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Sri Ram .P Date: 11/25/03 Course: Scientific Discovery Instructor: Dr. A. Vankley. Cell Mediated Immunity. “Discoveries concerning the specificities of Cell Mediated Immune defenses and their implications ”. Immunity?. Foreign Invaders. Self Markers. Markers of Non-Self.

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Sri Ram .P Date: 11/25/03 Course: Scientific Discovery Instructor: Dr. A. Vankley

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Sri ram p date 11 25 03 course scientific discovery instructor dr a vankley

Sri Ram .PDate: 11/25/03Course: Scientific Discovery

Instructor: Dr. A. Vankley


Cell mediated immunity

Cell Mediated Immunity

“Discoveries concerning the specificities of Cell Mediated Immune defenses and their implications ”


Immunity

Immunity?


Foreign invaders

Foreign Invaders


Self markers

Self Markers


Markers of non self

Markers of Non-Self


Organs and tissues of the immune system

Organs and tissues of the immune system


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  • Lymphatic vessels form a circulatory system that operates in close partnership with blood circulation.


Lymph node

Lymph Node


Cells of the immune system

Cells of the Immune System


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  • B cells become plasma cells, which produce antibodies when a foreign antigen triggers the immune response.


Antibody

Antibody


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  • Antibodies produced by cells of the immune system recognize foreign antigens and mark them for destruction.


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  • Activation of B cells to make antibody


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  • 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.


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  • Activation of helper T cells


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  • Activation of cytotoxic T cells


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Cytokines Complement


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Natural Killer cells , Phagocytes and Granulocytes

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Immunity and cancer

Immunity and Cancer


Human tissue typing for organ transplants

Human Tissue Typing for Organ Transplants


Rolf m zinkernagel

Rolf M. Zinkernagel


Rolf m zinkernagel1

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


Rolf m zinkernagel2

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 .


Rolf m zinkernagel3

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


Rolf m zinkernagel4

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


Peter c doherty

Peter C. Doherty


Peter c doherty1

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


Peter c doherty2

Peter C. Doherty

  • 1972-75:Research Fellow, Department of Microbiology, The John Curtin Schoolof 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 CurtinSchool of Medical Research, Australian National University, Canberra


Peter c doherty3

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  


Paired up

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.


Paired up1

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.


Background

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.


Background1

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.


Background2

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.


Techniques and study

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.


Techniques and study1

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 .


Observations

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.


Observations1

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.


Experiment

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 .


Experiment1

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.


Reassessment

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).


Reassessment1

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.


Further studies

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.


Further studies1

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


Similar finding

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.


How to interpret

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.


How to interpret1

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.


The best proposal

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.


Crucial findings

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.


Crucial findings and analysis

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


Intimacy model

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.


Codominant expression

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.


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  • 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


Conclusions

Conclusions

  • In 2nd 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.


Conclusions1

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.


Role of peptides

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


Role of peptides1

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.


Implications

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.


Role of thymus

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.


Role of thymus1

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.


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  • 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.


New vaccines

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.


New vaccines1

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.


Vaccinations

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.


Mutant viruses

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


Mutant viruses1

Mutant Viruses

  • Infected mice in the footpad gave 2 peaks of immune reactions.

  • Similar mutant virus are seen in HIV and HBV infections.


Mhc associations

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.


Mhc associations1

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.


Hla associated diseases ankylosing spondylitis

HLA associated diseases-Ankylosing Spondylitis


Autoimmune diseases

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.


Autoimmune diseases1

Autoimmune Diseases

  • Multiple sclerosis

  • Diabetes mellitus

  • Rheumatoid Arthritis

  • SLE

  • Psoriasis

  • Hashimotos thyroiditis,etc


Autoimmune diseases2

Autoimmune Diseases


Immunological memory

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.


Other related diseases

Other Related Diseases

  • 1- Immune complex diseases. Ex. Glomerulonephritis

  • 2-Immune Deficiency diseases. Ex. AIDS


Team work

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.


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  • In recognition of these contributions Peter Doherty and Rolf Zinkernagel were awarded the Nobel Peace Prize in Medicine in year 1996.


References

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.


References1

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


References2

References

  • 8-www.nobel.se

  • 9http://press2.nci.nih.gov/sciencebehind/immune/immune17.htm

  • 10www.niaid.nih.gov/publications/autoimmune/graphics/Synovium.gif


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