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Cellular Components of the Immune Response: Stem Cells and Stem Cell Transplantation Folder Title:Cells Updated: October 21, 2013 Filename: Cells.ppt Slide 2 Please put away all notes and any devices except for your Turning Point NXT Transmitter. No papers or computers on your desk please. No communication between or among students. Slide 3 I distributed a one-page copy of a Science note at the last class on Thursday the 17 th. What was the Science note about or what was its title? (If you were not in class last Thursday please state that in your response.) RankResponses 1 2 3 4 5 6Other Response Counter Slide 4 If a pharmaceutical agent has a name that ends in mab, what does that tell you about the agent? RankResponses 1 2 3 4 5 6Other Response Counter Slide 5 Immune System Make-up From 447Intro, Slides 54 and 55 Slide 6 Morphology & Staining of Blood Cells Kuby, 3rd Ed. Figure 3-1 ImmCells Slide 7 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 arent replaced correctly? If they are deficient in number? If they are produced in excess to what is needed? If they are not structurally normal? Slide 8 Blood Counts See Table 2-4, p. 30, Kuby 6 th Edition 5x10 9 /ml blood 7.3x10 6 /ml blood Ratio RBC to WBC = 685:1 WBC RBC WBC = White Blood Cells (Leucocytes) Slide 9 Mouse Whole Blood with Human Leukemia Cells Added at ~0.5% Diluted 1:500 for Counting Slide 10 Blood Cell Survival Times and Turn-Over Erythrocytes (Red Blood Cells)~ 4 Months Neutrophils1 Day LymphocytesYears White Blood Cell Generation3.7 x 10 11 /day (50 x World Human Population per Day) Slide 11 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. Slide 12 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 Slide 13 Genetically Programmed Cell Death: Apoptosis Slide 14 Bcl-2 gene: B-cell Leukemia associated gene Slide 15 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) Slide 16 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 Slide 17 200,000 peripheral blood cells restore viability 1,000 mixed stem cells and progenitor cells restore viability Slide 18 Pure Stem Cells See Figure 2-5 Kuby, 6th Ed. 30 to 100 Stem cells restore viability Slide 19 Please put away all notes and any devices except for your Turning Point NXT Transmitter. No papers or computers on your desk please. No communication between or among students. Slide 20 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? Slide 21 CD34 Purification of Stem Cells See Figure 3-9 Kuby, 3rd Ed. 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 beads Biotin Sticks Strongly to Avidin Slide 22 Stem Cell Transplantation in Medicine: In Immune deficiency diseases In immuno-suppressed states Autologous Transplants Syngeneic Donors Allogeneic Donors Slide 23 See p.38 Kuby, 4th Ed. Autologous Transplant Slide 24 Slide 25 Pluripotent Stem Cell and Lymphoid and Myeloid Lineages (Fig 2-1, Kuby 4th Ed. p. 28 Myeloid Stem Cell StemCell Slide 26 Hematopoiesis (formation of blood cells) Fig 2-1, Kuby 4th Ed. p. 28 HematoAll Slide 27 Lymphoid Lymphoid Lineage Fig 2-1 Kuby 4th Ed p. 28 Slide 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 antibody- dependent, cell mediated cytotoxicity (ADCC) Slide 29 Slide 30 Differentiation Antigen Markers (CD Antigens) on Lymphocytes Used to identify sub-populations of lymphocytes and to isolate them p. 34 Slide 31 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. Slide 32 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 Slide 33 Hematopoiesis Slide 34 Hematopoiesis (formation of blood cells) Fig 2-1, Kuby 4th Ed. p. 28 HematoAll Slide 35 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 Slide 36 Myeloid Lineage Myeloid Lineage (Kuby, Fig 2-1, 4th Ed., p. 28. See Figure 2-2 Hematopoiesis 6 th Edition p. 25) Slide 37 Myeloid to Monocyte Differentiation in the Monocyte Macrophage Lineage Slide 38 Tissue Macrophages Slide 39 BloodCells1 Slide 40 BloodCells2 Histiocyte (Connective Tissue) Osteoclast (Bone) Mesangial Cell (Kidney) Slide 41 Monocyte to Macrophage Monocyte Macrophage (MPH or MO) Monocyte to Macrophage Kuby, Immunology. 6th Edition Figure 2-7 MC&MPH Slide 42 Macrophage Ingesting and Degrading Bacterial Targets Kuby, Immunology, 6th Edition, Figure 2-8 MPHIngest bacteria Macrophage Antigen presentation Slide 43 Macrophage Factors MPhMake Kuby, 4th Edition, p. 44 Slide 44 Dendritic Cells from Sci Am Slide 45 Dendritic and T-Cell Slide 46 Dendritic Cell micrograph Slide 47 Types of Antigen-Presenting Dendritic Cells. Slide 48 RankResponses 1 2 3 4 5 6Other Slide 49 Differentiation and Function in the Granulocyte Lineage Neutrophils: Eosinophils: Basophils and Mast Cells Slide 50 Slide 51 Slide 52 BloodCells2 Histiocyte (Connective Tissue) Osteoclast (Bone) Mesangial Cell (Kidney) Slide 53 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. Slide 54 Macrophage and PMN Killing Agents MPhKill Kuby, 4th Edition, p. 43 Slide 55 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 Slide 56 A leukemia in the monocyte-macrophage lineage would be a(n) ______________ leukemia 1.Erythro 2.Myeloid 3.NK 4.Lymphocytic 5.T-Cell 6.Innate 7.Stem Cell Response Counter Slide 57 Cytokine Signaling and Cytokine Receptors in Normal Hematopoiesis and in Leukemia Slide 58 Myeloid Leukemia See Figure 3-6 Kuby, 3rd Ed. Slide 59 Macrophage Factors MPhMake Kuby, 4th Edition, p. 44 Slide 60 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 Slide 61 Cytokine Table See Table 3-1 Kuby 3rd Ed. Slide 62 TH1 and TH2 Slide 63 Appendix II, Pages A27 to A31 52 Cytokines from Interleukin 1 to Tumor Necrosis Factor Beta (TNF-B) Slide 64 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 1.Differentiate and enter a resting state 2.Secrete antibodies 3.Generate an auto-immune response 4.Degranulate 5.Proliferate without outside control 6.Enter apoptosis and die Response Counter Slide 65 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.Im totally lost. 2.Im having hard time, but I follow some of it. 3.Im OK. I can figure most of it out later. 4.Im following very well. There is no problem with the level of the course. 5.This isnt pitched at a level appropriate for an upper division undergraduate course. Please move to a higher level of challenge. Response Counter Slide 66 An Exercise in the Unification of the Human Family in the Digital Age. Search Maria Sophia and Violanda Slide 67 To Get to Molecular Visualizations Produced for Kuby Immunology http://bcs.whfreeman.com/immunology6e/ Or search Kuby Immunology, Click on Kuby Immunology 6e, go to Student Resources Slide 68 (This question is set to anonymous. Your name will not be linked to your answer) Are You Registered to Vote? 1.Yes 2.No 3.None of your business 4.Not eligible to vote in the United States Slide 69 I am here! 1.Yes 2.No Also try message to leader The next slide is a time to respond slide. This is designed in response to complaints about students consulting their notes or each other. Well try it out to see how it works, but I think this puts students for whom English is not their primary language at a disadvantage. Response Counter Slide 70 An Exercise In Cytokine Signaling and Cytokine Receptors