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Transplantation. Xiang Li, Urology Department West China Hospital, Sichuan University. Acknowlegement. To Dr. Lu Yiping and Dr. Wang jia To other Colleagues working on renal and liver transplantation. Transplantation is a Dream?. Dream of Paranoia

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transplantation

Transplantation

Xiang Li, Urology Department

West China Hospital, Sichuan University

acknowlegement

Acknowlegement

To Dr. Lu Yiping and Dr. Wang jia

To other Colleagues working on renal and liver transplantation

slide3

Transplantation is a Dream?

  • Dream of Paranoia
  • Dream of excellent surgeon who wants to excel himself.
  • Dream of excellent scientist who believe nothing is impossible.
slide4

Can you imagine?

Can you imagine?

Can you imagine?

contents
Contents
  • Basic concepts of transplantation
  • Clinical Organ transplantation
    • Renal Transplantation, RT
  • Transplantation Immunology
    • MHC and Tissue Matching
    • Graft Rejection
    • Immunosuppression
definition of transplantation
Definition of Transplantation
  • Implantation of „non-self” tissue into the body
  • the process of taking cells, tissues, or organs called a graft (transplant), from one part or individual and placing them into another (usually different individual).
  • donor: the individual who provides the graft.
  • recipient or host: the individual who receives the graft.
slide7
Blood Transfusion
    • First attempts were unsuccesful (MISMATCH)
    • Discovery of blood groups (Red cell antigens)
      • A-B Landsteiner 1900
      • Rh Levine, Stetson 1939
    • Succesful transfusion = Transplantation
  • Others: Bone, Tissue-engineering, etc
  • Transplantation
    • Organ Transplantation
classification of renal transplantation
Classification of Renal Transplantation
  • Auto-RT

Cadaveric

  • Allograft RTLiving related

Living Donor

Living unrelated

  • Xenograft RT (In experimental)
transplantation history
Transplantation History
  • experimental kidney transplantation -1912
    • Alexis Carel-Nobel prize
  • 1935 human kidney transplant in Russia - rejection
  • P.B. Medawar (1945) skin grafts
    • Self skin accepted
    • Relative not accepted !  What is the difference ?
    •  Immunologic mechanism
  • A. Mitchison (1950)
    • Lymphocytes are responsible for rejection
transplantation history11
Transplantation History
  • Peter Gorer (~1935)
    • Identification of 4 group of genes for RBC
  • Gorer and Gorge Snell (~1950)
    • Group II antigens are responsible for rejection
    •  Major HistoCompatibility genes (HLA)
    • Nobel prize 1980 George Snell
  • 1954 Succesful kidney transplant between identical twins in Boston – Peter Bent Brigham Hospital
    • Joseph Murray 1991 Nobel prize
history of the rt
HISTORY OF THE RT
  • 1933 First clinical RT (Voronov);
  • 1954 First long-term successful RT(Twin);
  • 1958 Discovery of HLA(Human Lym Antigen);
  • 1959 Radiation be used for immunosupp-

ression;

  • 1961 Azathioprine (Aza);
  • 1962 Prednisolone; Tissue Matching;
  • 1966 Cross-Matching;
  • Late 1960’ Preservation the Kidney>24hr ;
  • 1972 First successful RT(LRD) in china;
  • 1978 Clinical use of Cyclosporine(CsA).
key factors for succesful transplantation
Key factors for succesful transplantation
  • Knowledge of MHC haplotypes
  • Effective immunosuppression
  • Ability to identify and treat infections
  • Available donors
clinical organ transplantation

Clinical Organ Transplantation

Liver Transplantation

Renal Transplantation

liver transplantation
LIVER TRANSPLANTATION
  • Indication: End stage liver diseases (ESLD)
  • Hepatic Disease to ESLD
    • Congenital malfomation;
    • Congenital liver metabolic disorders;
    • Acute liver failure;
    • Chronic liver failure:

(1) Cirrhosis: Hepatitis B, Alcoholic;

(2) Parasites: Hydatid disease of liver, ect.

    • liver malignance
end stage renal diseases esrd

RENAL TRANSPLANTATION

END STAGE RENAL DISEASES (ESRD)

Definition:

(1) Various causes;

(2) Irreversible injury;

(3) Functional failure.

Morbidity

  • Europe:50/million;
  • China:90-100/million
treatment of esrd
TREATMENT OF ESRD
  • DIALYSIS

Chronic Ambulatory Peritoneal Dialysis (CAPD);

Hemodialysis (HD).

  • KIDNEY TRANSPLANTATION
renal transplantation
Renal Transplantation
  • Renal transplantation is associated with as survival benefit for patients with ESRD when compared to dialysis;
  • Even marginal donor kidneys confer a significant survival advantage over maintenance dialysis.
  • The preferred therapy for most of the Pts with ESRD;
  • More cost- effective; Better survival; Better life quality.
contraindication
CONTRAINDICATION
  • Active invasive infection;
  • Active malignance;
  • High probability of operative mortality;
  • Unsuitable anatomic situation for technical success;
  • Severe psychological or financial problem.
pre op selection
Pre-OP Selection
  • ABO Blood Group:Compatible;
  • Cytotoxicity Test:

Donor Lymphocyte Recipient Serum

  • Cross matching

Donor Lymphocyte Recipient Serum

Donor Serum Recipient’s Lymphocyte

  • Mixed Lymphocyte Culture
  • Tissue typing (HLA)
operation
OPERATION

DONOR

(1)Living donor

  • Nephrectomy via flank approach;
  • Nephrectomy via Laparoscope.
slide33
(2) Cadaveric Donor
  • Total midline incision;
  • in situ flashing: Euro-collins/UW solution;
  • Bilateral radical nephrectomy.
  • Low temperature preservation.
potential advantages of living versus cadaveric kidney donor
Potential Advantages of living versus cadaveric kidney donor
  • Better short-term result(about 95% versus 90 % 1-yr function);
  • Better long-term results(half-life of 12-20 yr versus 8-9 yr);
  • More consistent early function and easy of management;
potential advantages of living versus cadaveric kidney donor35
Potential Advantages of living versus cadaveric kidney donor
  • Avoidance of brain death stress;
  • Minimal incidence of delayed graft function;
  • Avoidance of long wait for cadaveric transplant;
potential advantages of living versus cadaveric kidney donor36
Potential Advantages of living versus cadaveric kidney donor
  • Capacity of time transplantation for medical and personal convenience;
  • Immunosuppressive regime may be less aggressive;
  • Help relieve stress on national cadaver donor supply;
  • Emotional gain to donor.
potential disadvantages of live donation
Potential disadvantages of live donation
  • Psychological stress to donor and family;
  • Inconvenience and risk of evaluation process(i.e., intravenous contrast);
  • Operative mortality(about 1 in 2000 Pts.);
  • Major post operative complications (about 2% of Pts.);
potential disadvantages of live donation38
Potential disadvantages of live donation
  • Minor postoperative complications(up to 50% of Pts.);
  • Long-term morbidity(possible mild hyper-tention and proteinuria);
  • Risk for traumatic injury to remaining kidney;
  • Risk for unrecognized covert chronic renal disease.
slide39

Recipient Operation

Extraperitoneally in the contralateral iliac fossa via Gibson incision.

Why contralateral ?

recipient operation
RECIPIENT OPERATION
  • Blood Vessel Anastomosis:
    • Donor renal V Recipient’sexternal iliac V
    • Donor renal A Recipient’s internal iliac A
  • Ureter Anastomosis:
    • Donor ureter Recipient’s bladder
    • Anti-reflux anastomosis
clinical phases of rejection
Clinical phases of rejection
  • Hyperacute rejection(minutes to hours)
      • Preexisting antibodies to donor HLA antigens
      • Complement activation, macrophages
  • Accelerated rejection
  • Acute rejection(around 10 days to 30 days)
      • Cellular mechanism (CD4, CD8, NK, Macrophages)
  • Chronic rejection(months to years !!)
      • Mixed humoral and cellular mechanism
      • CHRONIC REJECTION IS STILL HARD TO MANAGE !
immunosuppression
IMMUNOSUPPRESSION
  • Immunosuppresents play a very impor-tant role in organ transplantation;
  • Immuosuppresents extremely increase the effect and the survival rate of organ transplantation;
immunosuppression44
IMMUNOSUPPRESSION
  • Immunosuppresents are a double - edged sword;
  • the most important thing is to increase their positive effects, and in the same time decrease their side effects (i.e., organ toxicity, infection, tumors, ect.).
diagnosis of rejection
Diagnosis of rejection

Symptom/Sign

  • fever;
  • urinary output ;
  • graft tenderness;
  • graft size ;
  • hypertension;
  • myalgia/arthragia.
laboratory test
Laboratory Test
  • Serum creatine, SCr;
  • Urinary creatine, Ucr;
  • Color doppler scan;
  • radiorenogram;
  • Ateriogram;
  • Biopsy:

(1) Fine needle aspiration biopsy

(FNAB);

(2) Core needle biopsy(CNB).

treatment of kidney rejection
Treatment of kidney rejection
  • Hyperacute (Sometimes during the operation !)
    • No therapy, usually results in graft failure – kidney should be removed
  • Acute (Most frequently in the first 4 weeks)
    • BIOPSY !
    • Increase immunosuppression
      • Increase steroid dose
      • Increase cyclosporin (monitor serum level !)
      • ATG, ALG, OKT3
  • Chronic
    • ACE inhibitors, prostacyclin analog drugs
    • Steroid, Imuran, Cellcept
histocompatibility antigens
Histocompatibility Antigens
  • Major histocompatibility antigens
    • MHC class I molecules : almost all nucleated cells
    • MHC class II molecules : APCs, endothelium of renal arteries and glomeruli
  • Minor histocompatibility antigens : H-Y molecule
major histocompatibility antigens
Major histocompatibility antigens
  • Human leukocytic Antigen
    • HLA I. (α1, α2, α3, β2-microglobulin)
      • Gene-Code alleles: A, B, C loci
    • HLA II. (α1, α2, β1, β2)
      • Gene-Code alleles: DP, DQ, DR loci
    • HLA III.
      • Gene-Code alleles: C4A, TNF, HSP70
  • MHC complex: Gene
major histocompatibility antigens52
Major histocompatibility antigens
  • MHC loci are highly polymorphic
  • Many alternative alleles at a locus
  • The loci are closely linked to each other
  • A set of alleles is called a HAPLOTYPE
  • One inherites a haplotype from mother and another from father
  • The alleles are codominantly expressed
inheritance of mhc alleles
Inheritance of MHC alleles

Mother

Father

A/B

C/D

A/C A/D B/C B/D A/R1 R2/C R2/R1

Possible children of parents with HLA haplotype A/B and C/D

R1=C-D recombination

R2=A-B recombination

induction of immune responses against transplants
Induction of Immune Responses Against Transplants
  • alloantigens and xenoantigens : antigens that serve as the targets of rejection
  • the antibodies and T cells that react against these antigens are said to be alloreactive and xenoreactive, respectively.
  • allorecognition
    • direct
    • indirect
rejection
Rejection
  • Senzitization stage

Not needed in hyperacute reactions !

  • Effector stage
    • Alloantibodies: bind to endothelium, activate the complement system, and injure graft blood vessels
rejection58
Rejection
  • Effector stage (Mostly cellular mechanism)
    • Alloreactive T cells : recruit and activate macrophages ---> DTH response delayed type hypersensitivity
    • Alloreactive CTLs: CTL mediated cytotoxicity lyse graft endothelial and parenchymal cells directly
    • ADCC

CD4, CD8 lymphocytes, NK cells, macrophages

rejection59
Rejection

From: Kuby: IMMUNOLOGY (fourth edition, 2000)

tissue typing
Tissue typing
  • Microcytotoxicity assay
    • Known antibody to WBCs of donor / recipient
    • Complement mediated lysis if Ab present on cell surface
  • Mixed lymphocyte culture (MLC)
    • Irradiated donor lymphocytes (stimulants)
    • Incubated with recipient lymphocytes
    • 3H Thymidin incorporatin measured
  • Flow cytometry cross typing
  • DNA analysis
    • Genomic typing (very precise, many subtipes)
hyperacute rejection
Hyperacute Rejection
  • Occurs within minutes of transplantation
  • Pre-existing IgM (natural) antibodies against
    • ABO blood group antigens
    • less well-characterized antigens in xenograft
    • alloantigen, such as foreign MHC molecules, or alloantigen expressed on vasular endothelial cells
acute rejection
Acute Rejection
  • Occurs within days or weeks after transplantation
  • Acute vascular rejection
    • Necrosis of cells of the graft blood vessels (vasculitis)
    • Mediated by IgG antibodies against endothelial cell alloantigens and complement activation
acute rejection64
Acute Rejection
  • Acute cellular rejection
    • Necrosis of parenchymal cells with lymphocyte and macrophage infiltrates
    • Effector mechanisms :
      • CTLs
      • Activated macrophages
      • Natural killer cells
chronic rejection
Chronic Rejection
  • Occurs over months or years
  • Fibrosis with loss of normal organ structures
  • Wound healing following the cellular necrosis
  • A form of chronic DTH or a response to chronic ischemia caused by injury to blood vessels
prevention and treatment of allograft rejection 1
Prevention and Treatment of Allograft Rejection1
  • Immunosuppression
    • drugs that inhibit or kill T lymphocytes
    • toxins that kill proliferating T cells
    • antibodies that deplete or inhibit T cells
    • anti-inflammatory agents
prevention and treatment of allograft rejection 2
Prevention and Treatment of Allograft Rejection2
  • Reduce the immunogenicity of allografts
    • ABO blood group typing
    • HLA typing and matching
  • induce donor-specific tolerance
    • blood transfusion
graft versus host disease gvhd
Graft-versus-host Disease (GVHD)
  • Occurs in bone marrow recipients
  • Initiated by T cell recognition of host alloantigens
  • The effector cells are less well defined : NK cells, CD8+ CTLs, cytokines
acute gvhd
Acute GVHD
  • Epithelial cell necrosis :
    • Skin
    • Liver
    • The gastrointestinal tract
  • Characterized by skin rash, jaundice and diarrhea
immunosuppressive therapy 1
Immunosuppressive therapy 1.
  • Allogenic transplantation always require immunosuppressive therapy
  • Most of the drugs available are non-specific
  • Common side effects of therapy:
    • Infection
    • Cancer
    • Bone-marrow depression
immunosuppression 2
Immunosuppression 2.
  • Conventional drugs(1st phase)
    • Steroids /Prednisone/ (0.1-10 mg / kg)
    • Azathioprine /Imuran/ (0.5-3 mg/ kg)
    • Cyclophosphamide (0.5-20 mg/ kg)
    • Methotrexate (0.1-0.3 mg/ kg)
immunosuppression 3
Immunosuppression 3.
  • New drugs (1):
    • CYCLOSPORIN A (=REVOLUTION !)

2-8 mg/ kg

    • FK506 tacrolimus /PROGRAF/
    • Sirolimus - rapamycin
    • Gusperimus - dezoxyspergualin
effects of cyclosporins
Effects of cyclosporins
  • Receptor: cytoplasmic immunophillin

calcineurin blockage  NF-Atc

  • Rapamycin also binds to immunophillin, but

the complex does not block calcineurin, it blocks proliferation in G1 phase.

  • Highly lymphocyte specific. IL-2 action is impaired.
  • T lymphocyte (Th) is blocked.
immunosuppression 4
Immunosuppression 4.
  • Purin antagonists
    • IMURAN
    • CELLCEPT (micophenolate mofetil)
    • Mizoribin – bredinin
  • Pirimidin antagonists
    • Sodium-brequinar (highly lymphocyte specific)
monoclonal antibodies
Monoclonal antibodies
  • OKT3 (Anti CD3 mAb)
    • CD3 T cells
  • Anti-TAC (anti-IL2 receptor)
    • Activated T lymphocytes
  • Anti-CD4
  • Anti-LFA1 + anti-ICAM-1 – experimental
  • Anti-cytokine (IL-2, TNFα, IFNγ)
problems of transplantation
Problems of Transplantation
  • There are not enough organs
    • At least 150,000 patients in industrially developed countries badly need donor organs and tissues
    • Every 14 minutes another name is added to the national transplant waiting list.
    • About 16 people die because of the lack of available organs for transplant each day.
  • Rejection:
    • When the immune system of the host detects foreign graft tissue, it launches an attack, resulting in tissue rejection
gene technology may as a solution
Gene technology may as a solution
  • Gene technology offers the possibility to breed the desired organs in animals.

Lack of organs is no longer a problem

  • Gene technology makes it possible to humanize the bred organs - the immune system identifies the organ as its own tissue.
  • Immune system rejection is prevented
from which animals are we able to transplant organs
From which animals are we able to transplant organs

3. The Pig:

Surprisingly similar to our anatomy and physiology

1. The Chimpanzee:

Its DNA sequence differs from ours by only 2%

2. The Baboon:

Its organs are too small for a large adult human

slide82

Organ breeding:

  • A transgenic animal carries a foreign gene inserted into its genome.
  • The transgenic animal shows the specific characteristics which are coded on the inserted gene
  •  A gene which is responsible for the construction of a human organ makes the organism produce the organ additionally.
the insert of a foreign gene into an animal
The insert of a foreign gene into an animal

I. DNA microinjection

The DNA is inserted into the cell with a small syringe

II. Retrovirus gene transfer

The DNA is carried into a cell by a virus.

suppression of immune system rejection
Suppression of immune system rejection
  • The genes which are responsible for the own tissue not being rejected can be injected into an animal embryo
  • the organs of which are then similar to the ones of the human.
  • It is possible to humanize the bred organs by making certain genetic modifications.
  • Then the organs are accepted by the immune system.
conclusion
Conclusion
  • Transplantation provides us the means of restoring the function of a nonfunctional organ.
  • In the case of BMT it enables us to administer such high doses of chemotherapy that would destroy the BM as well as the residual tumor.
  • A lot immunologic knowledge had to be collected to understand what is happening.
conclusion86
Conclusion
  • HLA typing and matching is essential for allografting transplantation.
  • Effective immunosuppressive therapy (Cyclosporin) revolutionised organ transplantation.
  • The future is to transplant cells, that would restore the function of the affected organ.
  • Gene therapy is growing, and will cause another revolution like cyclosporin did in the 1980s.
slide87

To seek what everybody has sought

To think what nobody has thought

Try your best, everything will be possible