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Cellular Components of the Immune Response: Stem Cells and Stem Cell Transplantation Folder Title:

CellsNoTP

Updated: October 30, 2014

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?

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

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

Leukemia Cell About 20 u

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

Cysteine – aspartate protease

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) “Caspase” = cysteine-aspartate proteaase

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

How Can We get Our Hands on Stem Cells for Treatments? 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. To Here Thursday October 23rd, 2014

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

How Can We get Our Hands on Stem Cells for Treatments? Stem Cell Therapy in Medicine

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

Biotin attached To Antibody Fc Region

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

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

Treatments with Stem Cells In Immune deficiency diseases In immuno-suppressed states Autologous Transplants Non-Self Donors Syngeneic Donors Allogeneic Donors

Autologous Transplant

Step 2

Step 1

Step 3

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

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

Lymphoid Lineage Fig 2-1 Kuby 4th Ed p. 28

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)

Antigen-activated B- Cells

Differentiation Antigen Markers (CD Antigens) on Lymphocytes p. 34 Unique TCell Marker Unique TCell Marker

Distinguishes Tc from TH

Unique NK-Cell Marker

Unique BCell Marker Unique TCell Marker

Unique BCell Markers Unique NK-Cell Marker

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

Edition 6 (2007) :Appendix 1: Pages A1 to A26 339 CD Antigens on Leucocytes

Edition 7 (2013): Apendix 1: Pages A1 to A29 350 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 • • • •

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

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 See Slides 46, 47, 48, 49 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)

To Here Oct. 28, 2014

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. (Shown in Lymphoid Series in Slide 53)

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

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 Receptors in Normal Hematopoiesis and in Leukemia

An Exercise In Cytokine Signaling and Cytokine Receptors Need persons who speak: Spanish Chinese

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

Autocrine stimulation (Self-Signaling) and the Generation of Leukemias and other Cancers

See Figure 3-6 Kuby, 3rd Ed.

Appendix II, Pages A27 to A31 52 Cytokines from Interleukin 1 to Tumor Necrosis Factor Beta (TNF-B)

To Get to Animations & Molecular Visualizations Produced for Kuby Immunology http://bcs.whfreeman.com/immunology6e/ (Or search “Kuby Immunology”, Click on “Kuby Immunology 6e” , go to Student Resources)

Animations Chapter 2: Cells; Cell Death Chapter 10: Cell Death Chapter 11: Signal Transducton Chapter 13: Leucocyte Extravasation

Molecular Visualization Chapter 2: Cells and Organs Chose Other Chapters for Other Molecular Visualization

How Well Are You Following What is Being Presented so Far in theCourse? (This will be set to anonymous so you will not be identified and your response will not be graded) 1. 2. 3. 4.

5.

I’m totally lost. I’m having hard time, but I follow some of it. I’m OK. I can figure most of it out later. I’m following very well. There is no problem with the level of the course. This isn’t pitched at a level appropriate for an upper division undergraduate course. Please move to a higher level of challenge.

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