Transcript Cellular Components of the Immune Response

Cellular Components
of the
Immune Response:
Stem Cells and Stem Cell
Transplantation
Folder Title:
Cells
Updated: October 21, 2013
Filename: Cells.ppt
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I distributed a one-page copy of a Science note at the
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If a pharmaceutical agent has a name that ends in
“mab”, what does that tell you about the agent?
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Immune System Make-up
From 447Intro, Slides 54 and 55
Morphology &
Staining of
Blood Cells
Kuby, 3rd Ed.
Figure 3-1
ImmCells
Questions About Cellular Components
of the Immune Response
How many different cell types are there?
What are the numbers of the various cell types?
What do these different cell lineages do?
Where do they come from?
How Long do they last?
What becomes of them at the end of their functional life span?
What controls their replacement? (How does the hematopoietic
system know what needs to be replaced?)
What happens if they aren’t replaced correctly?
If they are deficient in number?
If they are produced in excess to what is needed?
If they are not structurally normal?
Blood Counts
“RBC”
“WBC”
5x109/ml blood
7.3x106/ml blood
Ratio RBC to WBC = 685:1
“WBC” = White Blood Cells (Leucocytes)
See Table 2-4, p. 30, Kuby 6th Edition
Mouse Whole Blood with
Human Leukemia Cells
Added at ~0.5%
Diluted 1:500 for Counting
Blood Cell Survival Times and Turn-Over
Erythrocytes (Red Blood Cells)
~ 4 Months
Neutrophils
1 Day
Lymphocytes
Years
White Blood Cell Generation
3.7 x 1011/day
(50 x World Human Population per Day)
Blood Cell Replacement Problems
At the correct time:
When cells are damaged, aged, or no longer functional or
necessary.
Replace with the correct cell type.
In the correct number.
Do not propagate errors arising during cell division.
Replacing Cells at the Correct time
Getting Rid of Aged or Damaged Cells
Without generating inflammation:
Genetically Programmed Cells Death (Apoptosis)
vs Inflammatory Lysis and Necrosis
Genetically Programmed
Cell Death: Apoptosis
Bcl-2 gene: B-cell Leukemia associated gene
Hematopoeisis and Leukemogenesis (Leukemia)
What happens if damaged cells are not destroyed?
What happens if Apoptosis is not invoked?
Bcl-2 gene up-regulation in leucocytes leads to leukemia.
(Strong inhibition of Apoptosis)
FAS Gene or Caspase Genes down-regulated or lost in
cells leads to leukemia and other cancer.
(Failure to initiate or promote Apoptosis)
Replacing Cells at the Correct Time
with the Correct Cell Type
Where Do the Blood Cells Come From?
Stem Cells and Partially Differentiated Progenitor Cells
Stem Cell Therapy in Medicine
200,000 peripheral blood cells restore
viability
1,000 mixed stem cells and
progenitor cells restore viability
Pure Stem Cells
30 to 100 Stem cells restore viability
See Figure 2-5
Kuby, 6th Ed.
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It takes 200,000 cells to restore viability in the lethally irradiated
mouse at the top, but only 1,000 cells are required for the mouse at
the bottom? Why is that?
Isolation of CD34+ Pluripotent Stem Cells
from Mixed Bone Marrow Mononuclear
Cells Using Monoclonal Antibody to CD34
Marker on Stem Cells
CD34 Purification of Stem Cells
See Figure 3-9
Kuby, 3rd Ed.
Antibody conjugated to Biotin.
Avidin coats insoluble beads
Biotin Sticks Strongly to Avidin
Stem Cell Transplantation in Medicine:
In Immune deficiency diseases
In immuno-suppressed states
Autologous Transplants
Syngeneic Donors
Allogeneic Donors
Autologous Transplant
See p.38
Kuby, 4th Ed.
Pluripotent Stem Cell
and Lymphoid and
Myeloid Lineages
(Fig 2-1, Kuby 4th Ed. p. 28
StemCell
Myeloid Stem Cell
Hematopoiesis
(formation
of blood cells)
Fig 2-1,
Kuby 4th Ed. p. 28
HematoAll
Lymphoid Lineage
Fig 2-1 Kuby 4th Ed
p. 28
Lymphoid
Cells of Lymphocyte Lineage
B-Lymphocytes: Antibody receptors and antibody production
T-Lymphocytes (Thymus-derived lymphocytes):
T-Cell Receptors
Helper T-Cells “CD4 positive”
Cytotoxic T-Cells “CD8 Positive”
Natural Killer Cells (“Non-B-Cell, Non-T-Cell Lymphocytes)
Recognize virally infected or transformed cells
Bind to antibody labelled cells as part of antibodydependent, cell mediated cytotoxicity (ADCC)
Differentiation Antigen Markers (CD Antigens) on Lymphocytes
p. 34
Used to identify sub-populations of lymphocytes and
to isolate them
Appendix 1: Pages A1 to A26
339 CD Antigens on Leucocytes
What cells types express them
What they do
e.g. CD4 is a co-receptor on helper T-cells.
Confirms binding of T-Cell with its T-Cell
Receptor to an antigen-presenting cell.
Natural Killer Cells
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•
•
•
Large Granular Lymphoctyes
Part of innate natural immune response
Usually without T-Cell Receptor or Membrane Antibody
Recognize patterns of surface molecules or unusual
expression of self-molecules (Class I MHC)
• Have anti-tumor and anti-viral activity
• CD16 Membrane Receptor for specific antibody regions
gives Antibody-dependent cell-mediated cytotoxic activity
• NKT Cells have TCR,
– Bind to MHC-like molecules CD1
– Secrete cytokines
Hematopoiesis
Hematopoiesis
(formation
of blood cells)
Fig 2-1,
Kuby 4th Ed. p. 28
HematoAll
Cells of Myeloid Lineage
Polymorphonuclear leukocytes: (Granulocytes)
Neutrophils, Eosinophils, Basophils, Mast Cells
Antimicrobial, allergic reactions, ADCC
Monocyte Macrophages: Mononuclear phagocytes
Antimicrobial, attack virally infected cells,
Phagocytosis, Endocytosis, & Pinocytosis
Degrade and present processed antigens
Denedritic Cells
Similar functions as for macrophages
(Note “Follicular Dendritic Cells, p. 40)
Different from bone-marrow derived dendritic cells
Erythrocytes: Red Blood Cells, carrying oxygen
Megacaryocytes: Produce platelets for blood clotting
Myeloid Lineage
Myeloid
Lineage
(Kuby, Fig 2-1,
4th Ed., p. 28.
See Figure 2-2
Hematopoiesis
6th Edition
p. 25)
Differentiation in the
Monocyte Macrophage
Lineage
Myeloid to Monocyte
Tissue Macrophages
BloodCells1
BloodCells2
Histiocyte
(Connective
Tissue)
Mesangial Cell
(Kidney)
Osteoclast (Bone)
Monocyte to Macrophage
Macrophage (MPH or MO)
Monocyte
Monocyte to Macrophage
Kuby, Immunology. 6th Edition
Figure 2-7
MC&MPH
Macrophage Ingesting and Degrading Bacterial Targets
Kuby, Immunology, 6th Edition, Figure 2-8
Macrophage
bacteria
Antigen presentation
MPHIngest
Kuby, 4th Edition, p. 44
Macrophage Factors
MPhMake
Dendritic Cells from Sci Am
Dendritic and T-Cell
Dendritic Cell micrograph
Types of Antigen-Presenting
Dendritic Cells.
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Differentiation and Function in the Granulocyte Lineage
Neutrophils:
Eosinophils:
Basophils and Mast Cells
BloodCells2
Histiocyte
(Connective
Tissue)
Mesangial Cell
(Kidney)
Osteoclast (Bone)
Differentiation and Function in the Granulocyte Lineage
Neutrophils:
Multi-lobed Nucleus (PMN) Polymorphonuclear Leucocyte
50% of circulating leukocytes.
Short-lived (Hours or Days).
Phagocytic
Circulates, extravasates out of vasculature into tissue.
Responds to chemotactic factors released by infection and inflammation
(e.g. from complement or blood-clotting reactions or cytokines released by
T-cells or macrophages).
Granules release peroxidase, lysozyme, hydrolases, proteases, collagenase.
Antimicrobial agents released.
Part of innate natural immune response.
Macrophage and PMN Killing
Kuby, 4th Edition, p. 43
Agents
MPhKill
Differentiation and Function in the Granulocyte Lineage
Eosinophils: Acidic Granules
Anti-parasitic immunity
1% of circulating leukocytes
Phagocytic
Basophils:
Less than 1% of circulating leukocytes
Non-phagocytic
Degranulate to release substances supporting allergic attack
Mast Cells:
Similar to Basophils, but in tissue sites
Secrete histamine in allergic attacks
A leukemia in the monocyte-macrophage lineage would be
a(n) ______________ leukemia
Erythro
Myeloid
NK
Lymphocytic
T-Cell
Innate
Stem Cell
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Cytokine Signaling and Cytokine Receptors
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Normal Hematopoiesis and in Leukemia
Myeloid Leukemia
See Figure 3-6
Kuby, 3rd Ed.
Kuby, 4th Edition, p. 44
Macrophage Factors
MPhMake
Key Hematopoietic Growth Factors
and Their Targets
Relatively Multi-Specific:
Granulocyte-Macrophage Colony-Stimulating Factor
GMCSF
Interleukin III - IL3
Relatively Mono-Specific:
Granulocyte Colony Stimulating Factor - GCSF
Macrophage Colony Stimulating Factor - MCSF
Erythropoietin - EPO
GrowFact
Cytokine Table
See
Table 3-1
Kuby
3rd Ed.
TH1 and TH2
Appendix II, Pages A27 to A31
52 Cytokines from Interleukin 1
to Tumor Necrosis Factor Beta (TNF-B)
If a potentially dividing cell with a cell division growth factor receptor in its
membrane also produces the growth factor itself, the cell is likely to
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Differentiate and enter a
resting state
Secrete antibodies
Generate an auto-immune
response
Degranulate
Proliferate without outside
control
Enter apoptosis and die
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An Exercise
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Receptors