Transplant Flashcards by RK Splendid

what are the 4 top most transplanted organs -?

Kidney
Liver

Heart
Pancreas

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what is an allograft?

transfer of on organ between 2 individuals of the same species eg human

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what is the 1/2 life of a kidney?

9-14 years

9 - deceased donor
14 - living donor

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why dont transplants last generally?

immune rejection
pre- and post-transplant patient management and monitoring
- drugs, T2DM, infections etc

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what is the Immune response to transplanted grafts?

3 phases:

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

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what are the Most relevant protein variations in clinical transplantation?

HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC) - most important
ABO blood group
Minor histocompatibility genes

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what is the role of HLA (human leukocyte antigens)?

Presentation of foreign antigens on HLA molecules to T cells is central to T cell activation

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what are the genetiics for HLA?

co-dominant - 2 alleles for each

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what are the HLA classes?

HLA Class I (A,B,C)– expressed on all cells

HLA Class II (DR, DQ, DP) – expressed on antigen-presenting cells but also can be upregulated on other cells under stress

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what are the structures of MHC class 1 and class 2?

Class 1
has an alpha chain and b globulin

Class 2:
has alpha chain and b chain.

The binding grooves are the most variable.

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mismatches are what?

the number of HLAs that the donor and recipient DO NOT have in common;

measured from HLA-A,B,DR
1:1:0 : the order is A-B-DR

most mismatches you can have is 6

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in t cell mediated rejection, what are the effectors?

how does it take place ?

The main effector cells here are T cells and macrophages.

HLA on donated tissue is presented to T cell, and is recognised by t cell hla.

t cell is then activated, via 3 signals

Graft infiltration by alloreactive CD4+ cells

 Proliferation
 Produce cytokines
 Provide help to activate CD8+ cells
 Provide help for B cell antibody production
 Recruit phagocytic cells

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how do ct8 t cells kill?

Release of toxins to kill target
Granzyme B
Punch holes in target cells

Perforin
Apoptotic cell death
Fas -Ligand

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how are B and Tcell mediated rejection identified?

Both: biopsy of the graft

T cell:
will see t cell infiltration; tubilitis, arthritis, interstitial inflammation

B cell:
Inflammatory cells will be in capillaries (inside ethe tubules and glomerulus)
Capillaries have complement fragments on surface

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how does Antibody-mediated rejection occur?

Phase 1 – exposure to foreign antigen
Phase 2 - proliferation and maturation of B cells with antibody production
Phase 3 – effector phase; antibodies bind to graft endothelium (capillaries of glomerulus and around tubules, arterial) -

so endothelium is what is injured

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what do the following tell you:

Anti-A or anti-B antibodies

anti-HLA antibodies

Anti-A or anti-B antibodies are naturally occurring

anti-HLA antibodies :
are not naturally occurring
Pre-formed – previous exposure to epitopes (previous transplantation, pregnancy, transfusion)
Post-formed - arise after transplantation

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how does B cell antibody production occur?

bone marrow makes early B cells

b2 cells goes to lymph node and is activated by CD4 helper T cell

undergoes affinity maturation - onee with best affinity for antigen selected

released

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what are the effects of antibodies produced by B cells

Antibody mediated injury:

opsonisation of cells -> neutralise toxins
recruitment of inflammatory cells eg NK cells

Complemented mediated injury
- antibody activates complement which then goes and does its thing …. pores form in endothelium of cell

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what is the membrane attack complex?

end of complement cascade - pores form in endothelium of cell

SO THE VESSEL

what is the difference between ABO and HLA in terms of antibodies?

wiith ABO, we havee naturally occuring antibodies to whichever antigen we dont have

with HLA, there must have been previous exposure to get antibody formation

without doing biopsy, how do you know there is rejection going on?

graft dysfunction (e.g. raised creatinine, raised LFT etc)

a patient who has recently had a transplant is experincing viral infections. what is the next course of action?

Reduce immunosuppression

treat infection

a patient who has recently had a transplant is experiencing sx suggestive of lymphoma. what could be the reason and what is the next course of action?

EBV related lymphoma’s ; Hodgkins and Burkitts

Next steps:
Reduce immunosuppression
Chemotherapy

what are the principles of Prevention and treatment of graft rejection?

Preventing rejection:
A. AB/HLA matching
B. Screening for anti-HLA antibodies
C. Immunosuppression: dampen the immune system of the recipient

Treating rejection:
Corticosteroids!
More immunosuppression

Is HLA matching in organ transplantation important always?

HLA matching is an important part of organ allocation procedure for: 1. Bone marrow 2. Kidney HLA matching not as important for: Heart Lung

How is donor and recipient HLA type determined?

PCR-based DNA sequence analysis determines the individuals genotype

Main cell injured in antibody mediated rejection is _____?

is endothelium

when do we Screen for antibodies for transplant?

Before transplantation At time of transplantation: when a specific deceased donor kidney has been assigned to the patient After transplantation, repeat measurements to check for new antibody production

How is Screening for anti-HLA antibodies conducted?

Cytotoxicity assays - does the recipient serum kill the donor’s lymphocytes in the presence of complement - uses dyes which turns orange if positive crossmatch Flow cytometry - does the recipient’s serum have antibodies that bind to the donor’s lymphocytes - uses flouresence antibodies thaty bind to antibodies if present. produces peak on the right of the graph if present Solid phase assays

what are the 3 signals of t cell activation?

MHC from APC Co-stimualtion from APC Interleukin-2

what are some drugs that can be used to prevent T-cell mediated rejection ?

Corticosteroids Mycophenolate mofetil Calcineurin inhibitors: Tacrolimus, Cyclosporine the umab's - monoclonal antibodies to CD's expressed on surface of T cells eg CD25

what are calcineurin inhibitors?

calcineurin is downstream of T cell receptor activation meaning these drugs work to inhibit immune attacks

What is the MOA of Mycophenolate mofetil?

Target the cell cycle and nucleotide synthesis

what are some drugs that can be used to prevent B-cell mediated rejection ?

Whole different set of drugs: 1. Anti-CD20 - Rituximab (deplete B cells) 2. Proteosome inhibitors - kill plasma cells 3. Complement inhibitors 4. Plamsa exhange - remove antibodies * 5. IVIG * 6. BAFF inhibitors 7. Anti-CD40 etc - stop T cell mediated B cell activation * these are what are really used in clinical practice

how does IVIG work?

reduces production of antibodies via negative feedback other mechanisms

when are steroids used in the context of transplants?

for treatment of acute episodes of immunosuppresion - in T cell mediated rejection - rather than as baseline immunosuppression even though it can be used so

what are the preferred drugs for baseline immunosuppression?

Calcinuerin inhibitors; Tacrolimus, Cyclosporine + Mycophenolate mofetil / Azathioprine

what is used for treatment of acute episodes of immunosuppresion?

DEPENDS IF T OR B cell (determien by biopsy) if antibody mediated: IVIG, plasma exhange, anti-CD20, anti-CD5

how many graft vs host disease present and what is the therapy?

Skin: rash Gut: nausea, vomiting, abdominal pain, diarrheoa, bloody stool Liver: jaundice GVHD prophylaxis: Methotrexate/Cyclosporine Treat with corticosteroids

what are common Post transplantation infections?

Increased risk of Opportunistic infections Cytomegalovirus BK virus Pneumocytis carinii and other infections too

what are common Post transplantation malignancy?

Viral associated (x 100): - Kaposi’s sarcoma (HHV8) - Lymphoproliferative disease (EBV) ``` Skin Cancer (x20) Risk of other cancers eg lung, colon also increased (x 2-3) ```

when might graft vs host disease occur ?

after an allogeneic transplant. In GvHD, the donated bone marrow or peripheral blood stem cells view the recipient’s body as foreign, and the donated cells/bone marrow attack the body.

what is the mechanism behind acute rejection? which system in the graft is affected most usually? type of reaction?

graft expresses antigens that are foreign in the host resulting in an immune response Triggers T cell mediaited response against foreign MHC They get leukocyte infiltration of graft vessels -> vessels often hit/targetted first reaction: type 4 hypersensitivity

Triggers T cell mediaited response against foreign MHC resulting in intimal thickening and fibrosis of graft vessels is seen in what? timeframe? type of reaction?

chronic rejection timeframe: months - years reaction: type 3&4 hypersensitivity

GvHD is what kind of reaction?

type 4 hypersensitivity

what causes hyperacute rejection? what kind of reaction?

ABO blood type mismatch Preformed antibodies conduct attack manifests as thombi and occlusion type 2 hypersensitivity - as its antibody mediated occurs immediately eg even during surgery