotype
Cell counts
CD14
CD86
DC-SIGN
CD40
CD80
16
DCNK efficiently take up antigen by endocytosis
and lose the ability to phagocytose
Cell counts
DQ-OVA uptake
mono alone monoIL-15
monoNK DCNK
DC GM/IL-4
Cell counts
beads-FITC
17
DCNK activate Th1 CD4 T cells
Proliferation
IFN?
IL-4
CD3
18
Summary Effects of NK Cells on DC Development
  • Human and mouse NK cells directly trigger
    differentiation of monocytes into Th1-promoting
    dendritic cells.
  • Synovial fluid obtained from patients with
    immune-mediated arthritis induces monocytes to
    differentiate into DC but only in the presence of
    NK cells.
  • In vivo NK cell depletion reduces the percentage
    of donor monocyte-derived DC in spleen and lymph
    nodes.

19
Cross-talk between NK cells, monocytes, DC, and T
cells during an immune response
IL-12
MHC class I HLA-E/Qa1b
IL-18
GM-CSF
IL-2
Type 1 IFN
CD40L IFNg TNF? IL-6
IL-15
CD4 Tconv
MHC II Ag
CD101 Treg
20
Acknowledgments
  • DC vaccines Larry Fong, Ron Levy, Wenru Song,
    Claudia Benike
  • NK-monocyte-DC crosstalk Kalle Soderstrom,
    Paula Colmenero, Angela Zhang
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