Dendritic Cell and its Role in Adaptive Immunity and Cancer Immunotherapy Amna Muhammad Ph. D...
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Transcript of Dendritic Cell and its Role in Adaptive Immunity and Cancer Immunotherapy Amna Muhammad Ph. D...
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Dendritic Cell and its Role in Adaptive Immunity and Cancer Immunotherapy
Amna MuhammadPh. D scholarBiochemistry
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Contents
• Introduction
• Dentritic cell and control of immunity
• Immunity
• Antigen Presentation to T cells
• Dendritic Cell and Immune Tolerance
• Dendritic cells and cancer
• Summary
• References
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Introduction• Immunology has long been focused:
• Antigen is any substance that causes your
immune system to produce antibodies against
it
• Lymphocytes are responsible for immune
responses. There are two main types of B cells
and T cells
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• But the mere presence of these two parties does not
always lead to immunity.
• A third party is required
• Dendritic cell (DC) system
- Initiator and modulator of the immune
response
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Adaptive Immunity
• The adaptive immune or specific immune
response consists of antibody responses and
cell-mediated responses.
• Both responses are carried out by
– B cells
– T cells
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T cells• Two main types:
1. CD4+: Stimulate other immune cells.2. CD8+ Cytotoxic T cells: Kill intracellularly-infected cells.
• Two major types of CD4+ T cells:1. TH1: Inflammatory T cells -- Stimulate
macrophages and promote inflammatory responses.
2. TH2: Helper T cells -- Stimulate B-cells to produce antibodies.
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Antigen Presentation to T cells
• Antigens are presented to T cells as short peptide
fragments bound to (MHC) molecules.
• Two types of MHC in humans and mice:
– MHC I: presents an 8-10 amino acid peptide to CD8+ T cells.
– MHC II: presents a longer peptide (13 aa or more) to CD4+
T cells.
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MHC / T cell Interactions
Class II MHCClass I MHC
TCR complex
CD8
CD8+ T cell
target cell
CD4
Antigen presenting cell
TCR complex CD4+ T cell
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CD4+ T cell Activation
• Three signals are required for T cell activation
1. Activation by antigen specific signal
– ( peptide/MHC-TCR binding)
2. Co-stimulatory signal
–CD28/CD80
3. Polarization signal
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CD8+ T cell Activation
• Activation by displaying MHC I/peptide
• co-stimulation
• Activation of the CD8+ cell causes up-regulation of the
IL-2 receptor and production of IL-2, leading to growth
and proliferation.
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Introduction to Dendritic cell (DC) system
• Professional antigen presenting cells
• Regulation of adaptive immune response
• Tolerize T cells to self-antigens
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Dendritic Cells and Control of Immunity
o Control B and T cell function
Capturing antigen
Antigen processing
Expression of antigen co-stimulatory molecules
Migration to lymphoid organ
Secretion of cytokines
Activation of lymphocytes
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Antigen Processing
• Antigen is fully digested into amino acids
• Loaded onto MHC class II molecules
• Antigen MHCII complexes are send to cell
surface
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Antigen Processing
Endoplasmic reticulum
Nucleus
Vesicle carryingMHC II
MHC II is assembled in ER
Display of MHC II + peptideon cell surface
Ingestion of microbe
Degradtion in lysozome
Vesicle fusion, assembly of
peptide/MHC II
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Maturation of DC
Immature DC Mature DC
High intracellular MHC II High surface MHC II
Many antigen capturing receptors
Very less antigen capturing receptors
Weak T cell stimulator Powerful T cell stimulator
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Migration of Dendritic Cells
• Loss of adhesion
• Travelling to lymphoid tissues
• Induce T cell response
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Immune Tolerence
• Immune system important task is to
- identify what is foreign and what is self
• Failure results in an autoimmune disease
• Diabetes mellitus type 1 or multiple sclerosis
etc
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DC and Cancer
• Constitutive activation of STAT 3 pathway leads to tumor expression and
suppression of dentritic cells
• Commensurate with their roles in regulating cytokine-dependent
inflammation and immunity, signal transducer and activator of
transcription (STAT) proteins are central in determining whether immune
responses in the tumour microenvironment promote or inhibit cancer.
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Cont…
• Until recently, most DC vaccines comprised DC or monocyte precursors of DC, isolated from the patient, loaded ex vivo with tumour antigen (Ag), and readministered to the patient. DC that migrated from the injection site to the draining lymph nodes were expected to prime or boost memory, tumour-specific T cells capable of eradicating the tumour.
• To date, the majority of trials have been Phase I studies on small cohorts of advanced cancer patients who had failed to respond to conventional therapies
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Cont…• These trials revealed that this approach: (1) is feasible in many malignancies; (2) is well tolerated with minimal toxicity; and (3) can induce tumour-specific immune responses in many
patients.
• Whilst early DC therapies resulted in limited clinical benefits, recent advances in our understanding of DC biology and new knowledge obtained from clinical trials have identified new strategies that are expected to improve clinical outcomes. Harnessing the unique capacity of different DC subtypes to drive specific immune responses in combinations with approaches designed to overcome tumour-mediated immune suppression and immune regulation, are emerging as key strategies for the development of new generation DC vaccines.
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DC pattern recognition receptors for cancer immunotherapy
• DC subsets express a range of unique and shared pattern recognition receptors (PRR), including CLRs and TLRs that can be harnessed to enhance the efficacy of cancer immunotherapy.
• Monoclonal antibodies (mAbs) specific for CLRs can be used to target Ag directly to particular DC subset(s) in vivo. This attractive approach circumvents the issues of poor DC migration.
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Key Notes
• NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells)
• MHC (major histocompatibilty complex)• INF (interferon) • IL (interleukin)• CD4 ( cluster of differentiation 4)
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References
• Steinman, R. M. and J. Banchereau. 2007. Taking dentritic cells into medicine. Nature. 449: 419-425
• Banchereau, J. and R. M. Steinman (1998). Dentritic cells and the control of immunity. Nature. 392: 245-252
• Yu, H., D. Pardoll and R. Jove .2009. STATs in cancer inflammation and immunity: a leading role for STAT3. Nature Reviews Cancer. 9: 798-809
• Oriss, B. Timothy , Krishnamoorthy, N. Ray, P. Ray, Anuradha. 2014. Dendritic cell c-kit signaling and adaptive immunity: implications for the upper airways. Current Opinion in Allergy & Clinical Immunology. 14:7-5