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year 4 CDM 2 > Case 14: Transplant > Flashcards

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
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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
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3
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HLH

A

A life threatening Immunodeficiency of severe hyperinflammation due to uncontrolled proliferation of activated lymphocytes and histiocytes.

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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

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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.
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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
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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
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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.
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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
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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
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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
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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
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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
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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
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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

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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.
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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
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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

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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
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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
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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
  1. 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
  2. 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))

year 4 CDM 2 (39 decks)

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