Immuno: Transplantation

Question 1

Which organ is most commonly transplanted?

Answer 1

• Kidneys
• Followed by Liver

Question 2

What is the average half-life of a transplanted kidney?

Answer 2

12 years

Question 3

What are the three phases of an immune response to a graft?

Answer 3

• Phase 1: recognition of foreign antigens
• Phase 2: activation of antigen-specific lymphocytes
• Phase 3: effect phase of graft rejection

Question 4

What are the most relevant cellular proteins that can determine compatibility?

Answer 4

ABO

HLA

Question 5

Which chromosome is HLA encoded on?

Answer 5

Chromosome 6

Question 6

What are the two major components of rejection?

Answer 6

• T cell-mediated rejection
• Antibody-mediated rejection

Question 7

Describe the basic structure of HLA Class I and Class II.

Answer 7

• Class I: have three alpha domains and a beta-2 microglobulin domain, has one transmembrane domain
• Class II: has two alpha and two beta domains, had two transmembrane domains

Question 8

Which alleles encode HLA Class I and Class II?

Answer 8

• Class I: A, B and C
• Class II: DP, DQ, DR

Question 9

Where are HLA Class I and Class II expressed?

Answer 9

• Class I: all cells
• Class II: antigen-presenting cells (can be upregulated at times of stress)

Question 10

What is the benefit of having high variability in the peptide-binding groove of MHC?

Answer 10

Can present a wide variety of antigens

Question 11

What is the disadvantage of the variability in the peptide-binding groove of MHC with regards to transplants?

Answer 11

This means that the host immune system can react with the slightly different MHC of the donor leading to rejection.

Question 12

Which HLA alleles are most immunogenic?

Answer 12

A, B and DR

Question 13

Where do the antigen-presenting cells that interact with host T cells come from?

Answer 13

From the recipient and the donor (the donor organ will contain many APCs)

NOTE: a lot of these interactions will happen in lymph nodes

Question 14

Which test is used to give a definitive diagnosis of graft rejection?

Answer 14

Biopsy

Question 15

Describe the effector phase of T-cell mediated graft rejection.

Answer 15

• T cells tether, roll and arrest on the endothelial cell surface
• They will migrate across into the interstitium and start attacking the tubular epithelium
• Macrophages (recruited by T cells) may also be seen in the interstitium

Question 16

What are the typical histological features of T-cell mediated rejection?

Answer 16

• Lymphocytic interstitial infiltration
• Ruptured tubular basement membrane
• Tubulitis (inflammatory cells within the tubular epithelium)

Question 17

What other explanation might there be for graft failure other than rejection?

Answer 17

Immunosuppressive drugs may be nephrotoxic

Question 18

What are the three phases of antibody-mediated rejection?

Answer 18

• Phase 1: eposure to foreign antigen
• Phase 2: proliferation and maturation of B cells with antibody production
• Phase 3: effector phase - antibodies bind to graft endothelium

Question 19

What is a key difference between the production of anti-AB and anti-HLA antibodies?

Answer 19

• Anti-AB antibodies are naturally occuring (pre-formed)
• Anti-HLA antibodies are not naturally occuring but can be pre-formed due to previous exposure to epitopes (e.g. previous transplant, pregnancy) or post-formed (after transplantation)

Question 20

Outline the pathophysiology of antibody-mediated transplant rejection.

Answer 20

• Antibodies bind to HLA on the endothelium of blood vessels within the transplanted organ
• The antibodies fix complement which leads to formation of MAC and endothelial cell lysis
• Binding of complement also recruits inflammatory cells
• This leads to inflammation of the microcirculation (capillaritis)
• This leads to procoagulant tendencies and closure of the microcirculation leading to graft fibrosis
• Antibodies can also cross-link MHC molecules and activate them

Question 21

What are the main histological features of antibody-mediated transplant rejection?

Answer 21

• Presence of inflammatory cells within the capillaries of the graft (HALLMARK)
• Immunohistochemistry can show fixation of complement fragments on the endothelial cell surface

Question 22

What are the three main approaches to preventing graft rejection?

Answer 22

• AB/HLA typing
• Screening for antibodies
• Overcoming organ mismatch tissues

Question 23

Which technology is used for AB/HLA typing?

Answer 23

DNA sequencing using PCR

Question 24

At what stages of transplantation will screening for antibodies be performed?

Answer 24

• Before transplantation
• At the time of transplant (once an organ has been assigned)
• After transplantation (check for new antibody formation)

Question 25

Name and describe three assays for anti-HLA antibodies.

Answer 25

* **Cytotoxic Assays:** tests whether patient serum binds donor lymphocytes in the presence of complement * **Flow Cytometry:** tests whether patient serum binds donor lymphocytes irrespective of complement * **Solid Phase Assays:** beads containing all the possible HLA epitopes are mixed with the patient's serum. This determines which HLA types the patient has antibodies against. Having many antibodies against different HLA epitopes suggests that the patient is highly sensitised.

Question 26

How can organ mismatch issues be overcome?

Answer 26

* Improve transplantation across tissue barriers * More donors * Organ exchange programmes * Xenotransplantation and stem cell research

Question 27

What T cell pathway is the main target for immunosuppressive drugs used in transplants?

Answer 27

* The main signal is between MHC and TCR * Downstream, there are a number of pathways that involve calcineurin which result in cell proliferation * Once activated, T cells will release IL2 which has autocrine and paracine effects on Th2 cells * These are all targets for immunosuppression

Question 28

Name two calcineurin inhibitors.

Answer 28

Tacrolimus Ciclosporin

Question 29

Name two cell cycle inhibitors

Answer 29

Mycofenolate mofetil Azathioprine

Question 30

Name two drugs that target TCR.

Answer 30

Anti-CD3 antibody (OKT3) Anti-thymocyte globulin

Question 31

Name an anti-CD52 antibody and state its effect.

Answer 31

Alemtuzumab - causes lysis of T cells

Question 32

Name an anti-CD25 antibody and state its effect.

Answer 32

Daclizumab - targets cytokine signalling

Question 33

What are the main immunosuppressive targets of B-cell mediated graft rejection?

Answer 33

* B cell activation * Secretion of antibodies by plasma cells * Effects of antibodies on endothelium

Question 34

What is rituximab?

Answer 34

Anti-CD20 - causes depletion of B cells

Question 35

How do BAFF inhibitors work?

Answer 35

Target cytokines (BAFF) that promotes B cell activation and growth

Question 36

Name a proteasome inhibitor and describe how it works.

Answer 36

* Bortezomib * Blocks the production of antibodies by plasma cells

Question 37

Name a complement inhibitor.

Answer 37

Eculizumab

Question 38

Outline the components of modern transplant immunosuppression regimes.

Answer 38

* Induction agent (e.g. OKT3, anti-CD52, anti-CD25) * Baseline immunosuppression (e.g. calcineurin inhibitor, mycofenolate mofetil, azathioprine, steroids) * Treatment of acute rejection * Cellular: steroids, OKT3 * Antibody-mediated: IVIG, plasma exchange, anti-CD20

Question 39

Briefly describe the pathophysiology of graft-versus-host-dsiease.

Answer 39

* During SCT, the host immune system is eradicated and replaced by autologous or allogeneic bone marrow * In allogeneic stem cell transplant, the donor lymphocytes can react with host tissues NOTE: if there is a malignancy, the graft can kill these cells

Question 40

How can GVHD be prevented?

Answer 40

* Methotrexate/ciclosporin

Question 41

List some symptoms of GVHD.

Answer 41

* Rash * Nausea and vomiting * Abdominal pain * Diarrhoea/bloody stools * Jaundice

Question 42

List some opportunistic infections that are more common in transplant recipients.

Answer 42

* CMV * BK virus * PCP

Question 43

List some malignancies that are more common in transplant recipients.

Answer 43

* Kaposi sarcoma (HHV8) * Lymphoproliferative disease (EBV) * Skin cancer