The Immunology of Bone Marrow Transplantation · The Immunology of Bone Marrow Transplantation Dr...

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

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

GermanyGermany

Mercedes

AudiMercedes

Mercedes

Volkswagen

Mercedes

Volkswagen

Mercedes

Porsche

Volkswagen

Mercedes

Porsche

Volkswagen

Mercedes

OpelAutobahn

Autobahn QuizAutobahn Quiz

What is the What is the Speed Limit Speed Limit on on the Autobahn ?the Autobahn ?

What is the What is the Speed Limit Speed Limit on on the Autobahn ?the Autobahn ?◊◊ 110 km/h110 km/h

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

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

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

Bremen and North West Germany

BremenBremen

Fairy Tale by the Brothers Grimm:

The Musicians of Bremen(Die Bremer Stadtmusikanten)

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

As Freelance Photographer and Journalist in Nicaragua, 1987

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

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

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

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

Brasil

Bolivia

New York, US

California, US

Mexico

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

Murnau

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

The United Kingdom

Breakfast Lunch Tea Dinner

Evening

Newcastle upon Tyne

Newcastle

Around Newcastle

Bamborough Castle

Durham

Farne Islands

Hadrian’s Wall

University of Newcastle

University Medical School

Royal Victoria Infirmary

On the Children’s Bone Marrow Transplant Unit

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

Tynemouth

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

Tokai UniversityIsehara, Kanagawa

Professor Hidetoshi Inoko

The Immunology ofThe Immunology ofBone Marrow TransplantationBone Marrow Transplantation

Dr Christian Dr Christian HarkenseeHarkensee

AimsAims

Share the fascination of how the immune Share the fascination of how the immune system workssystem works

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

OverviewOverviewIntroduction to the immune systemIntroduction to the immune systemBone Marrow Transplantation, its successes and Bone Marrow Transplantation, its successes and difficultiesdifficulties

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)

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

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

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

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

Bone Marrow

Components of the Immune SystemComponents of the Immune System

Innate Immune SystemInnate Immune System

Components of the Immune SystemComponents of the Immune System

Innate Immune System Innate Immune System Adaptive Immune SystemAdaptive Immune System

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))

Macrophage (‘big eater’)

Macrophage (‘big eater’) Granulocyte (‘suicide killer’)

Toxins

Innate ImmunityInnate Immunity

ComponentsComponentsCells: Macrophages, granulocytesCells: Macrophages, granulocytesToxins: Acids, complementToxins: Acids, complementSignal molecules: CytokinesSignal molecules: Cytokines

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

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

T-Lymphocyte

Antigen Receptor (TCR)

T-Lymphocyte

APC MHC

T-Lymphocyte

CD4-Effector cell CD8-Effector cell

T-regulatory cell T-memory cell

Antigen-specificClonal Expansion

APC MHC

T-Lymphocyte

B-Lymphocyte

Antigen Receptor (BCR)

T-Lymphocyte

Bacterium (“antigen”)

T-Lymphocyte

B-Lymphocyte

B-plasma cell

B-memory cell

Antibodies

Antigen Receptor (BCR)

T-Lymphocyte

B-Lymphocyte

B-plasma cell

B-memory cell

Antibodies

Adaptive ImmunityAntigen Receptor (BCR

Initiation Clonal expansion Contraction Maintenance

The kinetics of the T cell response

Effects of B-cells and T-cells

What happens if you have an injury ?

AcquiredImmunesytem

Infection

InnateImmunesytem

Removal

„Disease“ „Health“

SpecificImmunological

Memory

2. Infection

Prevention

Summary of Innate and Adaptive Immunity

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

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

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

HLA Gene Cluster

HLA Polymorphism

Bone Marrow Transplantation

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

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

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).

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

Bone Marrow Transplantation

Bone Marrow Harvest

Bone Marrow Transplantation – Early History

Animal experiments in 1940Animal experiments in 1940’’ss

Animal experiments in 1940Animal experiments in 1940’’ss1959: First human bone marrow 1959: First human bone marrow transplanttransplant

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

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

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)

Observations after TransplantationBone Marrow Transplant

Host immune system stronger than graft:Host attacks transplant-Transplant is destroyed=Graft rejection

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

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

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

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

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

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% !!!

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% !

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

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%

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 ?

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

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%

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.

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

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

Graft-versus-Host DiseaseBone marrow

Donor T-cell

Host Host dendritic cells

Donor T-cell

Damage to Organ

GVHD and GVT

GVHD GVHD –– a complex diseasea complex disease

Donor T-cell

Tissue Injury fromChemo/radiation

More dendritic cell activation-More GVHD

Donor Natural Killer Cell

Damage to Organ

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

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……

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

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

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

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

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

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

Consider becoming a donor ?Consider becoming a donor ?

Find out more: http://Find out more: http://www.jmdp.or.jpwww.jmdp.or.jp//

Thank You !!!

The Immunology of Bone Marrow Transplantation · The Immunology of Bone Marrow Transplantation Dr...

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