Cellular Componentsof the

Immune Response:Stem Cells and Stem Cell

Transplantation

Folder Title: CellsNoTPUpdated: October 28, 2015

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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 or functionally normal?

How We Learn Things:

Memorization vs Gradual Familiarity

Immune System Make-up

From 447Intro, Slides 54 and 55

Morphology & Staining of Blood Cells

Kuby, 3rd Ed. Figure 3-1

About 6 u diameter

About 20 u diameter

700 RBC to one leucocyte

Replacing Cells at the Correct Time with the Correct Cell Type

Hematopoiesis

Where Do the Blood Cells Come From?Stem Cells and Partially Differentiated Progenitor Cells

How Can We get Our Hands on Stem Cells for Treatments?

Stem Cell Therapy in Medicine

See Figure 2-1p. 28, 7th Editon

Hematopoiesis (formation

of blood cells)Fig 2-1,

Kuby 4th Ed. p. 28

Right to Left View

Hematopoiesis

Where Hematopoietic Cells Come From

Antibodies to differentiated end-product blood cells

Removesprogenitor (P) Cells

Isolation of CD34+ Pluripotent Stem Cells from Mixed Bone Marrow Mononuclear Cells Using Monoclonal Antibody to CD34 Marker on Stem Cells

Antibody conjugated to Biotin.Avidin coats insoluble beadsBiotin Sticks Strongly to Avidin

Biotin attached

To AntibodyFc Region

200,000 peripheral blood cells restore viability

1,000 mixed stem cells and progenitor cells restore viability

Pure Stem Cells

See Figure 2-5Kuby, 6th Ed.

30 to 100 Stem cells restore viability

To Here ThursdayOctober 23rd, 2014

Pluripotent Stem Cell and Lymphoid and Myeloid Lineages (Fig 2-1, Kuby 4th Ed. p. 28

Myeloid Stem CellStemCell

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Differentiation and Function Among “Granulocytes”,

Polymorpho-nuclear Leucocytes (PMN’s) :

Myeloid Lineage

Neutrophils, Eosinophils, Basophils/Mast Cells

Cells of Myeloid Lineage

Polymorphonuclear leukocytes: (Granulocytes)Neutrophils, Eosinophils, Basophils, Mast CellsAntimicrobial, allergic reactions, ADCC

Monocyte Macrophages: Mononuclear phagocytesAntimicrobial, attack virally infected cells,Phagocytosis, Endocytosis, & PinocytosisDegrade and present processed antigens

Denedritic CellsSimilar functions as for macrophages

See Slides 46, 47, 48, 49

Erythrocytes: Red Blood Cells, carrying oxygen

Megacaryocytes: Produce platelets for blood clotting

Myeloid LineageMyeloidLineage(Kuby, Fig 2-1,4th Ed., p. 28.See Figure 2-2 Hematopoiesis6th Editionp. 25)

BloodCells1

BloodCells2

Histiocyte (Connective Tissue)

Osteoclast (Bone)

Mesangial Cell(Kidney)

To HereOct. 28, 2014

Myeloid to Monocyte

Differentiation in the Myeloid Series to Monocyte

Macrophage Lineage

Tissue Macrophages

Differentiation and Function in Monocyte/Macrophage Dendritic

Cell Lineage

Differentiation and Function in the Granulocyte Lineage

Neutrophils: Eosinophils:

Basophils and Mast Cells

Differentiation and Function in the Granulocyte Lineage

Neutrophils: Multi-lobed Nucleus (PMN) Polymorphonuclear Leucocyte50% of circulating leukocytes.Short-lived (Hours or Days).PhagocyticCirculates, 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 Agents

MPhKill

Kuby, 4th Edition, p. 43

Differentiation and Function in the Granulocyte Lineage

Eosinophils: Acidic GranulesAnti-parasitic immunity1% of circulating leukocytesPhagocytic

Basophils: Less than 1% of circulating leukocytesNon-phagocyticDegranulate to release substances supporting allergic attack

Mast Cells:Similar to Basophils, but in tissue sitesSecrete histamine in allergic attacks

Monocyte to Macrophage

Monocyte

Macrophage (MPH or MO)

Monocyte to MacrophageKuby, Immunology. 6th EditionFigure 2-7

MC&MPH

Macrophage Ingesting and Degrading Bacterial TargetsKuby, Immunology, 6th Edition, Figure 2-8

MPHIngest

bacteria

Macrophage

Antigen presentation

Macrophage Factors

MPhMake

Kuby, 4th Edition, p. 44

Types of Antigen-PresentingDendritic Cells.

(Shown in Lymphoid Series in Slide 53)

Dendritic Cells from Sci Am

Dendritic and T-Cell

Dendritic Cell micrograph

Natural Killer Cells• 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

Megakaryocyte – Platelet Lineage:

Blood-Clotting Function

Differentiation and Function in the Lymphocyte Series

Cells of Lymphocyte Lineage

B-Lymphocytes: Antibody receptors and antibody production

T-Lymphocytes (Thymus-derived lymphocytes):T-Cell ReceptorsHelper T-Cells “CD4 positive”Cytotoxic T-Cells “CD8 Positive”

Natural Killer Cells (“Non-B-Cell, Non-T-Cell Lymphocytes)Recognize virally infected or transformed cellsBind to antibody labelled cells as part of antibody-

dependent, cell mediated cytotoxicity (ADCC)

Lymphoid LineageFig 2-1 Kuby 4th Edp. 28

TH1 and TH2

Antigen-activated B- Cells

Differentiation Antigen Markers (CD Antigens) on Lymphocytes

Used to identify sub-populations of lymphocytes and to isolate them

p. 34

Unique T-Cell Marker

Unique T-Cell Marker

Unique T-Cell Marker

Unique B-Cell Markers

Unique NK-Cell Marker

Unique NK-Cell Marker

Unique B-Cell Marker

Distinguishes Tc from TH

Edition 6 (2007) :Appendix 1: Pages A1 to A26339 CD Antigens on Leucocytes

Edition 7 (2013): Apendix 1: Pages A1 to A29350 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.

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.

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)

Replacing Cells at the Correct time

Getting Rid of Aged or Damaged CellsWithout generating inflammation:

Genetically Programmed Cells Death (Apoptosis)vs Inflammatory Lysis and Necrosis

Genetically ProgrammedCell Death: Apoptosis

Bcl-2 gene: B-cell Leukemia associated gene

Cysteine – aspartate protease

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)“Caspase” = cysteine-aspartate proteaase

Bcl-2 gene: B-cell Leukemia associated gene

Cysteine – aspartate protease

Shutting these down leads to failure of cell death and to leukemia

Increasing this leads to failure of cell death as to leukemia

Mouse Whole Blood with Human Leukemia Cells Added at ~0.5%Diluted 1:500 for Counting

Leukemia CellAbout 20 u

Cytokines, Cytokine Receptors, and Normal and Pathological

Cell Signaling

How do the multiplicity of hematopoietic cells at distant sites in the host “talk” to one another?

How do the cells “know” where to go and what to do?

Cytokine Signaling and Cytokine Receptorsin

Normal Hematopoiesis and in Leukemia

An ExerciseIn Cytokine Signaling and Cytokine

Receptors

Need persons who speak:SpanishChineseTibetan

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 - EPOGrowFact

Cytokine Table

See Table 3-1Kuby3rd Ed.

See Figure 3-6Kuby, 3rd Ed.

Autocrine stimulation (Self-Signaling) and the

Generation of Leukemias and other Cancers

Appendix II, Pages A27 to A3152 Cytokines from Interleukin 1

to Tumor Necrosis Factor Beta (TNF-B)

Autologous Cells in Transplantation Medicine

Stem Cell Therapy in Medicine

Autologous Transplant

Step 1

Step 2

Step 3

Stem Cell Transplantation in Medicine:(See pages 42-43, 7th Edition)

Treatments with Stem CellsIn Immune deficiency diseases

In immuno-suppressed states

Autologous Transplants

Non-Self DonorsSyngeneic DonorsAllogeneic Donors

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In the picture below: What cell is labelled Cell 1?

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Ce1l 1

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To Get to Animations & Molecular VisualizationsProduced for Kuby Immunology

http://bcs.whfreeman.com/immunology6e/

(Or search “Kuby Immunology”, Click on “Kuby Immunology 6e” , go to Student Resources)

AnimationsChapter 2: Cells; Cell DeathChapter 10: Cell DeathChapter 11: Signal TransductonChapter 13: Leucocyte Extravasation

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