Organ Transplantation: Dr. Roshan Mascarenhas Roshan - Mascarenhas@newcastle - Edu.my
Organ Transplantation: Dr. Roshan Mascarenhas Roshan - Mascarenhas@newcastle - Edu.my
Organ Transplantation: Dr. Roshan Mascarenhas Roshan - Mascarenhas@newcastle - Edu.my
Case 10.14 1
Learning Outcomes
Case 10.14 2
Links to Case
Case 10.14 3
Overview
Transplant rejection is a major problem because of
immunological reactions
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
OK
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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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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)
• 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
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Direct Allorecognition
• Donor APC (from transplanted
(up to 10% of recipient cells stimulated by non-self MHC – large polyclonal response) 16
Indirect Allorecognition
• Recipient APC process peptides from
organ
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
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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.
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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.
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Immunosuppressive Drugs in Transplantation
All of these drugs present toxic side effects and narrow therapeutic
ranges need to be achieved for optimal clinical outcome.
Immunosuppression Rejection
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Further reading
Hardinger KL and Brennan DC (2013) Novel Immunosuppressive
agents in kidney transplantation. World J Transplant, 3: 68-77
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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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