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Peter C. Doherty and Rolf M. Zinkernagel (presented by Sri Ram)

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  • 1. Sri Ram .P Date: 11/25/03 Course: Scientific Discovery Instructor: Dr. A. Vankley
  • 2. Cell Mediated Immunity
    • “Discoveries concerning the specificities of Cell Mediated Immune defenses and their implications ”
  • 3. Immunity?
  • 4. Foreign Invaders
  • 5. Self Markers
  • 6. Markers of Non-Self
  • 7. Organs and tissues of the immune system
  • 8.
    • Lymphatic vessels form a circulatory system that operates in close partnership with blood circulation.
  • 9. Lymph Node
  • 10. Cells of the Immune System
  • 11.
    • B cells become plasma cells, which produce antibodies when a foreign antigen triggers the immune response.
  • 12. Antibody
  • 13.
    • Antibodies produced by cells of the immune system recognize foreign antigens and mark them for destruction.
  • 14.
    • Activation of B cells to make antibody
  • 15.
    • T lymphocytes become CD4+ or helper T cells, or they can become CD8+ cells, which in turn can become killer T cells, also called cytotoxic T cells.
  • 16.
    • Activation of helper T cells
  • 17.
    • Activation of cytotoxic T cells
  • 18.
    • Cytokines Complement
  • 19.
    • Natural Killer cells , Phagocytes and Granulocytes
    asa
  • 20. Immunity and Cancer
  • 21. Human Tissue Typing for Organ Transplants
  • 22. Rolf M. Zinkernagel
  • 23. Rolf M. Zinkernagel
    • Born: January 6, 1944, Basel, Switzerland
    • Primary and Secondary Education in and around Basel.
    • 1962-68:University of Basel, Faculty of Medicine
    • 1969- Began his life as Surgeon in Basel but soon realized this was not his field.
    • 1969-70:Postdoctoral Fellow, Laboratory for Electron Microscopy, Institute of Anatomy, University of Basel
  • 24. Rolf M. Zinkernagel
    • 1971-1973 Postdoctoral Fellow, Institute of Biochemistry, University of Lausanne, Switzerland
    • He learnt his immunology here.
    • He also familiarized himself with the 51-Cr. Release assay to study the immune mechanism destruction of host cells.
    • His work with infectious agents and immunity studies motivated him for further study .
  • 25. Rolf M. Zinkernagel
    • 1973-75: Visiting Fellow, Department of Microbiology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    • 1976-79:Associate (Assistant Professor), Department of Immunopathology, Research Institute of Scripps Clinic, La Jolla, California
  • 26. Rolf M. Zinkernagel
    • 1979-88:Associate Professor, Department of Pathology, University of Zurich, University Hospital, Zurich
    • 1988-92-Full professor in same place
    • 1992-Head, Institute of Experimental Immunology, Zurich
  • 27. Peter C. Doherty
  • 28. Peter C. Doherty
    • Born: October 15, 1940, Australia
    • 1962:BVSc University of Queensland, Australia
    • 1966:MVSc University of Queensland, Australia
    • 1967-71:Scientific Officer, Senior Scientific Officer, Department of Experimental Pathology, Moredun Research Institute, Edinburgh, Scotland
  • 29. Peter C. Doherty
    • 1972-75:Research Fellow, Department of Microbiology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
    • 1975-82: Associate Professor/Professor, The Wistar Institute, Philadelphia, PA
    • 1982-88:Professor and Head, Department of Experimental Pathology, The John Curtin School of Medical Research, Australian National University, Canberra
  • 30. Peter C. Doherty
    • 1988:Chairman, Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN
    • 1992:Adjunct Professor, Departments of Pathology and Pediatrics, University of Tennessee, College of Medicine, Memphis, TN  
  • 31. Paired Up
    • Peter Doherty first studied the pathogenesis of Semliki Forest virus infection in the mouse, then switched to the lymphocytic choriomeningitis virus (LCMV) model which was a much more powerful tool for immunological analysis.
  • 32. Paired Up
    • Zinkernagel wanted to work with R. Blanden on cell-mediated immunity against Salmonella and Listeria to learn more about the role of cell-mediated versus antibody-dependent immune effector mechanisms in these infectious disease models . But lack of space in the lab paired both of them.
  • 33. Background In 1960-70s immunology was attempted to be understood in terms of infectious diseases. It was then Largely pre-occupied with antibody and T-cell responses against foreign protein antigens or chemically defined small molecules called haptens .
  • 34. Background
    • Mechanism of foreign-organ graft rejection was intensively studied, although the biological function of MHC was largely unclear.
    • Only few people studied immunity against infectious agents.
  • 35. Background
    • Antibacterial and antiviral T-cell mediated immunity and the capacity of immunized cytotoxic CD8+ T cells to destroy either virus infected or allogeneic target cells in vitro- was the work in progress at JCSMR.
  • 36. Techniques and Study
    • Doherty and Zinkernagel jointly begin work on CMI in LCMV (Lymphocytic choriomeningitis virus).
    • 51 cr. Release assays as cytotoxicity assay was used by Zinkernagel.
    • Doherty was efficient in cannulation and could draw few ml of CSF from cisterna magna of the mice.
  • 37. Techniques and Study
    • Whether inflammatory cells in the CSF of mice infected intra cerebrally with LCMV were cytolytic in vitro and whether there was any correlation between cytotoxic T- cell activity and severity of choriomeningitis .
  • 38. Observations
    • Cytotoxic T cells specifically destroying LCMV infected target cells could be found in CSF of normal mice but not in nude mice lacking thymus and T-cells.
    • T-cells probably also destroyed infected meningeal and ependymal cells in vivo and this was the pathogenic mechanism causing choriomeningitis.
  • 39.  
  • 40.  
  • 41.  
  • 42. Observations
    • The findings were published in the Journal of Experimental Medicine in March 1973.
    • Same journal had a paper showing mice with different major histocompatibility gene complexes differed in susceptibility to LCMV after cerebral infection.
    • This prompted to experiment further on this.
  • 43. Experiment
    • 6-8 mice of inbred and cross-bred strains were infected intra cerebrally with LCMV.
    • 2 of each were sacrificed on day 7 after infection when first mouse became sick. –to test antiviral cytotoxic T –cell activities in spleens.
    • Remaining mice were monitored for lethal disease during next 10days .
  • 44. Experiment
    • All mice died in course of time.
    • But only some generated virus-specific cytotoxic activity that was measurable in vitro.
    • Result- Either cytotoxic T-cells have nothing to do with choriomeningitis or the test was inadequate.
  • 45.  
  • 46. Reassessment
    • Mouse L-929 cells (fibroblast cell lines) were used as target cells to assess cytotoxic T-cell activity.
    • Fortunately the mouse CBA strain and the L-cells derived from mouse strain C3H were closely related.
    • Both possessed the same MHC-molecules (H-2k).
  • 47. Reassessment
    • Studying further, LCMV -immune spleen cells from all mice that possessed H-2k haplotype (as do CBA mice) including the cross breeds with H-2k lysed L-929 cells infected with virus.
    • But did not lyse uninfected targets or those infected with third-party virus.
    • All spleen cells derived from immunized mice that were not of H-2k type failed to do so.
  • 48. Further Studies
    • Two additional experiments showed that LCMV immune lymphocytes from non-H2k strains of mice were able to lyse LCMV infected target cells of same MHC –type.
    • LCMV did not infect these cell lines.
    • Used macrophages from the peritoneum of the mice as target cells. Adhered to plastic, readily infectable and labeled with Cr 51.
  • 49. Further Studies
    • Criss-cross experiments showed that LCMV immune T-cells from H-2b mice lyse LCMV-infected macrophages of H-2b origin but not those of other H-2 types and vice versa.
    • These findings were reported in December to Nature and were published in April,1974
  • 50. Similar Finding
    • TNP-specific cytotoxic T cells lysed syngeneic TNP-lated targets more efficiently than allogeneic TNP-lated targets.
    • European journal of immunology –same time . But independent.
  • 51. How to Interpret
    • Biological function of MHC and TA was unknown in early 1970s.
    • TA-Gorer and Snell
    • HLA-Dausset and Van Rood
    • Many patients were typed and disease susceptibilities were linked to TA
    • Mice MHC was mapped due to availability of well-bred strains.
  • 52. How to interpret
    • MHC polymorphism- to prevent mutual parasitism or transmission of tumor cells or to prevent viruses or pathogens mimicking TA and eliminate the species.
    • TA were though to act as enzymes or generators of antibody diversity.
  • 53. The best proposal
    • H.S Lawrence proposed infectious agents complexed with TA and formed a (self+x) complex.
    • All this was foundation to reveal the essential role of MHC and T-cell recognition.
  • 54. Crucial findings
    • Finding of double specifity by Tcells– for virus and MHC from intial experiements.
    • Findings that H-2 incompatible T-helper cells transfused to T-cell deficient nude mice were not able to help mice nude B cells make antibodies
    • Histo-incompatible B cells and T cells were not interacting successfully to produce a good IgM to IgG switch.
  • 55. Crucial findings and Analysis
    • Antigen specifc proliferative T-cell responses found only when primed T cells and antigen presenting cells were with same MHC type.
    • All in vitro and in vivo tests confirmed the HLA restriction for T cells.
    • Virus infection somehow caused alterations of TA on the cell surface by forming a complex of viral antigen with MHC molecules .
    • These alterations were recognized by the T-cell receptors
  • 56.  
  • 57.  
  • 58.  
  • 59. Intimacy Model
    • Foreign TA altered forms of self-TA
    • Lymphocytes and target cells interact mutually via TA. H-2k interacts best with H-2k in a symmetrical like-like complementarity.
    • This initmacy model was soon excluded by the F1-experiment showing virus specific cytotoxic T lymphocytes from heterozygote F1 mice consisted of at least 2 subpopulations-each being specific for infected H-2k and other for H-2b targets.
  • 60. Codominant Expression
    • Since MHC expressed codominantly some T-cell receptors of one population were probably specific for H-2k plus virus and other sub-population was specific for H-2b plus virus.
  • 61.  
  • 62.  
  • 63.
    • Working with Blanden’s experiments showed that H-2d and H-2k regions coding for class1MHC molecule were involved in virus-specific cytotoxic t-cell recognition.
    • This seperated MHC restricted recognition by virus-specific cytotoxic T-cells from MHC class 2
  • 64. Conclusions
    • In 2 nd letter to the Nature -T-cells might function to survey the integrity of TA. Recognition of cell surface alteration due to virus infection ,chemical modification or genetic differences may be accommodated in the same model.
    • General hypothesis formulated in Lancet was that function of MHC is to signal modifications of self-MHC to the immune system.
  • 65. Conclusions
    • Tried to extend the explanations to helper T cells-they might recognize antigen-induced modifications of 1a(as the MHC class 2 molecules) on B cells and macrophages.
    • Explained the extensive polymorphisms of MHC molecules minimizing failure of some pathogens to cause immuno-modification and risk general unresponsiveness.
  • 66. Role of Peptides
    • Not know then , MHC molecules are recognized as complex with antigenic peptide.
    • By works of Unanue, Grey and others on class 2 antigens and Townsted works showed- class 1 molecules of the virus infected cells present peptides ,9-10 amino acids long to virus specific cytotoxic t cells. These peptides were later successfully eluted
  • 67. Role of Peptides
    • In 1987 x-ray crystallography revealed a peptide binding cleft.
    • X-ray structure of the complete complex of the T cell receptor-MHC class1 plus the bound peptide in same year of Nobel prize.
    • Still unclear which part of the TCR and whether always corresponding parts of the TCR recognized the peptide and the MHC molecule in the same general position.
  • 68. Implications
    • The above findings and conclusions gave immense scope for further understanding of the immune system and its clinical implications in the field of medicine.
  • 69. Role of Thymus
    • Reconstitution of lethally radiated H-2b recipient mice with bone-marrow stem cells of (H-2k*H-2b)F-1 origin resulted in bone marrow chimeras tolerant to H-2k and H-2b .
    • When immunized these reacted against only H-2b+minor HC antigens or H-2b+virus only.
    • So, MHC restricted T cells were specifically selected during T cell maturation according to the MHC expressed in the thymus.
  • 70.  
  • 71. Role of Thymus
    • MHC specificity studied in mice that lacked thymus did not have mature t-cells.
    • Introducing H-2k thymus into F-1 mice gave T–cells recognizing virus infected H-2k but not infected H-2b target cells.
  • 72.
    • Clinical implications – It is not only necessary to deplete T cells to avoid lethal graft versus host disease.
    • But also, host, transplanted bone marrow and hosts own or transplanted thymus grafts must share MHC molecules.
    • Other wise no proper immune reaction can be mounted in such reconstituted hosts.
  • 73. New Vaccines
    • As peptides from viruses, bacteria and parasites are presented to the MHC class 1 or 2 molecules it was suggested that instead of live potentially harmful peptides could possibly be used as vaccines to induce T- cell responses.
  • 74. New vaccines
    • Peptide life was short lived therefore adjuvants are required to guarantee slow and long term release of the peptides triggering T cells over a prolonged period.
  • 75. Vaccinations
    • Positive vaccination- increase the T cell precursor frequency to enhance protection.
    • Negative vaccination- to reduce or delete Tcells by excess peptide . To exhaust or delete immuno patholgical disease causing T-cells. Tried in diabetes.
  • 76.  
  • 77. Mutant viruses
    • T cell epitope escapes mutant viruses-
    • Mutation of the 9-10 a.a peptides such that its presentation by MHC molecules or recognition by t-cells is no longer possible. this helps viruses escape immune surveillance
  • 78. Mutant Viruses
    • Infected mice in the footpad gave 2 peaks of immune reactions.
    • Similar mutant virus are seen in HIV and HBV infections.
  • 79. MHC Associations
    • Linkage between some disease susceptibilities and certain HLA-types – important role of MHC molecules in immunity.
    • These autoimmune or immunopathological diseases are linked often to HLA class1 rather than class 2 molecules.
  • 80. MHC Associations
    • As antigenicity and immunogenicity are linked to MHC and correlate with different strengths of the T cell response, shows that different MHC molecules directly determine and regulate resistance to diseases.
  • 81. HLA associated diseases-Ankylosing Spondylitis
  • 82. Autoimmune Diseases
    • Non cytopathologial viruses are not directly responsible for disease by themselves ,instead by the damaging effect of the protective T –cell responses.
    • Differences in MHC may influence the severity of the disease depending on the immunopathological response of T-cells.
    • These are the basis for autoimmune or immunopathological diseases.
  • 83.  
  • 84.  
  • 85.  
  • 86. Autoimmune Diseases
    • Multiple sclerosis
    • Diabetes mellitus
    • Rheumatoid Arthritis
    • SLE
    • Psoriasis
    • Hashimotos thyroiditis,etc
  • 87. Autoimmune Diseases
  • 88. Immunological memory
    • The concept of immunological memory has been exploited in vaccinations.
    • The B and T cells were found to exist as memory cells and hence maintained certain precursor levels to fight infections better.
    • The use of immune memory were explained for the mother and fetus.
  • 89.  
  • 90.  
  • 91.  
  • 92. Other Related Diseases
    • 1- Immune complex diseases. Ex. Glomerulonephritis
    • 2-Immune Deficiency diseases. Ex. AIDS
  • 93. Team Work
    • Thus the combined efforts of doctors, immunologists, geneticists, virologists, microbiologists, etc helped us reveal the recognition of viral infected cells by T cells.
    • Giving insight into immunological specificity and memory and help understand immunological disease pathogenesis.
  • 94.
    • In recognition of these contributions Peter Doherty and Rolf Zinkernagel were awarded the Nobel Peace Prize in Medicine in year 1996.
  • 95. References
    • 1. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngenic and semiallogeneic system. Nature 248, 701- 702, 1974. 2. Zinkernagel RM, Doherty PC. Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 251, 547-548, 1974. 3. Doherty PC, Zinkernagel RM. A biological role for the major histocompatibility antigens. Lancet, 1406-1409, 1975. 4. Zinkernagel RM, Doherty PC. MHC restricted cytotoxic T cells: Studies on the biological role of polymorphic major transplantation antigens determining T cell restriction specificity. Advances in Immunology 27, 51-177, 1979.
  • 96. References
    • 5-Press Release: The 1996 Nobel Prize in Physiology or Medicine
    • 6-Nobel Lecture, December 8, 1996 Cellular Immune Recognition and the Biological Role of Major Transplantation Antigens
    • 7-Nobel Lecture, December 8, 1996 Cell Mediated Immunity in Virus Infections
  • 97. References
    • 8-www.nobel.se
    • 9 http://press2.nci.nih.gov/sciencebehind/immune/immune17.htm
    • 10www.niaid.nih.gov/publications/autoimmune/graphics/Synovium.gif