ORGAN TRANSPLANTATION

Dr. Roshan Mascarenhas

roshan.mascarenhas@newcastle.edu.my

Case 10.14 1
 Learning Outcomes

• Describe the mechanism of transplant rejection

• Describe the role of immunosuppression in preventing allograft

rejection

Case 10.14 2
 Links to Case

Andrea McDonald is 44 and waiting for a liver transplant………………….

A suitable match has to be found, she’s on a waiting list……………………
she will never feel physically well unless she has a new liver ……Her
consultant told her that if she stopped drinking, she could have a
chance if she was able to get a transplant, a necessity now because
the liver is damaged beyond repair.

Case 10.14 3
 Overview
 Transplant rejection is a major problem because of
immunological reactions

 Currently success of transplantation depends on matching

donor and response to immunosuppressive drugs

Case 10.14 4
 Definition of terms
• Isograft
– transplantation between genetically identical
individuals
• Xenograft
– between different species
• chemically treated pig heart valves
• organs from transgenic pigs (science fiction?)
• Allograft
– between non-identical members of the same species
• conventional transplant surgery

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 The good (and less good) news

In 2014, about 7,200 liver transplants were performed in the U.S.

among both adults and children. Of those, about 330 involved livers
from living donors. At the same time, nearly 15,000 people were
registered on Lung
Kidney
the waiting list forLiver
a liver transplant. Heart

UK Transplant Activity report 2008-2009

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 Boston, 1954
Richard and Ronald Herrick

OK

First successful kidney transplant - between identical

twins 7
 The Major Histocompatibility Complex
(MHC) antigens
• In the clinic these are called human
leukocyte antigens (HLA)
– Class I: HLA-A, HLA-B, HLA-C
– Class II:HLA-DR, HLA-DP, HLA-DQ

• Each person expresses 2 variants of each

antigen (co-dominant: maternal and
paternal)

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 MHC Polymorphism
Class I MHC (Alleles; Proteins) Class II MHC (Alleles; Proteins)
– HLA-A – HLA-DR (A + B chain)
• n = 2013; 1448 • n = 1267; 903
– HLA-B – HLA-DP (A + B chain)
• n = 2605; 1988 • n = 189; 151
– HLA-C – HLA-DQ (A + B chain)
• n = 1551; 1119 • n = 223; 155

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10
 Basic Rejection Processes - 1
• Hyperacute rejection
– occurs rapidly (maybe minutes after transplantation)
– mediated by pre-formed antibodies and complement
– results in vascular damage and thrombosis
– generally easy to prevent by cross-matching
– rarely encountered (big problem in xenografting)

Panel Reactive Antibody (PRA)?

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 Basic Rejection Processes - 2

• Acute rejection
– episodes occur in most patients during the first 3
months after transplantation
– Quite well understood
– T-cell mediated response (therefore of most interest to
immunologists!)
• CD4 and CD8 T cells
– targeted at histocompatibility antigens (MHC)
– can be managed successfully in most cases by
immunosuppression
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Acute renal allograft Acute liver allograft
rejection rejection

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 Basic Rejection Processes - 3
• Chronic rejection
– occurs months and years after transplantation
– now the most common cause of graft failure
– generally observed as a fibro-proliferative disease
– cause largely unknown (? growth factors)
– variable organ sensitivity
• lung is very susceptible to obliterative bronchiolitis
– no good treatment

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 Alloantigen Presentation

Two ways of presenting donor antigen on transplant organ to

recipient T cells (which reject graft)

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 Direct Allorecognition
• Donor APC (from transplanted

organ) migrates to recipient

regional lymph node

• Recipient T cells with

corresponding TCR activated by

APC - recognise donor MHC (I or II)

+ peptide, 2nd signal given

• Activated host T cell migrates to graft and attacks it

• Direct cytotoxic T cell response ? Acute rejection

(up to 10% of recipient cells stimulated by non-self MHC – large polyclonal response) 16
 Indirect Allorecognition
• Recipient APC process peptides from

inflammed/dead cells from transplanted

organ

• Recipient APC presents foreign peptide

with self MHC to appropriate T cell,

activates 2nd signal

• Activated host T cell migrates to graft and attacks it.

• Fewer T cells activated - oligoclonal

• May activate macrophages, cause tissue injury, fibrosis, alloantibody response ?

Chronic rejection 17
 Bone marrow transplantation: a
special case
• Similar to solid organ transplantation
– But the other way around
• Transplantation of the immune system
• There is a potential for transplanted T cells to
respond to the recipient patient’s entire body!
– Termed “Graft versus Host Disease” or GvHD
• Reduce by very accurate tissue matching

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 Immunosuppression
• This is almost always necessary despite tissue
typing
• Present strategies block T cell-mediated
immune responses
• Almost all patients receive drug therapy for
the life of the graft

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Liver allograft survival – the 1st year
(we’re getting better at preventing acute rejection)

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 Immunosuppression
Corticosteroids
Prednisolone
Cytotoxic Drugs
Cyclophosphamide/chlorambucil
Methotrexate
Immunomodulatory Drugs
Ciclosporin/Tacrolimus/Sirolimus
Mycophenolate mofetil
Leflunomide
Immunomodulatory Biologicals
Polyclonal Antibodies
Monoclonal Antibodies
Other biologicals

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 Immunosuppressive Drugs - 1
• Commonly used maintenance drugs
– Corticosteroids

– Cyclosporin A and Tacrolimus

• Inhibit T cell activation; calcineurin inhibitors; primarily
block the production of T-Cell growth factor (IL-2)

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 Immunosuppressive Drugs - 2
• Commonly used ‘rescue’ drugs
– High-dose steroids
– Mycophenolate mofetil
• block T cell proliferation (similar to anti-cancer drugs)
– Anti T-Cell antibodies
• include polyclonal preparations (eg ATG) and
monoclonal antibodies (eg OKT-3)
– Highly specific ‘humanised’ chimeric antibodies
• including antagonistic antibodies targeted at the IL-2
receptor (eg basiliximab)

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 Antibody Based Immunosuppression
Daclizumab is a humanised
monoclonal antibody to the alpha
subunit of the IL-2 receptor (IL2-R)
(CD25) of T cells.

It is given in multiple doses, the first 1

hour before the transplant, and 5
further doses given at 2 weeks after
the transplant.

The antibody prevents IL-2 binding to

the receptor and thus IL-2 mediated T
cell activation.

Has also been in trial in the UK for the

treatment of MS. 24
 Antibody Based Immunosuppresion
Basiliximab is a chimeric mouse –
human monoclonal antibody to the
IL2-R (CD25) of T cells.

It is given in two doses, the first within

2 hours of the transplant, and the
second 4 days after the transplant.

The antibody prevents IL-2 binding to

the receptor and thus IL-2 mediated T
cell activation.

In the UK is recommended for all

kidney transplants.

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GvHD in BMT
 Antibody Based Immunosuppresion
OKT3 (muromonab) is a murine
monoclonal antibody against the ε
chain of the CD3 complex.

It is given immediately after the

diagnosis of acute rejection. 5mg
doses are given daily for 10-14 days.

In the body OKT3 acts in two phases.

Firstly circulating T cells are depleted
by opsonisation in the liver and
cytolysis. In the second phase the CD3
complex is removed producing
immuno-incompetent T cells.

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Immunosuppressive Drugs in Transplantation

Nature Clinical Practice Nephrology (2006) Changes in maintenance

immunosuppression in kidney transplant recipients. AZA, azathioprine; CSA,
cyclosporin: MMF, Mycophenolate mofetil; SRL, sirolimus; TAC. tacrolimus 27
 Immunomosuppresive Drugs in Transplantation
All patients who undergo solid organ transplantation require lifelong
immunosuppressive therapy to prevent allograft rejection.

All of these drugs present toxic side effects and narrow therapeutic
ranges need to be achieved for optimal clinical outcome.

Application of pharmacogenomics to individualize the dosing strategy

holds promise but the clinical application is yet to be proven.

Thus blood levels of the drugs vary significantly in different individuals

and ethnicities making the dosing information of little value in
prediction of blood levels of the drugs.

Therefore, therapeutic drug monitoring (TDM) is essential in post-

transplantation patient care.
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 Immunosuppression:
a delicate balancing act

Immunosuppression Rejection

•Toxicity •Graft failure

•Cancer
•Infection
•Quality of life
•Hair growth
•Tremor
•Gum overgrowth

Drugs must be taken every day for

remainder of the patient’s (or graft’s) life
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 30
Cold Spring Harb Perspect Med 2013;3:a015487
 Quiz
• Login to Socrative student

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 Further reading
Hardinger KL and Brennan DC (2013) Novel Immunosuppressive
agents in kidney transplantation. World J Transplant, 3: 68-77

Halleck et al (2013) New perspectives of immunosuppression.

Transplant Proc, 45: 1224-31.

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 Donor: A1, B8, B39, DR1, DR3
Paternal Maternal

A1 A1

B8 B39

DR1 DR3

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 Recipient: A1, A24, B9, DR1, DR4
Paternal Maternal

A1 A24

B9 B9

DR1 DR4

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