Imm - Transplantation

Question 1

Which is the most commonly transplanted organs

Answer 1

1st most common transplanted organs = KIDNEYS (average ½ life of a kidney is 12 years)
2nd most common = LIVER

Question 2

What are the phases of immune response to a transplanted graft

Answer 2

Phase 1: recognition of foreign antigens
Phase 2: activation of antigen specific lymphocytes
Phase 3: effector phase of graft rejection (cells cause injury to graft)

Question 3

Which protein variations are most important for matching in transplantation

Answer 3

1. HLA (Chr 6 by MHC) - DR > B > A
2. ABO groups
3. Others
   (minor histocompatibility genes)

Question 4

What are the two major pathways of rejection and how do you tell between them

Answer 4

T cell or antibody mediated

Can only tell them apart with biopsy (both are acute with raised creatinine/CK)
T cell = responds well to treatment
Antibody - more difficult to treat

Question 5

What are the number of HLA mismatches between family members

Answer 5

Parents/child: ≥3 always matched (all on one chromosome - can’t be <3)
Siblings: 25% 6MM, 50% 3MM, 25% 0MM

Question 6

Describe T-cell mediated transplant rejection

Answer 6

1. Presentation of the foreign HLA in MHC by APCs (BOTH donor and host APCs) in the lymph nodes
2. Co-stimulatory signals → effector phase → inflammation → raised CK
3. Proliferation and activation of CD4/8 → cytokine release (IL-2) → autocrine activation of T cells
4. T cells tether, roll and arrest on the endothelial cell surface → migrates through the interstitium → tubular epithelium attack

Question 7

What are the histological features of T-cell mediated rejection

Answer 7

Lymphocytic interstitial infiltration
Ruptured tubular basement membrane
Tubilitis (inflammatory cells within the tubular epithelium)
Macrophages
Creatinine rise

Question 8

Describe antibody-mediated transplant rejection

Answer 8

1. B cell exposure to foreign antigen
2. Proliferation and maturation of B cells with Ab production
3. Abs bind to HLA on the graft endothelium (capillaries of glomerulus and around the tubules) → INTRA-VASCULAR inflammation
   - Endothelial cell lysis
   - Inflammatory cell recruitment
   - CAPILLARITIS (mononuclear, NK and neutrophils in the capillaries)
4. Pro-coagulation tendencies and closure of the microcirculation → graft fibrosis

Question 9

What is the histology of antibody-mediated transplant rejection

Answer 9

Inflammatory cell infiltrate
Capillaritis (inflammatory cells in the microcirculation – a cardinal feature of antibody mediated rejection) - inflammatory cells seen within the vasculature, not in tubules
Immunohistochemistry: fixation of complement fragments on endothelial cell surfaces

Question 10

How is HLA screened for transplantation

Answer 10

Before, at the time of, and after transplantation

HLA typing via PCR DNA sequencing (esp. for BM and kidney)
Anti-HLA Ab screening:
- Cytotoxicity assay: recipients serum against donor lymphocytes (+ve = cell lysis)
- Flow cytometry: recipients serum binds to donor lymphocytes
- Solid phase assay: recipient serum mixed with beads and labelled to determine with HLA epitopes the Abs bind to (highly sensitised = lots of Abs)

Question 11

How is transplant rejection treated

Answer 11

T cell: steroids (IV 3x then oral) / OKT3/ATG
Antibody-mediated: IVIVg, Plasma exchange, anti-C5, anti-CD20 (Rituximab)

Question 12

What is the immunosuppression regime for transplantation

Answer 12

1. Induction of immnosuppression:
   - Anti-CD52 (alentuzumab)
   - Anti-CD25 (basiliximab)
   - OKT3/ATG
2. Baseline immunsuppresssion:
   - Tacrolimus or ciclosporin
   - Steoirs
   - Azathioprine /mycophenolate mofetil

Question 13

What are the types of time-dependent transplant reactions and what is the histology

Answer 13

Hyperacute = mins-hours (pre-formed Abs) → necrosis, thrombosis
Acute = < 6 months → cellular infiltrates (Cellular), vasculitis and C4 deficiency (Ab)
Chronic = >6 months → fibrosis, glomerulonephropathy, vasculopathy, Bronchiolitis obliterans (BOOP)