Case 14: Transplant Flashcards
1
Q
Lymphocyte patterns in immunodeficiency 1
A
- Primary or secondary immunodeficiency: Lymphopenia
- SCID: low T cells +/- B cell and NK cell lymphopaenia
- Infection, malignancy, drugs: low CD4+
- Secondary agammaglobulinemia: absent B cells
- Viral infection, leukaemia and lymphoma: Lymphocytosis
2
Q
Lymphocyte patterns in immunodeficiency 2
A
- CGD: defective neutrophil function
- Haemophagocytic Lymphohistiocytosis (HLH): defects in NK cell and cytotoxic T cell function
- Lymphoproliferative disease: isolated low IgM
- Liver disease: high IgM
- Chronic infection and inflammation: raised polyclonal IgA (also seen in elderly)
- Sjogrens syndrome and HIV: raised IgG
3
Q
HLH
A
A life threatening Immunodeficiency of severe hyperinflammation due to uncontrolled proliferation of activated lymphocytes and histiocytes.
4
Q
Paraprotein
A
A marker of plasma cell disorder such as multiple myeloma. Investigated with serum electrophoresis. Its the immunoglobulin product of a single cell clone. Confirmed with Immunofixation
5
Q
Pre Transplantation tests
A
- Hep B sAg, Hep B sAb, HIV Ag/Ab, Hep C Ab, CMV IgG and IgM
- ABO blood group
- HLA typing: HLA-DR, HLA-A and HLA-B. Preferable are: HLA-C, HLA-DP and HLA-DQ
- Anti-HLA antibody serology
- Cross match: T cell crossmatch is a contraindication to transplant. If antibody detected in host, then should undergo plasmapheresis pre-transplant.
6
Q
Transplantation: common definitions
A
- Transplantation: The transfer (engraftment) of human cells, tissues or organs from a donor to a recipient with the aim of restoring function(s) in the body
- Graft – The transplanted tissue
- Donor – The source of the graft
- Recipient – The individual receiving the transplant
- Allo (as in “allograft”) – from a genetically different member of the same species
7
Q
Transplantation: use and epidemiology
A
- Solid organ transplants are used in: kidney, heart, liver, lung, pancreas or bowel disease
- Many people need repeat transplantation but demand for organs outstrips supply
- Half of lung transplants are lost in 5 years
8
Q
Immune response to transplants
A
- Immune response in transplant are primarily: polymorphic HLA gene products i.e. MHC
- Other targets include AB blood group antigens and minor histocompatibility antigens
- Antigen-specific response directed by lymphocytes (B and T cells)
- Other factors in rejection: Innate immune cells, including NK cells, macrophages and neutrophils, as well as endothelial cells.
9
Q
HLA- Human Leukocyte Antigen
A
- Major Histocompatibility Complex (MHC), genes involved in antigen processing and presentation on chromosome 6
- Class 1 (HLA-A, -B and -C) expressed on all cells as MHC-1 and present antigens to CD8 T cells
- Class II (HLA-DR, -DP and -DQ) expressed on APCs as MHC-2 and present antigen to CD4 T cells
10
Q
Types of transplant rejection
A
- Hyperacute: minutes to hours, pre-existing antibodies (previous pregnancy, transfusion, transplantation etc)
- Acute: days to weeks, Cellular (T-cell mediated), Humoral (antibody production requiring T and B cell function)
- Chronic: months to years, complex aetiology
11
Q
Hyperacute rejection
A
- Targets: blood group antigens and MHC molecules
- Rare due to screening and cross matching
- Rapid extensive thrombosis and graft infarct, usually needing graft removal
- Due to pre-existing anti-donor antibodies in the recipient
- Treatment is removal of organ
12
Q
MoA of Hyperacute rejection
A
- Rapid binding of antibodies to graft antigens
- Activation of complement: Cell lysis, increased leucocyte recruitment / inflammation
- Endothelial activation, release of pro-thrombotic substances (e.g. Von Willebrand factor); Platelet aggregation, thrombosis, and occlusion of graft microvasculature
- Causes thrombosis and graft infarction usually needing graft removal
13
Q
MoA acute rejection
A
- T cells recognise antigens on APC’s from the donor graft (direct) or on the recipients APC’s (indirect).
- When activated the APC express co-stimulatory molecules i.e. B7 which bind to receptors on T cells causing them to proliferate into effector cells.
- Need both the antigen and the co-stimulatory molecules to activate the T cell
14
Q
Effects of T cells in acute rejection
A
- CD8 (cytotoxic) T cells infiltrate the graft recognise foreign MHC-1 and kill the cell
- CD4 Th(helper)1 effector cells: infiltrate the graft and recognise foreign MHC-2, causing the release of proinflammatory cytokines (IFN-Y, TNF) which recruit neutrophils and Macrophages causing tissue damage, altered vascular function and ischaemia
15
Q
Effects of T cells in acute rejection: CD4 TH2 cells
A
CD4 TH2 effector cells recruit B cells to differentiate into plasma cells. Plasma cells produce antibodies targeting donor antigens (donor specific antibodies - DSAs). Circulating DSAs bind to graft endothelial cells, activate complement, endothelial cell damage, microvascular thrombosis in graft
15
Q
Antibody mediated acute rejection
A
- Antibodies to donor antigens bind to antigens on endothelial cells.
- This leads to complement activation leading to formation of MAC pores and inflammatory cell recruitment.
- This leads to inflammation and complement-mediated cell lysis results in graft damage and microvascular thrombosis.
16
Q
Acute rejection: Diagnosis
A
- Presentation: acute deterioration in graft function (rise in creatinine and decreased urine output in renal, deranged LFTs in liver, cardiac failure in heart etc.). Pain and graft oedema
- Screening for rejection routinely: U&Es, urinalysis in kidney, LFTs in liver, PFTs in lung, echo in heart etc
- Gold standard: biopsy with histological findings
- Serological test: identify donor specific antibodies
17
Q
Acute cellular rejection (ACR) vs Acute antibody mediated rejection (AMR) biopsy findings
A
Acute cellular rejection (ACR) biopsy findings: diffuse cellular infiltrate and lack of complement C4d staining. Dense lymphocytic infiltration
Acute antibody mediated rejection (AMR) biopsy findings: Mononuclear cells (lymphocytes/monocytes) infiltration. C4d deposition.
Difference between ACR and AMR: complement is activated in AMR
18
Q
Treatment of cellular rejection (T cell mediated)
A
- No antibodies or complement
- Treated with increased immunosuppression
- High dose puled IV methylprednisolone 500mg daily for 3 doses
- With or without T cell depleting therapy, depending on severity: Anti-thymocyte globulin (ATG)
- Usually responds well to treatment
19
Q
Treatment of antibody mediated rejection
A
- Potent immunosuppression to remove donor specific antibodies (DSA)
- Methylprednisolone IV 500 mg daily for 3 days
- Plasma exchange (plasmapheresis) - to directly remove DSAs
- High dose (immunomodulatory dose) IV immunoglobulin
- Anti-B cell agents: Bortezomib (proteasome inhibitor – depletes plasma cells), or Rituximab (anti-CD20, B cell-depleting agent)
- Other immunosuppression continued as standard
- Infection prophylaxis with antibiotics and anti-virals including co-trimoxazole and valganciclovir
- Responds less well than cellular rejection
20
Q
Chronic transplant rejection features
A
- Occurs 6 months post transplantation- main cause of long term graft loss
- Main features: vascular disease within the graft (transplant vasculopathy)- accelerated atherosclerosis and narrowing of the graft vessel causing fibrosis and ischaemia.
- Driven by chronic inflammation targeting the graft vasculature and non-immune mechanisms (cellular and antibody mediated)
- Calcineurin inhibitor (Tacrolimus, Ciclosporin) toxicity may play a part- drugs used post transplant to prevent rejection
21
Q
Treatment for chronic rejection
A
- Difficult no specific treatment
- Indication for re-transplantation
- Management of complications: heart failure ie heart transplant, Dialysis in renal failure
22
Q
Prevention of transplant rejection
A
- ABO blood group compatibility: for solid organ transplant (preferred but not required for HSCT)
- Histocompatibility: Matching of HLA alleles, particularly DLA-DR, HLA-A and HLA-B. Vary by organ (more important in renal, less with liver)
- Cross matching: Physical or virtual. Checking for donor specific antibodies in the recipients blood
- Immunosuppression: started at time of treatment
23
Q
Transplants: cross matching
A
- Physical cross-match: Preferred, recipient serum mixed with separated donor B and T cells separately: Cytotoxic reaction indicates preformed antibodies (donor-specific antibodies – DSA)
- Virtual cross-match: looking at whether relevant anti-HLA antibodies have been detected previously in recipient’s serum: Multiplex serological assays looking for anti-HLA antibodies
24
Q
Prevention of transplant rejection: induction immunosuppression
A
- Steroid (IV methylprednisolone)
- Calcineurin inhibitor (tacrolimus or ciclosporin): Blocks T cell activation
- Antiproliferative agent (e.g. Mycophenolate mofetil – MMF)
- Other anti-T cell therapies:
- Basilixumab (anti-IL2 mAb, prevents T cell proliferation)
- If high risk also T cell depleting induction therapy with ATG (anti-thymocyte globulin) or alemtuzimab (anti-CD52 mAB- causes cytopaenia). Transiently decreases recipient T cells
25
Q
Prevention of transplant rejection: Maintenance Immunosuppression
A
- Triple drug therapy:
- Corticosteroids (prednisolone)- reducing over months
- Calcineurin inhibitor (Tacrolimus or Ciclosporin)
- Antiproliferative agent: Azathioprine, Mycophenolate mofetil (MMF), Sirolimus (rapamycin)
- Example: Prednisolone, MMF and Tacrolimus
26
Q
Graft versus host disease (GvHD)
A
- Graft contains donor T cells which are foreign to the recipient
- The graft mounts an immune response against the host (to be expected)
- Associated primarily with allogeneic haematopoietic stem cell transplantation (HSCT)
- Can occur: solid organ transplantation (liver, small bowel), blood products
- Graft rejects host (opposite to transplant rejection)
- Dangerous in immunocompromised
27
Q
GvHD mechanism
A
- Activation of host APCs: Damage to host tissue by underlying disease causes cytokine release and stimulation of APCs
- Donor T cell activation: Donor T cells recognize alloantigen (recipient antigens) on both donor and recipient APCs in lymph nodes and differentiate into effector cells
- Cellular and Inflammatory Effector Stage: Activated donor CD8 (cytotoxic) T cells migrate to affected organs and kill host cells causing tissue damage. Release of inflammatory cytokines (e.g , influx of inflammatory cells (e.g. neutrophils) mediating further tissue damage
28
Q
GvHD types
A
- Acute: onset <100 days after transplant. Affects 3 sites skin, liver and gut. Graded from 0-4 based on the 3 sites affected and their combined score. Ranges from none to life threatening
- Chronic: affects variety of organ sites, tend to evolve from acute GvHD
29
Q
Acute GvHD presentation
A
- Skin: Painful or pruritic erythematous macules → Confluent erythema, erythroderma → Subepidermal bullae, vesicles, desquamation
- Liver: Deranged LFTs, Jaundice
- Gut: Abdo pain, Diarrhoea, GI bleeding, Ileus
30
Q
Acute GvHD diagnosis
A
- Biopsy of skin, liver or gut to confirm diagnosis
- Biopsy: shows lymphocyte infiltration
- Organs: symptoms and signs, deranged LFT
31
Q
Chronic GvHD presentation
A
- Skin: Same as acute, atrophy of oral mucoser, sclerodermatous skin changes (skin thickening), joint contractures
- Pulmonary: obstructive lung disease, dyspnoea, wheeze, cough, no response to bronchodilators
- Neuromuscular: weakness, neuropathic pain, muscle cramps
- Ocular: Sicca syndrome, Haemorrhagic conjunctivitis
- Gut: same as acute, also strictures and dysmotility
- Liver: same as acute. Rarely portal HTN, cirrhosis, liver failure
32
Q
GvHD prevention
A
- Donor selection (choose good match)
- Depletion of T cells from donor graft
- Drugs to suppress donor T cells: steroids, ciclosporin, MMF
- Same as prevention of transplant rejection
33
Q
GvHD treatment
A
- Depends on severity
- If mild skin may be only topical steroids
- Systemic steroids and MMF if severe
- Very severe not responsive to high dose steroids - ATG and other T cell targeted therapies (Alemtuzumab) – outlook is poor
- In malignant disease treating mild GvHD must be balanced against potential benefit from graft versus tumour effect. When you have GvHD but with the tumour
34
Q
Allergy
A
An inappropriate damaging immune response to a non harmful substance. Antigens that cause allergy are allergens.
35
Q
Allergy triggers
A
- Food (commonest in children): nuts, fish, shellfish, wheat, milk
- Drugs (commonest in older people): Penicillin, Cephalosporin, anaesthesia. Immediate or delayed. If old penicillin allergy offer testing
- Venom: wasp, bees. Desensitisation therapy can be offered
- Others: latex, contrast media, hair dye
36
Q
Classification of Hypersensitivity reactions
A
- Type 1: Immediate IgE mediated. Examples: anaphylaxis, allergy
- Type 2: Cytotoxic. Caused by Antibody/Complement against the cell surface. Example: Graves, Myasthenia Gravis
- Type 3: Immune complex deposition in tissues causing inflammation. Examples: SLE, RA
- Type 4: Delayed, T cell reaction on non harmful antigens. Examples: Steven Johnson syndrome, Chronic transplant rejection, contact dermatitis
37
Q
Type 1 hypersensitivity
A
- Most allergies
- Immediate reaction, within minutes usually
- IgE antibodies causes release of Histamine from mast cells and basophils
- Three phases: Sensitization (body experiences allergen for first time), Immediate phase reaction, Late phase reaction (6-12 hours after first symptoms)
- Monitor anaphylaxis patients for at least 4-6 hrs after reaction stops in case there is a late phase reaction
38
Q
Type 1 hypersensitivity- Sensitisation:
A
- Allergens enter the blood stream and are picked up by APC and present them to naive T cells.
- The naive T cells develop into T helper cells (with IL4 help).
- They activate B cells which undergo class switching to produce specific IgE antibodies as plasma cells
- IgE antibodies coat the surface of mast cells in tissues and circulation
- Patient is sensitised to the allergen
39
Q
Type 1 hypersensitivity- Immediate phase reaction
A
- Next time the patient encounters the allergen it will bind to >2 of the IgE antibodies on the mast cell causing them to cross link
- This will cause degranulation of the mast cell releasing mediators (histamine and triptase)
40
Q
Effects of histamine release
A
- Bronchoconstriction
- Mucous secretion
- Reduce cardiac contractility
- Increased vascular permeability
- Vasoconstriction: reduce blood to tissues
- Vasodilation: reduced blood to heart
- At contact site: oedema, itching and rash
41
Q
Clinical manifestations of allergy
A
- Respiratory: SOB, tachypnoea, wheeze, stridor, chest tightness, respiratory arrest
- Cardiovascular: tachycardia/bradycardia, palpitation, hypotension, cardiac arrest
- GI: abdo pain, N+V, diarrhoea (can cause shock)
- CNS: feeling of impending doom, headache, altered mental state, confusion, drowsiness
- Skin: urticaria (raised, itchy rash of red and white lesion), angiodema
42
Q
Allergy clinical manifestations classification
A
- Mild Symptoms: Oral symptoms, Urticaria, Angioedema (including facial angioedema).
- Moderate Symptoms: Abdominal pain, Nausea/Vomitting, Mild wheeze, “Lump” in throat, diarrhoea.
- Severe Symptoms or Anaphylaxis: Any compromise of airway, breathing or circulation.
43
Q
Severe symptoms or anaphylaxis clinical manifestations
A
- Can present with tongue swelling which impedes the airway, severe wheeze or oxygen requirements.
- Difficulty speaking or swallowing due to laryngeal oedema or a choking sensation.
- Symptoms of circulatory collapse (dizziness, lightheaded)
44
Q
Treatment for different allergy classifications
A
- Mild: oral antihistamine
- Moderate: oral antihistamine +/- prednisolone. Under observation for symptom progression
45
Q
Type 1 hypersensitivity: Late phase reaction
A
- T helper 2 cells, and the newly recruited eosinophils and basophils secrete pro-inflammatory mediators, cytokines and chemokines in the late phase which can trigger a second reaction (after 6-12 hours).
- Repeat exposure can lead to ongoing local inflammation and structural damage seen in allergic rhinitis and allergic asthma
46
Q
Food allergy
A
- Allergy is an adverse immune mediated response to an allergen
- Hypersensitivity reaction to a normally harmless substance tolerated by others who are not allergic
- A food allergic reaction may present as aversion, refusal and/or phobia
47
Q
Types of adverse food reactions
A
- Immune mediated (allergy and coeliac)
- Non immune mediated (food intolerance)
48
Q
The atopic march progression
A
- Infancy: atopic dermatitis, food allergy
- Allergic rhinitis, allergic asthma
49
Q
Types of allergy
A
- IgE mediated: acute onset. Release of histamine via IgE mechanisms. Urticaria, angiodema
- Non IgE mediated allergy: delayed onset, T cell mediated. Release of histamine via non IgE mechanisms i.e. via mast cells, basophils or Eosinophils. Causes Dysmotility, Eosinophilic Oesophagitis, FPIES
- Mixed IgE and non IgE mediated i.e. Eosinophilic gastroenteritis
- Systemic allergy: when the IgE mediated allergy involves all body system including the upper airway or cardiovascular system. Immediate (Anaphylaxis- circulatory collapse and shock), Delayed (Food protein Induced Enterocolitis (FPIES))
