Lecture 12 - Transplant Immunology I Flashcards
Which organs are commonly transplanted?
- Corneas
- Lungs
- Liver
- Heart
- Kidneys
- Pancreas
- Intestines
- Femoral and saphenous veins
- Bone
- Skin
- Tendons
What are the various types of transplant?
Give examples of tissues / organs that are commonly transplanted for each
- Autograft
• Transplant of tissue from one location to another within an individual
• Skin grafts - Isograft
• Transplant between genetically identical individuals
• Kidneys - Allograft
• Transplant between two different individuals of the same species
• Solid organs transplant - Xenograft
• Transplant between to individuals of different species
• Porcine valves
List some of the highlights of transplantation over the past centuries
1668 - van Meeneren
1869 - Reverdin
1906 - Zirm
1954 - Joseph Murray
• First kidney transplant
1963 - James Hardy
• First lung transplant
1963 - Thomas Starzl
• First liver transplant
1964 - Christiaan Barnard
• First heart transplant
List the immunoprivileged sites in the body
- Eye
- Brain
- Testis
- Uterus
Describe the ABO blood groups
Four groups:
1. A
• Natural Abs against B in circulation
- B
• Natural Abs against A - AB
• No natural Abs
• Universal recipient - O
• Abs against A and B
• Universal donor
The A and B refer to terminal residues on carbohydrates on the surface of our RBCs
Who discovered the ABO blood groups
Landsteiner
1901
Describe Medawar’s experiments with skin grafts
Demonstrated that graft rejection was immune mediated
Observations:
• Skin grafts between genetically identical (identical MHC) individuals (mice) were accepted
- Skin grafts to allogeneic recipients resulted in rapid rejection: ‘First set rejection’
- Repeated this results in accelerated rejection of graft: ‘Second set rejection’
Which hallmarks of the immunological response are seen in transplant rejection?
Memory
Specificity
Increasing magnitude with subsequent exposure
Which cells mediate transplant rejection?
T cells
• CD4+
• CD8+
B cells
When were HLA molecules discovered?
1959
Dausset and van Rood
Where are MHC molecules encoded?
p arm of Ch. 6
List the various HLA loci
Class I:
• B
• C
• A
Class II:
• DP
• DQ
• DR
HLA genes are highly…
polymorphic
Describe the pros and cons of HLA polymorphism
Pros:
• Means that individuals wan present a wide range of peptides
Cons:
• Challenging to match for transplantation between individuals
Where is most of the ‘variation’ in HLA molecules?
CDRs
Within the peptide binding cleft
Class I: α1 domain
Class II: β1 domain
Which are the major molecules responsible for transplant rejection?
MHC
Characterise the correlation between HLA matching and transplant rejection
With increasing HLA mismatches, transplant rejection is more likely
Is is possible for HLA matched transplants to be rejected?
Yes
There are other Ags that can mediate rejection:
Minor histocompatability Ags
Compare importance of HLA matching in renal and lung transplant
Renal transplant:
• HLA matching is important
• Hence, there is a national registry
Lung tx:
• Matching is not as important
• No national registry
• Lungs are routinely transplanted across HLA mismatch
Describe minor histocompatability Ags
Allopeptides presented by MHC molecules on the graft cells
Peptides derived from:
• Proteins only present in the donor (e.g. H-Y male Ags)
• Polymorphic proteins
Describe how H-Y Ags can cause rejection
Ags encoded on the Y chromosome will be absent in females, and thus the immune system will not be tolerant of them
When organs are transplanted from males into females, there is de novo generation of Abs against these H-Y Ags
Detection of H-Y Ab in recipient correlates with acute transplant rejection
Describe how polymorphic proteins can lead to transplant rejection
Give examples
There are many proteins that can be polymorphic
The recipient’s immune system will not be tolerised against these slightly different Ags
Examples of minor H Ags: • HA-1 • HA-2 • HA-8 • HB-1
These Ags have certain HLA restrictions
In an ideal world, recipients would be HLA typed before transplant to make sure that they do not have the HLA molecules that will present these minor H Ags
List the different types of rejection reactions
Describe the following features of each:
• Time frame
• Cause
- Hyperacute
• Minutes - hours
• Pre-formed Abs against donor Ags - Acute
• Days - weeks
• Primary activation of T cells - Chronic
• Months to years
• Causes unclear
Describe the pathogenesis of hyperacute allograft rejection
In what situations can it occur?
Can occur when:
1. Individual presensitised to graft Ags
• Blood group
• MHC
- Previously experienced Ags:
• Blood transfusion
• Transplant
• Pregnancy
Pathogenesis:
1. Transplantation of organ
- Abs immediately bind to Ags in vasculature
- C’ activation
- Recruitment of inflammatory cells
• PMNs - Lytic enzymes released by neutrophils
- Formation of thrombi
- Occlusion of blood vessels of graft
- Graft haemorrhages
What does one look for in histologic diagnosis of hyper acute rejection?
Fixation of C’
esp. C4d
Describe the two ways that allorecognition can occur
- Indirect allorecognition
- Self MHCs take up donor Ag in graft
- Foreign peptide presented in self MHC
- Now appears ‘foreign’ to T cells
- Direct allorecognition
- Donor APCs migrate to recipient LNs
- Allogeneic MHC recognised strongly by recipient T cells
Describe the role of the various lymphocytes in acute rejection
– CD8+ T cells –
- Direct / indirect Ag presentation
- CD8+ T cells become activated
- CTLs infiltrate into graft
- CTLs recognise graft Ag and kill the cells (perforin dep.)
– CD4+ T cells –
- Direct / indirect Ag presentation
- CD4+ T cells become activated
- Th1 produce IFN-gamma, helping macrophages
Macrophages phagocytose graft cells
– B cells –
Th2 produce IL-4 and IL-5, helping B cells produce Ab against graft Ag
Abs bind graft vascular endothelium
C’ activation and ADCC in graft vasculature
List the various cytokines secreted by Th1
- IFN-gamma
• Helps macrophages to kill ingested pathogens - TNF and LT
• Causes local tissue destruction - GM-CSF
• Stimulates monocyte production in BM - Chemokines
• Recruits macrophages
Describe the pathogenesis of chronic rejection
1. Smouldering injury: • Ischemia / reperfusion injury • Infection • Dyslipidaemia • Hypertension
- Chronic low level injury and repair of graft vasculature
- Fibrosis of graft vasculature
- Progressive narrowing of graft vasculature / tubules
• Bronchioles → Bronchiolitis obliterans syndrome
• Renal tubules → chronic allograft nephropathy
• Coronary arteries
• Bile ducts → Vanishing bile duct syndrome
Compare the ‘pathology’ in each of the types of rejection
Hyperacute rejection:
→ Pathology of coagulation
Acute:
→ Pathology of inflammation
Chronic:
→ Pathology of tissue remodelling
