sri ram .p date: 11/25/03 course: scientific discovery instructor: dr. a. vankley

Sri Ram .PSri Ram .PDate: 11/25/03Date: 11/25/03

Course: Scientific DiscoveryCourse: Scientific DiscoveryInstructor: Dr. A. VankleyInstructor: Dr. A. Vankley

Cell Mediated ImmunityCell Mediated Immunity

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

Immunity?Immunity?

Foreign InvadersForeign Invaders

Self MarkersSelf Markers

Markers of Non-SelfMarkers of Non-Self

Organs and tissues of the Organs and tissues of the immune systemimmune system

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

Lymph NodeLymph Node

Cells of the Immune System Cells of the Immune System

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

AntibodyAntibody

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

Activation of B cells to Activation of B cells to make antibody make antibody

T lymphocytes T lymphocytes become CD4+ or become CD4+ or helper T cells, or helper T cells, or they can become they can become CD8+ cells, which in CD8+ cells, which in turn can become turn can become killer T cells, also killer T cells, also called cytotoxic T called cytotoxic T cells.cells.

Activation of helper T Activation of helper T cells cells

Activation of cytotoxic Activation of cytotoxic T cells T cells

Cytokines ComplementCytokines Complement

Natural Killer cells , Phagocytes and Natural Killer cells , Phagocytes and Granulocytes Granulocytes

asaasa

Immunity and Cancer Immunity and Cancer

Human Tissue Typing for Organ Human Tissue Typing for Organ Transplants Transplants

Rolf M. ZinkernagelRolf M. Zinkernagel


Born: January 6, 1944, Basel, Switzerland Born: January 6, 1944, Basel, Switzerland Primary and Secondary Education in and around Primary and Secondary Education in and around

Basel.Basel. 1962-68:University of Basel, Faculty of 1962-68:University of Basel, Faculty of

Medicine Medicine 1969- Began his life as Surgeon in Basel but 1969- Began his life as Surgeon in Basel but

soon realized this was not his field.soon realized this was not his field. 1969-70:Postdoctoral Fellow, Laboratory for 1969-70:Postdoctoral Fellow, Laboratory for

Electron Microscopy, Institute of Anatomy, Electron Microscopy, Institute of Anatomy, University of Basel University of Basel


1971-1973 Postdoctoral Fellow, Institute of 1971-1973 Postdoctoral Fellow, Institute of Biochemistry, University of Lausanne, Biochemistry, University of Lausanne, Switzerland Switzerland

He learnt his immunology here.He learnt his immunology here. He also familiarized himself with the 51-Cr. He also familiarized himself with the 51-Cr.

Release assay to study the immune mechanism Release assay to study the immune mechanism destruction of host cells.destruction of host cells.

His work with infectious agents and immunity His work with infectious agents and immunity studies motivated him for further study . studies motivated him for further study .


1973-75:1973-75:Visiting Fellow, Department of Microbiology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia

1976-79:Associate (Assistant Professor), 1976-79:Associate (Assistant Professor), Department of Immunopathology, Department of Immunopathology, Research Institute of Scripps Clinic, La Research Institute of Scripps Clinic, La Jolla, California Jolla, California


1979-88:Associate Professor, Department 1979-88:Associate Professor, Department of Pathology, University of Zurich, of Pathology, University of Zurich, University Hospital, Zurich University Hospital, Zurich

1988-92-Full professor in same place1988-92-Full professor in same place 1992-Head, Institute of Experimental 1992-Head, Institute of Experimental

Immunology, Zurich Immunology, Zurich

Peter C. DohertyPeter C. Doherty


Born: October 15, 1940, Australia Born: October 15, 1940, Australia 1962:BVSc University of Queensland, Australia 1962:BVSc University of Queensland, Australia 1966:MVSc University of Queensland, Australia 1966:MVSc University of Queensland, Australia 1967-71:Scientific Officer, Senior Scientific 1967-71:Scientific Officer, Senior Scientific

Officer, Department of Experimental Pathology,Officer, Department of Experimental Pathology,Moredun Research Institute, Edinburgh, Moredun Research Institute, Edinburgh, Scotland Scotland


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

1975-82: Associate Professor/Professor, The 1975-82: Associate Professor/Professor, The Wistar Institute, Philadelphia, PA Wistar Institute, Philadelphia, PA

1982-88:Professor and Head, Department of 1982-88:Professor and Head, Department of Experimental Pathology, The John CurtinExperimental Pathology, The John CurtinSchool of Medical Research, Australian National School of Medical Research, Australian National University, Canberra University, Canberra


1988:Chairman, Department of 1988:Chairman, Department of Immunology, St. Jude Children's Research Immunology, St. Jude Children's Research Hospital, Hospital, Memphis, TN Memphis, TN

1992:Adjunct Professor, Departments of 1992:Adjunct Professor, Departments of Pathology and Pediatrics, University of Pathology and Pediatrics, University of Tennessee, College of Medicine, Tennessee, College of Medicine, Memphis, TN Memphis, TN

Paired UpPaired Up

Peter Doherty first studied the Peter Doherty first studied the pathogenesis of Semliki Forest virus pathogenesis of Semliki Forest virus infection in the mouse, then switched to infection in the mouse, then switched to the lymphocytic choriomeningitis virus the lymphocytic choriomeningitis virus (LCMV) model which was a much more (LCMV) model which was a much more powerful tool for immunological analysis. powerful tool for immunological analysis.

Paired UpPaired Up

Zinkernagel wanted to work with R. Zinkernagel wanted to work with R. Blanden on cell-mediated immunity Blanden on cell-mediated immunity against Salmonella and Listeria to learn against Salmonella and Listeria to learn more about the role of cell-mediated more about the role of cell-mediated versus antibody-dependent immune versus antibody-dependent immune effector mechanisms in these infectious effector mechanisms in these infectious disease models . But lack of space in the disease models . But lack of space in the lab paired both of them.lab paired both of them.

Background Background

In 1960-70s immunology was In 1960-70s immunology was attempted to be understood in terms of attempted to be understood in terms of infectious diseases. It was then Largely infectious diseases. It was then Largely pre-occupied with antibody and T-cell pre-occupied with antibody and T-cell responses against foreign protein responses against foreign protein antigens or chemically defined small antigens or chemically defined small molecules called haptensmolecules called haptens. .

BackgroundBackground

Mechanism of foreign-organ graft rejection Mechanism of foreign-organ graft rejection was intensively studied, although the was intensively studied, although the biological function of MHC was largely biological function of MHC was largely unclear.unclear.

Only few people studied immunity against Only few people studied immunity against infectious agents.infectious agents.

BackgroundBackground

Antibacterial and antiviral T-cell mediated Antibacterial and antiviral T-cell mediated immunity and the capacity of immunized immunity and the capacity of immunized cytotoxic CD8+ T cells to destroy either cytotoxic CD8+ T cells to destroy either virus infected or allogeneic target cells in virus infected or allogeneic target cells in vitro- was the work in progress at JCSMR.vitro- was the work in progress at JCSMR.

Techniques and StudyTechniques and Study

Doherty and Zinkernagel jointly begin Doherty and Zinkernagel jointly begin work on CMI in LCMV (Lymphocytic work on CMI in LCMV (Lymphocytic choriomeningitis virus).choriomeningitis virus).

51 cr. Release assays as cytotoxicity 51 cr. Release assays as cytotoxicity assay was used by Zinkernagel.assay was used by Zinkernagel.

Doherty was efficient in cannulation and Doherty was efficient in cannulation and could draw few ml of CSF from cisterna could draw few ml of CSF from cisterna magna of the mice.magna of the mice.

Techniques and StudyTechniques and Study

Whether inflammatory cells in the CSF of Whether inflammatory cells in the CSF of mice infected intra cerebrally with LCMV mice infected intra cerebrally with LCMV were cytolytic in vitro and whether there were cytolytic in vitro and whether there was any correlation between cytotoxic T- was any correlation between cytotoxic T- cell activity and severity of cell activity and severity of choriomeningitis .choriomeningitis .

ObservationsObservations

Cytotoxic T cells specifically destroying Cytotoxic T cells specifically destroying LCMV infected target cells could be found LCMV infected target cells could be found in CSF of normal mice but not in nude in CSF of normal mice but not in nude mice lacking thymus and T-cells. mice lacking thymus and T-cells.

T-cells probably also destroyed infected T-cells probably also destroyed infected meningeal and ependymal cells in vivo meningeal and ependymal cells in vivo and this was the pathogenic mechanism and this was the pathogenic mechanism causing choriomeningitis.causing choriomeningitis.

ObservationsObservations

The findings were published in the The findings were published in the Journal of Experimental Medicine in March Journal of Experimental Medicine in March 1973.1973.

Same journal had a paper showing mice Same journal had a paper showing mice with different major histocompatibility gene with different major histocompatibility gene complexes differed in susceptibility to complexes differed in susceptibility to LCMV after cerebral infection.LCMV after cerebral infection.

This prompted to experiment further on This prompted to experiment further on this.this.

ExperimentExperiment

6-8 mice of inbred and cross-bred strains 6-8 mice of inbred and cross-bred strains were infected intra cerebrally with LCMV. were infected intra cerebrally with LCMV.

2 of each were sacrificed on day 7 after 2 of each were sacrificed on day 7 after infection when first mouse became sick. –infection when first mouse became sick. –to test antiviral cytotoxic T –cell activities to test antiviral cytotoxic T –cell activities in spleens.in spleens.

Remaining mice were monitored for lethal Remaining mice were monitored for lethal disease during next 10days . disease during next 10days .

ExperimentExperiment

All mice died in course of time.All mice died in course of time. But only some generated virus-specific But only some generated virus-specific

cytotoxic activity that was measurable in cytotoxic activity that was measurable in vitro.vitro.

Result- Either cytotoxic T-cells have Result- Either cytotoxic T-cells have nothing to do with choriomeningitis or the nothing to do with choriomeningitis or the test was inadequate.test was inadequate.

ReassessmentReassessment

Mouse L-929 cells (fibroblast cell lines) Mouse L-929 cells (fibroblast cell lines) were used as target cells to assess were used as target cells to assess cytotoxic T-cell activity.cytotoxic T-cell activity.

Fortunately the mouse CBA strain and the Fortunately the mouse CBA strain and the L-cells derived from mouse strain C3H L-cells derived from mouse strain C3H were closely related. were closely related.

Both possessed the same MHC-molecules Both possessed the same MHC-molecules (H-2k).(H-2k).

ReassessmentReassessment

Studying further, LCMV -immune spleen cells Studying further, LCMV -immune spleen cells from all mice that possessed H-2k haplotype (as from all mice that possessed H-2k haplotype (as do CBA mice) including the cross breeds with H-do CBA mice) including the cross breeds with H-2k lysed L-929 cells infected with virus.2k lysed L-929 cells infected with virus.

But did not lyse uninfected targets or those But did not lyse uninfected targets or those infected with third-party virus. infected with third-party virus.

All spleen cells derived from immunized mice All spleen cells derived from immunized mice that were not of H-2k type failed to do so.that were not of H-2k type failed to do so.

Further StudiesFurther Studies

Two additional experiments showed that Two additional experiments showed that LCMV immune lymphocytes from non-H2k LCMV immune lymphocytes from non-H2k strains of mice were able to lyse LCMV strains of mice were able to lyse LCMV infected target cells of same MHC –type.infected target cells of same MHC –type.

LCMV did not infect these cell lines.LCMV did not infect these cell lines. Used macrophages from the peritoneum Used macrophages from the peritoneum

of the mice as target cells. Adhered to of the mice as target cells. Adhered to plastic, readily infectable and labeled with plastic, readily infectable and labeled with Cr 51.Cr 51.

Further StudiesFurther Studies

Criss-cross experiments showed that Criss-cross experiments showed that LCMV immune T-cells from H-2b mice LCMV immune T-cells from H-2b mice lyse LCMV-infected macrophages of H-2b lyse LCMV-infected macrophages of H-2b origin but not those of other H-2 types and origin but not those of other H-2 types and vice versa.vice versa.

These findings were reported in December These findings were reported in December to Nature and were published in April,1974 to Nature and were published in April,1974

Similar FindingSimilar Finding

TNP-specific cytotoxic T cells lysed TNP-specific cytotoxic T cells lysed syngeneic TNP-lated targets more syngeneic TNP-lated targets more efficiently than allogeneic TNP-lated efficiently than allogeneic TNP-lated targets.targets.

European journal of immunology –same European journal of immunology –same time . But independent.time . But independent.

How to Interpret How to Interpret

Biological function of MHC and TA was Biological function of MHC and TA was unknown in early 1970s.unknown in early 1970s.

TA-Gorer and SnellTA-Gorer and Snell HLA-Dausset and Van RoodHLA-Dausset and Van Rood Many patients were typed and disease Many patients were typed and disease

susceptibilities were linked to TAsusceptibilities were linked to TA Mice MHC was mapped due to availability Mice MHC was mapped due to availability

of well-bred strains.of well-bred strains.

How to interpretHow to interpret

MHC polymorphism- to prevent mutual MHC polymorphism- to prevent mutual parasitism or transmission of tumor cells parasitism or transmission of tumor cells or to prevent viruses or pathogens or to prevent viruses or pathogens mimicking TA and eliminate the species.mimicking TA and eliminate the species.

TA were though to act as enzymes or TA were though to act as enzymes or generators of antibody diversity.generators of antibody diversity.

The best proposalThe best proposal

H.S Lawrence proposed infectious agents H.S Lawrence proposed infectious agents complexed with TA and formed a (self+x) complexed with TA and formed a (self+x) complex.complex.

All this was foundation to reveal the All this was foundation to reveal the essential role of MHC and T-cell essential role of MHC and T-cell recognition.recognition.

Crucial findingsCrucial findings

Finding of double specifity by Tcells– for Finding of double specifity by Tcells– for virus and MHC from intial experiements.virus and MHC from intial experiements.

Findings that H-2 incompatible T-helper Findings that H-2 incompatible T-helper cells transfused to T-cell deficient nude cells transfused to T-cell deficient nude mice were not able to help mice nude B mice were not able to help mice nude B cells make antibodiescells make antibodies

Histo-incompatible B cells and T cells Histo-incompatible B cells and T cells were not interacting successfully to were not interacting successfully to produce a good IgM to IgG switch.produce a good IgM to IgG switch.

Crucial findings and AnalysisCrucial findings and Analysis

Antigen specifc proliferative T-cell responses Antigen specifc proliferative T-cell responses found only when primed T cells and antigen found only when primed T cells and antigen presenting cells were with same MHC type.presenting cells were with same MHC type.

All in vitro and in vivo tests confirmed the HLA All in vitro and in vivo tests confirmed the HLA restriction for T cells.restriction for T cells.

Virus infection somehow caused alterations of Virus infection somehow caused alterations of TA on the cell surface by forming a complex of TA on the cell surface by forming a complex of viral antigen with MHC molecules .viral antigen with MHC molecules .

These alterations were recognized by the T-cell These alterations were recognized by the T-cell receptors receptors

Intimacy ModelIntimacy Model

Foreign TA altered forms of self-TAForeign TA altered forms of self-TA Lymphocytes and target cells interact mutually Lymphocytes and target cells interact mutually

via TA. H-2k interacts best with H-2k in a via TA. H-2k interacts best with H-2k in a symmetrical like-like complementarity.symmetrical like-like complementarity.

This initmacy model was soon excluded by the This initmacy model was soon excluded by the F1-experiment showing virus specific cytotoxic T F1-experiment showing virus specific cytotoxic T lymphocytes from heterozygote F1 mice lymphocytes from heterozygote F1 mice consisted of at least 2 subpopulations-each consisted of at least 2 subpopulations-each being specific for infected H-2k and other for H-being specific for infected H-2k and other for H-2b targets.2b targets.

Codominant ExpressionCodominant Expression

Since MHC expressed codominantly some Since MHC expressed codominantly some T-cell receptors of one population were T-cell receptors of one population were probably specific for H-2k plus virus and probably specific for H-2k plus virus and other sub-population was specific for H-2b other sub-population was specific for H-2b plus virus.plus virus.

Working with Blanden’s experiments Working with Blanden’s experiments showed that H-2d and H-2k regions coding showed that H-2d and H-2k regions coding for class1MHC molecule were involved in for class1MHC molecule were involved in virus-specific cytotoxic t-cell recognition.virus-specific cytotoxic t-cell recognition.

This seperated MHC restricted recognition This seperated MHC restricted recognition by virus-specific cytotoxic T-cells from by virus-specific cytotoxic T-cells from MHC class 2MHC class 2

ConclusionsConclusions

In 2In 2ndnd letter to the Nature -T-cells might function letter to the Nature -T-cells might function to survey the integrity of TA. Recognition of cell to survey the integrity of TA. Recognition of cell surface alteration due to virus infection ,chemical surface alteration due to virus infection ,chemical modification or genetic differences may be modification or genetic differences may be accommodated in the same model.accommodated in the same model.

General hypothesis formulated in Lancet was General hypothesis formulated in Lancet was that function of MHC is to signal modifications of that function of MHC is to signal modifications of self-MHC to the immune system.self-MHC to the immune system.

ConclusionsConclusions

Tried to extend the explanations to helper Tried to extend the explanations to helper T cells-they might recognize antigen-T cells-they might recognize antigen-induced modifications of 1a(as the MHC induced modifications of 1a(as the MHC class 2 molecules) on B cells and class 2 molecules) on B cells and macrophages.macrophages.

Explained the extensive polymorphisms of Explained the extensive polymorphisms of MHC molecules minimizing failure of some MHC molecules minimizing failure of some pathogens to cause immuno-modification pathogens to cause immuno-modification and risk general unresponsiveness. and risk general unresponsiveness.

Role of PeptidesRole of Peptides

Not know then , MHC molecules are recognized Not know then , MHC molecules are recognized as complex with antigenic peptide.as complex with antigenic peptide.

By works of Unanue, Grey and others on class 2 By works of Unanue, Grey and others on class 2 antigens and Townsted works showed- class 1 antigens and Townsted works showed- class 1 molecules of the virus infected cells present molecules of the virus infected cells present peptides ,9-10 amino acids long to virus specific peptides ,9-10 amino acids long to virus specific cytotoxic t cells. These peptides were later cytotoxic t cells. These peptides were later successfully eluted successfully eluted

Role of PeptidesRole of Peptides

In 1987 x-ray crystallography revealed a peptide In 1987 x-ray crystallography revealed a peptide binding cleft.binding cleft.

X-ray structure of the complete complex of the T X-ray structure of the complete complex of the T cell receptor-MHC class1 plus the bound peptide cell receptor-MHC class1 plus the bound peptide in same year of Nobel prize.in same year of Nobel prize.

Still unclear which part of the TCR and whether Still unclear which part of the TCR and whether always corresponding parts of the TCR always corresponding parts of the TCR recognized the peptide and the MHC molecule in recognized the peptide and the MHC molecule in the same general position.the same general position.

ImplicationsImplications

The above findings and conclusions gave The above findings and conclusions gave immense scope for further understanding immense scope for further understanding of the immune system and its clinical of the immune system and its clinical implications in the field of medicine.implications in the field of medicine.

Role of ThymusRole of Thymus

Reconstitution of lethally radiated H-2b recipient Reconstitution of lethally radiated H-2b recipient mice with bone-marrow stem cells of (H-2k*H-mice with bone-marrow stem cells of (H-2k*H-2b)F-1 origin resulted in bone marrow chimeras 2b)F-1 origin resulted in bone marrow chimeras tolerant to H-2k and H-2b . tolerant to H-2k and H-2b .

When immunized these reacted against only H-When immunized these reacted against only H-2b+minor HC antigens or H-2b+virus only. 2b+minor HC antigens or H-2b+virus only.

So, MHC restricted T cells were specifically So, MHC restricted T cells were specifically selected during T cell maturation according to selected during T cell maturation according to the MHC expressed in the thymus.the MHC expressed in the thymus.

Role of ThymusRole of Thymus

MHC specificity studied in mice that lacked MHC specificity studied in mice that lacked thymus did not have mature t-cells.thymus did not have mature t-cells.

Introducing H-2k thymus into F-1 mice Introducing H-2k thymus into F-1 mice gave T–cells recognizing virus infected H-gave T–cells recognizing virus infected H-2k but not infected H-2b target cells.2k but not infected H-2b target cells.

Clinical implications – It is not only Clinical implications – It is not only necessary to deplete T cells to avoid lethal necessary to deplete T cells to avoid lethal graft versus host disease.graft versus host disease.

But also, host, transplanted bone marrow But also, host, transplanted bone marrow and hosts own or transplanted thymus and hosts own or transplanted thymus grafts must share MHC molecules.grafts must share MHC molecules.

Other wise no proper immune reaction can Other wise no proper immune reaction can be mounted in such reconstituted hosts.be mounted in such reconstituted hosts.

New VaccinesNew Vaccines

As peptides from viruses, bacteria and As peptides from viruses, bacteria and parasites are presented to the MHC class parasites are presented to the MHC class 1 or 2 molecules it was suggested that 1 or 2 molecules it was suggested that instead of live potentially harmful peptides instead of live potentially harmful peptides could possibly be used as vaccines to could possibly be used as vaccines to induce T- cell responses. induce T- cell responses.

New vaccinesNew vaccines

Peptide life was short lived therefore Peptide life was short lived therefore adjuvants are required to guarantee slow adjuvants are required to guarantee slow and long term release of the peptides and long term release of the peptides triggering T cells over a prolonged period.triggering T cells over a prolonged period.

VaccinationsVaccinations

Positive vaccination- increase the T cell Positive vaccination- increase the T cell precursor frequency to enhance precursor frequency to enhance protection.protection.

Negative vaccination- to reduce or delete Negative vaccination- to reduce or delete Tcells by excess peptide . To exhaust or Tcells by excess peptide . To exhaust or delete immuno patholgical disease delete immuno patholgical disease causing T-cells. Tried in diabetes. causing T-cells. Tried in diabetes.

Mutant virusesMutant viruses

T cell epitope escapes mutant viruses-T cell epitope escapes mutant viruses- Mutation of the 9-10 a.a peptides such that Mutation of the 9-10 a.a peptides such that

its presentation by MHC molecules or its presentation by MHC molecules or recognition by t-cells is no longer possible. recognition by t-cells is no longer possible. this helps viruses escape immune this helps viruses escape immune surveillancesurveillance

Mutant VirusesMutant Viruses

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

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

MHC AssociationsMHC Associations

Linkage between some disease Linkage between some disease susceptibilities and certain HLA-types – susceptibilities and certain HLA-types – important role of MHC molecules in important role of MHC molecules in immunity. immunity.

These autoimmune or immunopathological These autoimmune or immunopathological diseases are linked often to HLA class1 diseases are linked often to HLA class1 rather than class 2 molecules.rather than class 2 molecules.

MHC AssociationsMHC Associations

As antigenicity and immunogenicity are As antigenicity and immunogenicity are linked to MHC and correlate with different linked to MHC and correlate with different strengths of the T cell response, shows strengths of the T cell response, shows that different MHC molecules directly that different MHC molecules directly determine and regulate resistance to determine and regulate resistance to diseases.diseases.

HLA associated diseases-HLA associated diseases-Ankylosing SpondylitisAnkylosing Spondylitis

Autoimmune DiseasesAutoimmune Diseases

Non cytopathologial viruses are not Non cytopathologial viruses are not directly responsible for disease by directly responsible for disease by themselves ,instead by the damaging themselves ,instead by the damaging effect of the protective T –cell responses.effect of the protective T –cell responses.

Differences in MHC may influence the Differences in MHC may influence the severity of the disease depending on the severity of the disease depending on the immunopathological response of T-cells.immunopathological response of T-cells.

These are the basis for autoimmune or These are the basis for autoimmune or immunopathological diseases.immunopathological diseases.


Multiple sclerosisMultiple sclerosis Diabetes mellitusDiabetes mellitus Rheumatoid ArthritisRheumatoid Arthritis SLESLE PsoriasisPsoriasis Hashimotos thyroiditis,etcHashimotos thyroiditis,etc

Immunological memoryImmunological memory

The concept of immunological memory The concept of immunological memory has been exploited in vaccinations.has been exploited in vaccinations.

The B and T cells were found to exist as The B and T cells were found to exist as memory cells and hence maintained memory cells and hence maintained certain precursor levels to fight infections certain precursor levels to fight infections better.better.

The use of immune memory were The use of immune memory were explained for the mother and fetus.explained for the mother and fetus.

Other Related DiseasesOther Related Diseases

1- Immune complex diseases. Ex. 1- Immune complex diseases. Ex. GlomerulonephritisGlomerulonephritis

2-Immune Deficiency diseases. Ex. AIDS2-Immune Deficiency diseases. Ex. AIDS

Team WorkTeam Work

Thus the combined efforts of doctors, Thus the combined efforts of doctors, immunologists, geneticists, virologists, immunologists, geneticists, virologists, microbiologists, etc helped us reveal the microbiologists, etc helped us reveal the recognition of viral infected cells by T cells.recognition of viral infected cells by T cells.

Giving insight into immunological specificity Giving insight into immunological specificity and memory and help understand and memory and help understand immunological disease pathogenesis.immunological disease pathogenesis.

In recognition of these In recognition of these contributions Peter contributions Peter Doherty and Rolf Doherty and Rolf Zinkernagel were Zinkernagel were awarded the Nobel awarded the Nobel Peace Prize in Peace Prize in Medicine in year Medicine in year 1996.1996.

ReferencesReferences

1. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated 1. Zinkernagel RM, Doherty PC. Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within a syngenic and cytotoxicity in lymphocytic choriomeningitis within a syngenic and semiallogeneic system. Nature 248, 701- 702, 1974. semiallogeneic system. Nature 248, 701- 702, 1974.

2. Zinkernagel RM, Doherty PC. Immunological surveillance against 2. Zinkernagel RM, Doherty PC. Immunological surveillance against altered self components by sensitised T lymphocytes in lymphocytic altered self components by sensitised T lymphocytes in lymphocytic choriomeningitis. Nature 251, 547-548, 1974. choriomeningitis. Nature 251, 547-548, 1974.

3. Doherty PC, Zinkernagel RM. A biological role for the major 3. Doherty PC, Zinkernagel RM. A biological role for the major histocompatibility antigens. Lancet, 1406-1409, 1975. histocompatibility antigens. Lancet, 1406-1409, 1975.

4. Zinkernagel RM, Doherty PC. MHC restricted cytotoxic T cells: 4. Zinkernagel RM, Doherty PC. MHC restricted cytotoxic T cells: Studies on the biological role of polymorphic major transplantation Studies on the biological role of polymorphic major transplantation antigens determining T cell restriction specificity. Advances in antigens determining T cell restriction specificity. Advances in Immunology 27, 51-177, 1979.Immunology 27, 51-177, 1979.


5-Press Release: The 1996 Nobel Prize in 5-Press Release: The 1996 Nobel Prize in Physiology or Medicine Physiology or Medicine

6-Nobel Lecture, December 8, 1996 6-Nobel Lecture, December 8, 1996 Cellular Immune Recognition and the Cellular Immune Recognition and the Biological Role of Major Biological Role of Major Transplantation Antigens Transplantation Antigens

7-Nobel Lecture, December 8, 1996 Cell 7-Nobel Lecture, December 8, 1996 Cell Mediated Immunity in Virus Infections Mediated Immunity in Virus Infections


8-www.nobel.se8-www.nobel.se 99

http://press2.nci.nih.gov/sciencebehind/imhttp://press2.nci.nih.gov/sciencebehind/immune/immune17.htmmune/immune17.htm

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

sri ram .p date: 11/25/03 course: scientific discovery instructor: dr. a. vankley

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