Transplantation

Question 1

Prognosis of orgna transplantations

Answer 1

50% renal lost in 10-12 years
50% lungs at 5 years
Many cases require repeat transplantation - demand>supply

Question 2

What is immune repsonse in organ transplant against

Answer 2

polymorphic HLA gene products incl MHC molecules
AB blood group antigens, minorHC
Antigen specific repsonses directed by lymphocytes
all immune cells play role

Question 3

What does HLA code for

Answer 3

MHC complex
HLa on chromosome 6

Question 4

What genes code for class 1 MHC molecules

Answer 4

HLA-A, B and C
All cells - present atigens to CD8

Question 5

What genes code for class II MHC molecules

Answer 5

HLA-DR, DP, DQ
On APCs present antigen to CD4

Question 6

Stages of transplant refjection

Answer 6

Hyperacute
Acute
Chronic

Question 7

When does hyperacute rejection occur

Answer 7

Minutes to hours after
Pre-exisitng antibody to

Question 8

Acute rejection types and when

Answer 8

Days to weeks
Cellula - T cell mediated or humoral - B cell mediated and T cell

Question 9

What happens in hyperacute rejection

Answer 9

Antibodies rapidly bind to raft antigens targeting blood group and MHC
Activation of complement cascade -> cell lysis MAC and inflammation
Endothelial activation, release of pro-thrombotic substances - platelet aggregation, thrombosis, occlusion of graft microvasculature
Rapid thrombosis and infarction of graft -> death of graft
V rare now due to genetic atching with donor

Question 10

Key step in acute rejeciton

Answer 10

Donor antigens recognition by recipient T cells
Presented on donor ACs or processed and presented by recipient APCs

Question 11

Direct presentation vs indirect acute rejeciton

Answer 11

Direct - Donor APC present anigen to recipient T cells
Indirect - Recipient APCs take up antigens from donor -> recipient cells

Question 12

Mechanism of acute rejection

Answer 12

Donor antigen recognition by recipient T cells
APCs activated expressing co-timulatory molecule eg B7 binds to ligands on T cells ->
effector cells
CD8 - -> tissue damage
CD4 Th 1 cells -> Tissue damage, altered vascular function, ischaemia
CD4 Th2 cells ->B cells activated -> donor specific antibodies -> bind to donor cells, activate complement, endothelial damage and microvasc thrombodiss

Question 13

Presentation acute transplant rejection

Answer 13

Acute deterioration in graft function
Pain in region of graft, graft oedema

Question 14

Investigations for acute graft rejection

Answer 14

Screening for graft function
Differntials of infection, immunosupressant toxicity
Diagnosis w biopsy
Serological tests - Donor specific antibodies

Question 15

Main featires of crhonic rejection

Answer 15

Vascular disease within graft
Fibrosis in graft tissue

Question 16

Pathology of chronic rejection

Answer 16

Chronic inflammation and non immune
Immune is both cellular and humoral
also calcineurin inhibitor toxicity eg ciclosporin, tacrolimus toxicity

Question 17

What cytokines are relased by CD4 Th1 cells

Answer 17

IFN gamma
IL-12

Question 18

Matching receipient to donor for transplant

Answer 18

ABO blood group compatability
Histocompatability - HLA mathcing
Cross matching - test for DSAs in recipient blood.

Question 19

Which HLAs are more importnat to match

Answer 19

esp HL-DR, HLA-A, HLA-B (rest are preferred by not required, vary by organ type)
Complete match is very rare
Renal transplant mathcing v importatn
Liver transplantation may not be required

Question 20

Cross matching testing

Answer 20

Physical cross match - recipient serum mixed w separated donor lymphcytes - B and T cells separately
Cytotoxic reaction = present
Virtual cross match -are relevant anti-HLA antibodies been detected prev in recipietns serum - multiplex serological assays for anti-HLA antibodies

Question 21

Immunosupression psot transplant induction treatment

Answer 21

Combination
Steroid - IV methylprednisolone
Calcineurin inhibitor - tacrolimus or ciclosporin
Antiproliferative agesnt eg mycophenolate mofetil - MMF
Other anti-T cell therapies -
Basilixumab - anti-IL2 mAb, prevents T cell proliferation

Question 22

What do calcineurin inhbitors do

Answer 22

Block T cell activation by TCR path

Question 23

What add if high risk to inuction immunosupression for transplant

Answer 23

If high risk also T cell depleting induction (reduce circulating T cells) therapy w ATG - antithymocyte globulin or alemtuzimab - antiCD52 mAB

Question 24

Long term maintenance immunosuppression

Answer 24

Corticosteroid (gradually reducing dose over first 3 months)
Clacineurin inhibitor - tacrolimus or ciclosporin
Antiproliferative eg azathioprine, mycophenolate mofetil, sirolimus (rapamycin)

Question 25

Treatment for cellular rejection - T cell mediated

Answer 25

Increased immunosupression - high dose IV methylprednisolone 500mg for 3 days With or without T cell depeleting therapy eg ATG Usually responds v well

Question 26

Treating antibody mediated acute rejection

Answer 26

Potent immunosupression and treatment to remove or supress DSAs eg methylpred, plasmapharesis to directly remove High dose IVIG (dmapends immune repsonse) Anti B cell agents Other immunospurpression cont as standard Infection prophylaxis incl co-trimoxazole and valganciclovir

Question 27

Anti B cell agents

Answer 27

Bortezomib - proteasome inhibitor - depletes plasma cells Rituximab - anti CD20 B cell monoclonal antibody

Question 28

Chronic rejection treatent

Answer 28

Manage complications eg HF treat, dialusis End stage -> indication for re-transplantation

Question 29

What is graft vs host disease

Answer 29

T cells in donor organ reconise recipient as oreign -> immune response against host

Question 30

What is GvHD primarily ass w

Answer 30

Allogenic haematopoietic stem cell transplantation Solid organ transplants esp liver and small bowel Transfusion of irradiated blood products in immunocomp

Question 31

Stages of GvHD

Answer 31

Activation of recipient APCs (by cytokines and underlying disease) Donor T cell activation - recognise recipient antigen on donor and recipient APCs Cellular and inflammatory effector stage - activated donor CD8 - kill host cells. Inflam cytokines release attract inflam cells -> further tissue damage

Question 32

Types of GvHD and when occur

Answer 32

acute - <100 dyas after transplant Chronic ->100 days

Question 33

Acute GvHD where effected

Answer 33

skin, liver, gut

Question 34

Chronic GvHD features

Answer 34

Most originate as acute 20% de novo 10% after acute GvHD resolved Various sites

Question 35

Features of skin GvHD

Answer 35

Painful or pruritic erythematous macules Confluent erythema, erythroderma Subepidermal bullae, vesicles, desquamation

Question 36

Liver acute GvHD

Answer 36

Deranged LFTs Jaundice

Question 37

Bowel acute GvHD

Answer 37

Abdo pain, diarrhoea, GI bleeding, ileus, small bowel obstruction

Question 38

Staging of acute GvHD

Answer 38

Grades I-IV Considers affect on skin, bowel, lvier IV - life threatening Depends on function of affected areas

Question 39

Diagnosis of GvHD

Answer 39

Clinical evidence of related dysfunction - symtpoms and signs, deranged LFTs Biopsy of skin, liver or gut - inflammatory infiltrate

Question 40

Features of chronic GvHD

Answer 40

Skin - same as acute Pulmonary - Obsteuctive, dyspnoea, wheeze, cough, non response to bronchdilators NM - weakness, neuropathic pain, muscle cramps Ocular - sicca syndrome, haemorrhagic conjunctivitis Gut - similar to acute Liver - same as acute GvHD. Rare - portal H[TN, cirrhosis, liver failrue

Question 41

Prevention of GvHD

Answer 41

Donor selection Depeltion of T cells from donor graft Drugs to supress donor T cells - steroids, ciclosporin, MMF

Question 42

Treating GvHD

Answer 42

Depends on severiyy Mild skin - topical steroids Systemic steroids and MMF if more severe V severe = ATG and other T cell targeted therapies - poor outlook May be beneficial in malignant disease - balance

Question 43

What needs to be tested pre transplantation

Answer 43

HLA typing ABO blood group Anti-HLA antibodies serology Hep BsAg,sAb, HIV, hep C Ab, CMV IgG +IgM

Question 44

What physical cross match result is an absolute contraindication to transplant

Answer 44

T cell crossmatch - activation of T cells -> cell lysis when recipient and host mixed B cell not complete contraindiactino