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The Immunology ofThe Immunology ofBone Marrow TransplantationBone Marrow Transplantation
Dr Christian Dr Christian HarkenseeHarkenseePostPost--Doctoral JSPS FellowDoctoral JSPS Fellow
Tokai University, Tokai University, IseharaIsehara, Kanagawa, Kanagawa
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Who I am Who I am –– Chris Chris HarkenseeHarkensee
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Who I am Who I am –– Chris Chris HarkenseeHarkensee
Born 1968 in Hamburg, grown up in Bremen, Born 1968 in Hamburg, grown up in Bremen, GermanyGermany
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GermanyGermany
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Mercedes
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AudiMercedes
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Audi
BMW
Mercedes
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Audi
BMW
Volkswagen
Mercedes
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Audi
BMW
Volkswagen
Mercedes
Opel
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Porsche
Audi
BMW
Volkswagen
Mercedes
Opel
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Porsche
Audi
BMW
Volkswagen
Mercedes
OpelAutobahn
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Autobahn QuizAutobahn Quiz
What is the What is the Speed Limit Speed Limit on on the Autobahn ?the Autobahn ?
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Autobahn QuizAutobahn Quiz
What is the What is the Speed Limit Speed Limit on on the Autobahn ?the Autobahn ?◊◊ 110 km/h110 km/h
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Autobahn QuizAutobahn Quiz
What is the What is the Speed Limit Speed Limit on on the Autobahn ?the Autobahn ?◊◊ 110 km/h110 km/h◊◊ 220 km/h220 km/h
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Autobahn QuizAutobahn Quiz
What is the What is the Speed Limit Speed Limit on on the Autobahn ?the Autobahn ?◊◊ 110 km/h110 km/h◊◊ 220 km/h220 km/h◊◊ 330 km/h330 km/h
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Autobahn QuizAutobahn Quiz
What is the What is the Speed Limit Speed Limit on on the Autobahn ?the Autobahn ?◊◊ 110 km/h110 km/h◊◊ 220 km/h220 km/h◊◊ 330 km/h330 km/h◊◊ no speed limitno speed limit
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Autobahn QuizAutobahn Quiz
What is the What is the Speed Limit Speed Limit on on the Autobahn ?the Autobahn ?◊◊ 110 km/h110 km/h◊◊ 220 km/h220 km/h◊◊ 330 km/h330 km/h◊◊ no speed limitno speed limit
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Bremen and North West Germany
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BremenBremen
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Fairy Tale by the Brothers Grimm:
The Musicians of Bremen(Die Bremer Stadtmusikanten)
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Who I am Who I am –– Chris Chris HarkenseeHarkensee
Born 1968 in Hamburg, grown up in Bremen, Born 1968 in Hamburg, grown up in Bremen, GermanyGermany1987 Grammar School Graduation, Bremen 1987 Grammar School Graduation, Bremen Travel to Nicaragua, Costa Rica. National Service Travel to Nicaragua, Costa Rica. National Service in Bremenin Bremen
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As Freelance Photographer and Journalist in Nicaragua, 1987
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Who I am Who I am –– Chris Chris HarkenseeHarkensee
Born 1968 in Hamburg, grown up in Bremen, Born 1968 in Hamburg, grown up in Bremen, GermanyGermany1987 Grammar School Graduation, Bremen 1987 Grammar School Graduation, Bremen Travel to Nicaragua, Costa Rica. National Service Travel to Nicaragua, Costa Rica. National Service in Bremenin Bremen1989 1989 –– 1997 Medical School at Humboldt 1997 Medical School at Humboldt University, Berlin. Internships in Bolivia, Peru, University, Berlin. Internships in Bolivia, Peru, USA. Graduation as a Doctor of MedicineUSA. Graduation as a Doctor of Medicine
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Love Parade
Tacheles Club
9 November 1989 – Fall of Berlin WallChristo wraps Reichstag Building
Potsdamer Platz rebuild
Love Parade
3 October 1990 – German Reunification
Berlin
19
89
-19
97
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Rudolf VirchowFounder of cellular pathology
Emil von BehringDiscoverer of DiphteriaPioneer in vaccine development
Robert KochDiscoverer of TB, choleraFounder of MicrobiologyAnd Infectiology
Charité University HospitalHumboldt University Berlin
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Charité Doctors introducing Western Medicine to Japan – 1854-1912
Monument to Professor Barth at Tokyo Medical School
Japan’s first Paediatric Hospital, Tokyo University (1874)
Patient file
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Brasil
Bolivia
New York, US
Peru
California, US
Cuba
Mexico
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Who I am Who I am –– Chris Chris HarkenseeHarkensee
Born 1968 in Hamburg, grown up in Bremen, Born 1968 in Hamburg, grown up in Bremen, GermanyGermany1987 Grammar School Graduation, Bremen 1987 Grammar School Graduation, Bremen Travel to Nicaragua, Costa Rica. National Service Travel to Nicaragua, Costa Rica. National Service in Bremenin Bremen1989 1989 –– 1997 Medical School at Humboldt 1997 Medical School at Humboldt University, Berlin. Internships in Bolivia, Peru, University, Berlin. Internships in Bolivia, Peru, USA. Graduation as a Doctor of MedicineUSA. Graduation as a Doctor of Medicine19981998--2000 Doctor in a children2000 Doctor in a children’’s rehabilitation s rehabilitation hospital in hospital in MurnauMurnau, Bavaria , Bavaria –– met my future wifemet my future wife
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Murnau
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Who I am Who I am –– Chris Chris HarkenseeHarkensee
Since 2000 Since 2000 –– working as a childrenworking as a children’’s doctor in s doctor in the United Kingdom (Scarborough, Chester, the United Kingdom (Scarborough, Chester, Liverpool, Newcastle). Training as a specialist in Liverpool, Newcastle). Training as a specialist in immunology and infectionimmunology and infection
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The United Kingdom
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Breakfast Lunch Tea Dinner
Evening
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Newcastle upon Tyne
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Newcastle
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Around Newcastle
Bamborough Castle
Durham
Farne Islands
Hadrian’s Wall
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University of Newcastle
University Medical School
Royal Victoria Infirmary
On the Children’s Bone Marrow Transplant Unit
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Who I am Who I am –– Chris Chris HarkenseeHarkensee
Since 2000 Since 2000 –– working as a childrenworking as a children’’s doctor in s doctor in the United Kingdom (Scarborough, Chester, the United Kingdom (Scarborough, Chester, Liverpool, Newcastle). Training as a specialist in Liverpool, Newcastle). Training as a specialist in immunology and infectionimmunology and infectionTwo children Two children –– born 2004 and 2007born 2004 and 2007
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Tynemouth
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Who I am Who I am –– Chris Chris HarkenseeHarkensee
Since 2000 Since 2000 –– working as a childrenworking as a children’’s doctor in s doctor in the United Kingdom (Scarborough, Chester, the United Kingdom (Scarborough, Chester, Liverpool, Newcastle). Training as a specialist in Liverpool, Newcastle). Training as a specialist in immunology and infectionimmunology and infectionTwo children Two children –– born 2004 and 2007born 2004 and 2007Researcher with a JSPS fellowship at Tokai Researcher with a JSPS fellowship at Tokai University, Kanagawa University, Kanagawa
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JAPAN
Tokai UniversityIsehara, Kanagawa
Professor Hidetoshi Inoko
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The Immunology ofThe Immunology ofBone Marrow TransplantationBone Marrow Transplantation
Dr Christian Dr Christian HarkenseeHarkensee
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AimsAims
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AimsAims
Share the fascination of how the immune Share the fascination of how the immune system workssystem works
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AimsAims
Share the fascination of how the immune Share the fascination of how the immune system workssystem worksLearn something Learn something ‘‘cutting edgecutting edge’’ about a about a scientific hot topic scientific hot topic –– bone marrow bone marrow transplantationtransplantation
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OverviewOverviewIntroduction to the immune systemIntroduction to the immune systemBone Marrow Transplantation, its successes and Bone Marrow Transplantation, its successes and difficultiesdifficulties
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Immune SystemImmune System
A body system of organs, tissues and cells, A body system of organs, tissues and cells, that differentiates self from that differentiates self from nonselfnonself, , recognises danger (tissue recognises danger (tissue signals, tumoursignals, tumourcells) and eliminates antigens (kills cells) and eliminates antigens (kills pathogenic organisms, like bacteria and pathogenic organisms, like bacteria and viruses) viruses)
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Where is our Immune System?Where is our Immune System?
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Where is our Immune System?Where is our Immune System?
Immune cells are found in Immune cells are found in all all tissues and tissues and organsorgans
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Where is our Immune System?Where is our Immune System?
Immune cells are found in Immune cells are found in all all tissues and tissues and organsorgansSome immune cells circulate in the blood Some immune cells circulate in the blood and lymph systemand lymph system
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Where is our Immune System?Where is our Immune System?
Immune cells are found in Immune cells are found in all all tissues and tissues and organsorgansSome immune cells circulate in the blood Some immune cells circulate in the blood and lymph systemand lymph systemImmune cells are produced, and develop, Immune cells are produced, and develop, in the bone marrow and thymus in the bone marrow and thymus
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Where is our Immune System?Where is our Immune System?
Immune cells are found in Immune cells are found in all all tissues and tissues and organsorgansSome immune cells circulate in the blood Some immune cells circulate in the blood and lymph systemand lymph systemImmune cells are produced, and develop, Immune cells are produced, and develop, in the bone marrow and thymus in the bone marrow and thymus The spleen is a special filter organ for cells The spleen is a special filter organ for cells in the bloodin the blood
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Bone Marrow
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Components of the Immune SystemComponents of the Immune System
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Components of the Immune SystemComponents of the Immune System
Innate Immune SystemInnate Immune System
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Components of the Immune SystemComponents of the Immune System
Innate Immune System Innate Immune System Adaptive Immune SystemAdaptive Immune System
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Innate Immune SystemInnate Immune System
Inherited / born withInherited / born withRecognises self/nonRecognises self/non--self, dangerself, dangerNonNon--specific, broad activityspecific, broad activityDoes not change / learnDoes not change / learnMainly protects against pathogens living Mainly protects against pathogens living outside cells (outside cells (extracellularextracellular))
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Macrophage (‘big eater’)
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Macrophage (‘big eater’)
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Macrophage (‘big eater’) Granulocyte (‘suicide killer’)
Toxins
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Innate ImmunityInnate Immunity
ComponentsComponentsCells: Macrophages, granulocytesCells: Macrophages, granulocytesToxins: Acids, complementToxins: Acids, complementSignal molecules: CytokinesSignal molecules: Cytokines
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Macrophage (‘big eater’) Granulocyte (‘suicide killer’)
Toxins
Antigen presenting cell
Neutrophil cell
Eosinophil cell
Basophil cell
Mast cell
The Innate Immune System
Non-cellular factors:-Complement-Cytokines
Natural Killer CellMHC Receptor
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Adaptive ImmunityAdaptive Immunity
Develops throughout lifeDevelops throughout lifeRecognises self/nonRecognises self/non--self, infected cellsself, infected cellsHighly specific against pathogens, learns Highly specific against pathogens, learns from contact to pathogens from contact to pathogens Effective against both intracellular and Effective against both intracellular and extracellularextracellular pathogenspathogens
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T-Lymphocyte
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T-Lymphocyte
Antigen Receptor (TCR)
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T-Lymphocyte
Antigen Receptor (TCR)
APC MHC
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T-Lymphocyte
Antigen Receptor (TCR)
CD4-Effector cell CD8-Effector cell
T-regulatory cell T-memory cell
Antigen-specificClonal Expansion
APC MHC
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T-Lymphocyte
Antigen Receptor (TCR)
CD4-Effector cell CD8-Effector cell
T-regulatory cell T-memory cell
Antigen-specificClonal Expansion
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T-Lymphocyte
Antigen Receptor (TCR)
CD4-Effector cell CD8-Effector cell
T-regulatory cell T-memory cell
Antigen-specificClonal Expansion
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T-Lymphocyte
Antigen Receptor (TCR)
CD4-Effector cell CD8-Effector cell
T-regulatory cell T-memory cell
B-Lymphocyte
Antigen-specificClonal Expansion
Antigen Receptor (BCR)
T-Lymphocyte
Bacterium (“antigen”)
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T-Lymphocyte
Antigen Receptor (TCR)
CD4-Effector cell CD8-Effector cell
T-regulatory cell T-memory cell
B-Lymphocyte
Antigen-specificClonal Expansion
Antigen-specificClonal Expansion
B-plasma cell
B-memory cell
Antibodies
Antigen Receptor (BCR)
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T-Lymphocyte
Antigen Receptor (TCR)
CD4-Effector cell CD8-Effector cell
T-regulatory cell T-memory cell
B-Lymphocyte
Antigen-specificClonal Expansion
Antigen-specificClonal Expansion
B-plasma cell
B-memory cell
Antibodies
Adaptive ImmunityAntigen Receptor (BCR
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Initiation Clonal expansion Contraction Maintenance
Time
The kinetics of the T cell response
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Effects of B-cells and T-cells
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Effects of B-cells and T-cells
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What happens if you have an injury ?
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AcquiredImmunesytem
Infection
InnateImmunesytem
Removal
„Disease“ „Health“
SpecificImmunological
Memory
2. Infection
Prevention
Summary of Innate and Adaptive Immunity
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MHC and HLA polymorphismMHC and HLA polymorphism
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MHC and HLA polymorphismMHC and HLA polymorphism
What is MHC ? What is MHC ? –– Major Major HistocompatibilityHistocompatibilityComplex (MHC) is a cell receptor on antigen Complex (MHC) is a cell receptor on antigen presenting cells recognising the bodypresenting cells recognising the body’’s self/nons self/non--selfself
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MHC and HLA polymorphismMHC and HLA polymorphism
What is MHC ? What is MHC ? –– Major Major HistocompatibilityHistocompatibilityComplex (MHC) is a cell receptor on antigen Complex (MHC) is a cell receptor on antigen presenting cells recognising the bodypresenting cells recognising the body’’s self/nons self/non--selfselfWhat is HLA ? What is HLA ? –– Human Leukocyte Antigen Human Leukocyte Antigen (HLA) are the genes encoding for MHC(HLA) are the genes encoding for MHC
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MHC and HLA polymorphismMHC and HLA polymorphism
What is MHC ? What is MHC ? –– Major Major HistocompatibilityHistocompatibilityComplex (MHC) is a cell receptor on antigen Complex (MHC) is a cell receptor on antigen presenting cells recognising the bodypresenting cells recognising the body’’s self/nons self/non--selfselfWhat is HLA ? What is HLA ? –– Human Leukocyte Antigen Human Leukocyte Antigen (HLA) are the genes encoding for MHC(HLA) are the genes encoding for MHCWhat is polymorphism ? What is polymorphism ? –– variations between variations between people in the sequence of their genespeople in the sequence of their genes
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HLA Gene Cluster
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HLA Polymorphism
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Bone Marrow Transplantation
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Bone Marrow Transplantation
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What is Bone Marrow Transplantation?What is Bone Marrow Transplantation?
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What is Bone Marrow Transplantation?What is Bone Marrow Transplantation?
Transfer of Bone Marrow from a healthy donor Transfer of Bone Marrow from a healthy donor into a patient with Bone Marrow or Blood into a patient with Bone Marrow or Blood DiseaseDisease
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What is Bone Marrow Transplantation?What is Bone Marrow Transplantation?
Transfer of Bone Marrow from a healthy donor Transfer of Bone Marrow from a healthy donor into a patient with Bone Marrow or Blood into a patient with Bone Marrow or Blood DiseaseDiseaseDonor Bone Marrow replaces sick patientDonor Bone Marrow replaces sick patient’’s s marrow with a healthy marrow, curing patientmarrow with a healthy marrow, curing patient’’s s underlying diseaseunderlying disease
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TerminologyTerminology
The person who is ill and receives the bone The person who is ill and receives the bone marrow transplant is called marrow transplant is called host host or or recipient.recipient.The person who gives the bone marrow is called The person who gives the bone marrow is called the the donor.donor.The bone marrow that is given to the host is The bone marrow that is given to the host is called called graft, bone marrow transplant (BMT) or graft, bone marrow transplant (BMT) or haematopoietic stem cell transplant (HSCT).haematopoietic stem cell transplant (HSCT).
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Bone Marrow Transplantation Bone Marrow Transplantation –– why ?why ?
80801010Severe Autoimmune DiseaseSevere Autoimmune Disease
909000Inborn Metabolic DiseaseInborn Metabolic Disease
909000Inborn Immune DeficiencyInborn Immune Deficiency
8080--1001001010--3030Acute LeukaemiaAcute Leukaemia
909000Inborn severe AnaemiaInborn severe Anaemia
808000Lethal Radiation DoseLethal Radiation Dose
2005 2005 –– Cure %Cure %1970 1970 –– Cure %Cure %DiseaseDisease
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Bone Marrow Transplantation
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Bone Marrow Harvest
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Bone Marrow Transplantation – Early History
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Bone Marrow Transplantation – Early History
Animal experiments in 1940Animal experiments in 1940’’ss
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Bone Marrow Transplantation – Early History
Animal experiments in 1940Animal experiments in 1940’’ss1959: First human bone marrow 1959: First human bone marrow transplanttransplant
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Bone Marrow Transplantation – Early History
Animal experiments in 1940Animal experiments in 1940’’ss1959: First human bone marrow 1959: First human bone marrow transplanttransplant19601960’’s: Twins: Twin--sibling donor transplants for sibling donor transplants for endstageendstage leukaemia leukaemia –– 90% die90% die
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Bone Marrow Transplantation – Early History
Animal experiments in 1940Animal experiments in 1940’’ss1959: First human bone marrow 1959: First human bone marrow transplanttransplant19601960’’s: Twins: Twin--sibling donor transplants for sibling donor transplants for endstageendstage leukaemia leukaemia –– 90% die90% die1969: First HLA1969: First HLA--matched transplant, first matched transplant, first unrelated donor transplantunrelated donor transplant
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Bone Marrow Transplantation – Early History
Animal experiments in 1940Animal experiments in 1940’’ss1959: First human bone marrow 1959: First human bone marrow transplanttransplant19601960’’s: Twins: Twin--sibling donor transplants for sibling donor transplants for endstageendstage leukaemia leukaemia –– 90% die90% die1969: First HLA1969: First HLA--matched transplant, first matched transplant, first unrelated donor transplantunrelated donor transplant1975: First donor registry (UK)1975: First donor registry (UK)
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Observations after TransplantationBone Marrow Transplant
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Observations after TransplantationBone Marrow Transplant
Host immune system stronger than graft:Host attacks transplant-Transplant is destroyed=Graft rejection
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Observations after TransplantationBone Marrow Transplant
Host immune system stronger than graft:Host attacks transplant-Transplant is destroyed=Graft rejection
Graft immune systemStronger than host:Transplant attacks host-Host severely ill / killed=Graft-versus-Host Disease, GVHD
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Doctors learned thatDoctors learned that……
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Doctors learned thatDoctors learned that……
A working immune system in the host rapidly A working immune system in the host rapidly rejects the bone marrow transplantrejects the bone marrow transplant
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Doctors learned thatDoctors learned that……
A working immune system in the host rapidly A working immune system in the host rapidly rejects the bone marrow transplantrejects the bone marrow transplantHLA mismatch between donor and host leads to HLA mismatch between donor and host leads to GraftGraft--versusversus--host disease mediated by donor host disease mediated by donor TT--cellscells
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Doctors learned thatDoctors learned that……
A working immune system in the host rapidly A working immune system in the host rapidly rejects the bone marrow transplantrejects the bone marrow transplantHLA mismatch between donor and host leads to HLA mismatch between donor and host leads to GraftGraft--versusversus--host disease mediated by donor host disease mediated by donor TT--cellscellsGraftGraft--versusversus--tumortumor effect (also mediated by effect (also mediated by donor Tdonor T--cells) is the most powerful mechanism cells) is the most powerful mechanism known to known to erradicateerradicate tumortumor cellscells
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How can we stop graft rejection ?How can we stop graft rejection ?
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How can we stop graft rejection ?How can we stop graft rejection ?
Kill host immune system Kill host immune system –– high dose high dose chemotherapy and radiationchemotherapy and radiation
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How can we stop graft rejection ?How can we stop graft rejection ?
Kill host immune system Kill host immune system –– high dose high dose chemotherapy and radiationchemotherapy and radiationEffect: Graft rejection now <5% !!!Effect: Graft rejection now <5% !!!
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How can we stop graft rejection ?How can we stop graft rejection ?
Kill host immune system Kill host immune system –– high dose high dose chemotherapy and radiationchemotherapy and radiationEffect: Graft rejection now <5% !!!Effect: Graft rejection now <5% !!!Problem: GraftProblem: Graft--versusversus--Host Disease now >50% !Host Disease now >50% !
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How can we stop How can we stop GraftGraft--versusversus--Host Disease ?Host Disease ?
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How can we stop How can we stop GraftGraft--versusversus--Host Disease ?Host Disease ?
HLA matching, use of sibling donorsHLA matching, use of sibling donors
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How can we stop How can we stop GraftGraft--versusversus--Host Disease ?Host Disease ?
HLA matching, use of sibling donorsHLA matching, use of sibling donorsEffect: Reduction of GraftEffect: Reduction of Graft--versusversus--Host Disease Host Disease to ~30to ~30--50%50%
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How can we stop How can we stop GraftGraft--versusversus--Host Disease ?Host Disease ?
HLA matching, use of sibling donorsHLA matching, use of sibling donorsEffect: Reduction of GraftEffect: Reduction of Graft--versusversus--Host Disease Host Disease to ~30to ~30--50%50%Problem: Why still so much GVHD ?Problem: Why still so much GVHD ?
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How can we stop How can we stop GraftGraft--versusversus--Host Disease ?Host Disease ?
HLA matching, use of sibling donorsHLA matching, use of sibling donorsEffect: Reduction of GraftEffect: Reduction of Graft--versusversus--Host Disease Host Disease to ~30to ~30--50%50%Problem: Why still so much GVHD ?Problem: Why still so much GVHD ?Depletion of TDepletion of T--cells in bone marrow graftcells in bone marrow graft
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How can we stop How can we stop GraftGraft--versusversus--Host Disease ?Host Disease ?
HLA matching, use of sibling donorsHLA matching, use of sibling donorsEffect: Reduction of GraftEffect: Reduction of Graft--versusversus--Host Disease Host Disease to ~30to ~30--50%50%Problem: Why still so much GVHD ?Problem: Why still so much GVHD ?Depletion of TDepletion of T--cells in bone marrow graftcells in bone marrow graftEffect: Reduction of GraftEffect: Reduction of Graft--versusversus--Host Disease Host Disease to 15to 15--25%25%
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How can we stop How can we stop GraftGraft--versusversus--Host Disease ?Host Disease ?
HLA matching, use of sibling donorsHLA matching, use of sibling donorsEffect: Reduction of GraftEffect: Reduction of Graft--versusversus--Host Disease Host Disease to ~30to ~30--50%50%Problem: Why still so much GVHD ?Problem: Why still so much GVHD ?Depletion of TDepletion of T--cells in bone marrow graftcells in bone marrow graftEffect: Reduction of GraftEffect: Reduction of Graft--versusversus--Host Disease Host Disease to 15to 15--25%25%Problem: GraftProblem: Graft--versusversus--tumortumor effect was lost effect was lost ––more patients dying. GVHD largest Problem after more patients dying. GVHD largest Problem after transplantation.transplantation.
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Graft versus Host DiseaseGraft versus Host Disease
An immune reaction of the bone marrow graft An immune reaction of the bone marrow graft against tissue and organs of the hostagainst tissue and organs of the hostUsually starts between 20Usually starts between 20--100 days after 100 days after transplanttransplant
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Graft versus Host DiseaseGraft versus Host Disease
GVHD mostly affects skin, liver GVHD mostly affects skin, liver and boweland bowelGVHD also makes prone to GVHD also makes prone to severe infectionsevere infectionIt ranges from mild (grade 1) It ranges from mild (grade 1) to severe (grade 4)to severe (grade 4)2020--50% of hosts get GVHD50% of hosts get GVHD2020--30% of GVHD patients die 30% of GVHD patients die of GVHD or infectionof GVHD or infection
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Graft-versus-Host DiseaseBone marrow
Donor T-cell
Skin
Liver
Bowel
Host
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Graft-versus-Host DiseaseBone marrow
Donor T-cell
Skin
Liver
Bowel
Host Host dendritic cells
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Graft-versus-Host DiseaseBone marrow
Donor T-cell
Skin
Liver
Bowel
Host
Damage to Organ
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GVHD and GVT
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GVHD GVHD –– a complex diseasea complex disease
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Graft-versus-Host DiseaseBone marrow
Donor T-cell
Skin
Liver
Bowel
Host
Tissue Injury fromChemo/radiation
More dendritic cell activation-More GVHD
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Graft-versus-Host DiseaseBone marrow
Donor Natural Killer Cell
Skin
Liver
Bowel
Host
Damage to Organ
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GVHD GVHD –– a complex diseasea complex disease
Cellular mechanisms: Antigen presenting cells, Cellular mechanisms: Antigen presenting cells, TT--cells (CD4, CD8, Tcells (CD4, CD8, T--regulatory cells), Natural regulatory cells), Natural Killer Cells, stem cellsKiller Cells, stem cellsMinor Minor histocompatibilityhistocompatibility antigensantigensOrgan mechanisms: Thymus, GVHD target Organ mechanisms: Thymus, GVHD target organsorgansSelf/foreign recognition versus Danger signal Self/foreign recognition versus Danger signal recognitionrecognitionSignal molecules: Cytokines, apoptosisSignal molecules: Cytokines, apoptosis
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GVHD GVHD –– Genetics beyond HLAGenetics beyond HLA
Polymorphisms in genes other than HLA have Polymorphisms in genes other than HLA have been linked to GVHD:been linked to GVHD:Natural Killer Cell immune receptorsNatural Killer Cell immune receptorsCytokinesCytokinesApoptosis moleculesApoptosis moleculesEtc. etcEtc. etc……
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Research at Tokai University into the Genetics of GVHD
• Research Project on 800 bone marrow transplant donor/recipientpairs from the Japanese Marrow Donor Programme (JMDP) registry
• Testing of polymorphisms (SNP, MS) in 3000 candidate genes of the immune system
• Goal is to develop a tool that can reliably predict GVHD beforetransplantation, enabling doctors to take steps to stop GVHD from happening
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Future directions in GVHDFuture directions in GVHD
Less tissue damage: Less chemotherapy and Less tissue damage: Less chemotherapy and radiotherapyradiotherapyPreventing GVHD and enhancing GVT by TPreventing GVHD and enhancing GVT by T--cell cell depletion plus enrichment with depletion plus enrichment with tumortumor--specific Tspecific T--cell clonescell clonesStudy of genetic risks Study of genetic risks –– improved matching, improved matching, improved clinical managementimproved clinical managementUse of specific TUse of specific T--regulatory cells, stem cells, regulatory cells, stem cells, dendriticdendritic cellscells
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SummarySummary
Our immune system is amazing in keeping us Our immune system is amazing in keeping us healthy every day in the face of the constant healthy every day in the face of the constant threat from infections and threat from infections and tumorstumors
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SummarySummary
Our immune system is amazing in keeping us Our immune system is amazing in keeping us healthy every day in the face of the constant healthy every day in the face of the constant threat from infections and threat from infections and tumorstumorsBone Marrow Transplantation is a new therapy Bone Marrow Transplantation is a new therapy with enormous life saving potential for many with enormous life saving potential for many diseasesdiseases
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SummarySummary
Our immune system is amazing in keeping us Our immune system is amazing in keeping us healthy every day in the face of the constant healthy every day in the face of the constant threat from infections and threat from infections and tumorstumorsBone Marrow Transplantation is a new therapy Bone Marrow Transplantation is a new therapy with enormous life saving potential for many with enormous life saving potential for many diseasesdiseasesGraftGraft--versusversus--Host Disease is the biggest problem Host Disease is the biggest problem in preventing a successful transplantin preventing a successful transplant
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SummarySummary
Our immune system is amazing in keeping us Our immune system is amazing in keeping us healthy every day in the face of the constant healthy every day in the face of the constant threat from infections and threat from infections and tumorstumorsBone Marrow Transplantation is a new therapy Bone Marrow Transplantation is a new therapy with enormous life saving potential for many with enormous life saving potential for many diseasesdiseasesGraftGraft--versusversus--Host Disease is the biggest problem Host Disease is the biggest problem in preventing a successful transplantin preventing a successful transplantResearchers all over the world are working on Researchers all over the world are working on making transplants safermaking transplants safer
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Consider becoming a donor ?Consider becoming a donor ?
Find out more: http://Find out more: http://www.jmdp.or.jpwww.jmdp.or.jp//
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Thank You !!!