Respiratory Immunology 6: Transplantation Flashcards
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
Hyperacute rejection due to pre-existing anti-donor HLA antibodies: mechanism?
Antibody binds to foreign HLA molecules
Activates immune cascade, inc. complement
Endothelial damage, inflammation and thrombosis
Hyperacute rejection
Clinical features of hyperacute rejection?
Occurs within minutes-hours after transplantation
Thrombosis of graft - often with neutrophil infiltrate and widespread necrosis (organ may turn black)
Irretrievable graft loss
Prevention of hyperacute rejection?
ABO matching:
Standard ABO blood typing
Blood group cross matching
Identify if recipient has any anti-HLA antibodies by screening (once a year to ensur they have no new antibodies) and HLA cross-matching
Treatment of hyperacute rejection?
No treatments for overwhelming complement activation
Could use plasmapheresis
Method of cross-matching between donor and recipient?
Directly test if serum from recipient is able to bind and/or kill donor lymphocytes - serum potentially contains anti-donor antibodies and result is specific to that donor (thus, performed just prior to transplantation)
Positive croos-match is a contraindication to transplantation - risk of hyperacute rejection, increased risk of acute rejection, poor long term graft survival and is true for all types of solid organ transplant
Summary of hyperacute rejection: time, pathology, mechanism and treatment?
Time - minutes to hours
Pathology - thrombosis and necrosis
Mechanism - preformed antibodies and complement fixation
Treatment - none
What is acute vascular rejection?
Rejection predominantly ANTIBODY-MEDIATED (may have formed de-novo before transplantation or may have existed before but unidentified by crossmatching as weak)
Mechanism of acute vascular rejection?
T cells provide co-stimulatory signals and cytokines to activate B cells, which produce antibodies against graft antigens:
Initiate complement activation
Phagocyte recruitment
Summary of acute vascular rejection: time, pathology, mechanism and treatment?
Time - 5-30 days
Pathology - vasculitis and Type II hypersensitivity
Mechanism - de novo antibody and complement fixation
Treatment - immunosuppression
What is chronic allograft failure (“chronic rejection”)?
Major cause of graft loss that affects all types of solid organ transplant
Cellular proliferation of smooth muscle of vessel wall and occlusion of lumen
Interstitial fibrosis and scarring is common
Risk factors for chronic allograft failure?
Immune:
More prevalent in HLA mismatch
Associated with previous acute rejection episodes
Non-immune: Initial delayed graft function Non compliance with medication Hypertension Hyperlipidaemia Older donor age Recipient infection eg Cytomegalovirus Calcineurin inhibitors (Ciclosporin, Tacrolimus)
Treatment of chronic allograft failure?
Immunosuppression - usually tried but too late
Prevention - treatment of hyperlipidaemia and hypertension
Summary of chronic allograft failure: type, pathology, mechanism and treatment?
Time - >30 days
Pathology - fibrosis and scarring
Mechanism - immune and non-immune mechanisms
Treatment - minimise drug toxicity, hypertension and hyperlipidaemia and good control of anti-rejection
Other problems occurring in transplantation?
Drug toxicity
Major complications of long-term immune suppression - infection, malignancy and atherosclerosis
Risks depend on - overall level of immunosuppression and specific immune pathway targeted
Examples of immunosuppressant drug side effects?
Nephrotoxicity (poisonous effect of some substances) - caused by nephrotoxic drugs, diabetes and hypertension
Ciclosporin (immunosuppressant) - can cause gingival hypertrophy, facial hair growth (alternative drug is tacrolimus)
Preventing infection in immunosuppressed individuals?
High index of suspicion - inform lab of opportunistic infection; LOW THRESHOLD FOR ANTIBIOTICS
Vaccination - e.g: influenze; avoid live vaccines
Specific prophylaxis during times of increased immune supression
Indications for transplantation?
Advanced respiratory failure with life expectancy
