Respiratory Immunology 6: Transplantation Flashcards
(41 cards)
Uses of transplantation?
Only definitive treatment option for end-stage heart, lung and liver disease
In kidney disease, it provides a significant survival advantage compared with dialysis
How do T lymphocytes recognise foreign antigens?
See peptides presented by exhibited on a defined framework on an antigen-presenting cell
What is HLA?
Provide framework for T cell activation (changes in HLA can affect T cell activation); when viruses enter a cell, parts can remain on HLA molecules, as can foreign antigens
Types of HLA?
Two types: HLA class I (HLA-A, HLA-B, HLA-C) are expressed by all nucleated cells HLA class II (HLA-DR, HLA-DQ, HLA-DP) are only expressed on antigen-presenting cells Each individual possesses 2 variants of each HLA molecule (so 6 on all nucleated cells and 12 on antigen-presenting cells)
Describe polymorphism in HLA genes
372 HLA-A alleles
661 HLA-B alleles
401 HLA-DRB1 alleles
…clinically important and maintains diversity
Generation of diversity via polymorphisms in HLA genes?
Proteins are processed into many component peptides and each peptide binds to only a few HLA molecules
Each HLA molecule exhibits diversity in the range of peptides that can bind to it - maximises diversity at the level of the individual and within populations
Methods of preventing transplant rejection?
Minimise the stimulus - HLA matching in transplantation
Blood group matching - ALL CELLS, NOT JUST RBCS, HAVE BLOOD GROUP ANTIGENS
Describe HLA matching in transplantation
Maximise the similarity between recipient and donor HLA; difference between donor and recipient is expressed as number of MISMATCHES at HLA-A, HLA-B and HLA-DR
Hierarchy of importance - HLA-DR»_space; HLA-B > HLA-A
What is the “best” HLA type?
No “best” type but individuals with common types are likely to get a transplant quickly
Disadvantages of HLA matching?
Limited benefit if donor pool is small
May penalize individuals with rare variants, e.g: from minority ethnic groups
Organs where HLA matching is used to allocate donor?
Stem cell transplantation - essential and HLA mismatching is a major preventable cause of graft vs host disease
Kidney transplantation - clear benefit
Organs where HLA matching is not used to allocate donor?
Lung, heart - limited donor pool and prolongation of “cold ischaemic time”
Liver - benefit controversial
Mechanism of T cells activation?
T cells are recognising foreign antigen - foreign antigen presenting cells have different HLA
T cells become activated and make IL-2 which causes proliferation and other effector functions activation
Effector functions of activated T cells?
Produce cytokines
Provide help to activate CD8+ cells
Provide help to B cells for antibody production
Recruit phagocytic cells
What occurs in acute cellular rejection?
Most common form of rejection CLASSIC TYPE IV HYPERSENSITIVITY REACTION
Recognition of donor antigens by CD4+ T lymphocytes:
CD4+ cell activation
Production of cytokines - help for CD8+ cells, help for B cells and recruitment and activation of macrophages and neutrophils
Not noticed immediately as help needed to begin
Acute cellular rejection: function of activated CD8+ lymphocytes?
Are cytotoxic; methods of killing:
Release of toxins to kill target - inc. granzyme B
Punch holes in target cells - using perforin
Induce apoptotic cell death of target - using Fas- ligand and Th1 cytokine
Production of such moelcules can assist diagnosis of acute cellular rejection
Acute cellular rejection: functions of activated macrophages and neutrophils?
Phagocytosis
Release of proteolytic enzymes
Production of cytokines
Production of oxygen radicals and nitrogen radicals
Acute cellular rejection: T cell help of B cell activation?
If T cell activation is not stopped, B cells will also become activated:
T cells provide CO-STIMULATORY signals and cytokines to activate B cells
B cells produce antibody against graft antigens
Acute cellular rejection: functions of activated B cells?
Antibody production results in: Complement activation Opsonisation Activation of NK cells Recruitment of phagocytes
Signs and symptoms of acute cellular rejection?
Deteriorating graft function:
Kidney transplant - rise in creatine, fluid retention and hypertension
Liver transplant - RISE in LFTs (Liver Function Tests) and coagulopathy
Lung transplant - breathlessness, pulmonary infiltrate
Pain and tenderness over graft
Fever
Summary of acute cellular rejection: time, pathology, mechanisms and treatment?
Time - 5-30 days
Pathology - cellular infiltration and Type IV hypersensitivity
Mechanism - CD4 and CD8 T cells, B cells and phagocytes
Treatment - immunosuppression
What is hyperacute rejection?
Rapid destruction of graft withing minutes-hours
Mediated by PRE-FORMED ANTIBODIES that react with donor cells
Also occurs if recipient has pre-existing anti-donor HLA antibodies
Reasons an individual would have preformed antibodies against donor cells?
Second transplant from same donor
Mother making antibodies against Rhesus +ve child - second baby’s cells, if Rhesus +ve, are destroyed
DIFFERENT BLOOD TYPES
Mechanism of hyperacute rejection when giving wrong blood group tranfusion and example?
Giving a heart transplant from blood group B donor to blood group A recipient (serum contains naturally occurring anti-B antibodies)
Circulating, preformed, recipient anti-B antibodies binds to B blood group antigens on donor epithelium
Activates complement - leads to complement-mediated lysis, opsonisation and increased permeability
Other cells rapidly recruited, like phagocytes
Disruption of endothelium - platelets activated, inflammation and thrombosis
Hyperacute rejection
