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Path - Immuno > Transplant > Flashcards

Transplant Flashcards

1
Q

what are the 4 top most transplanted organs -?

A

Kidney
Liver

Heart
Pancreas

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2
Q

what is an allograft?

A

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

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3
Q

what is the 1/2 life of a kidney?

A

9-14 years

9 - deceased donor
14 - living donor

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4
Q

why dont transplants last generally?

A
  1. immune rejection
  2. pre- and post-transplant patient management and monitoring
    - drugs, T2DM, infections etc
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5
Q

what is the Immune response to transplanted grafts?

A

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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6
Q

what are the Most relevant protein variations in clinical transplantation?

A
  1. HLA (human leukocyte antigens) coded on chromosome 6 by Major Histocompatibility complex (MHC) - most important
  2. ABO blood group
  3. Minor histocompatibility genes
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7
Q

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

A

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

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8
Q

what are the genetiics for HLA?

A

co-dominant - 2 alleles for each

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9
Q

what are the HLA classes?

A

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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10
Q

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

A

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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11
Q

mismatches are what?

A

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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12
Q

in t cell mediated rejection, what are the effectors?

how does it take place ?

A

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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13
Q

how do ct8 t cells kill?

A

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

Perforin
Apoptotic cell death
Fas -Ligand

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14
Q

how are B and Tcell mediated rejection identified?

A

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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15
Q

how does Antibody-mediated rejection occur?

A

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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16
Q

what do the following tell you:

Anti-A or anti-B antibodies

anti-HLA antibodies

A

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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17
Q

how does B cell antibody production occur?

A

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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18
Q

what are the effects of antibodies produced by B cells

A

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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19
Q

what is the membrane attack complex?

A

end of complement cascade - pores form in endothelium of cell

SO THE VESSEL

20
Q

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

A

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

21
Q

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

A

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

22
Q

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

A

Reduce immunosuppression

treat infection

23
Q

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?

A

EBV related lymphoma’s ; Hodgkins and Burkitts

Next steps:
Reduce immunosuppression
Chemotherapy

24
Q

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

A

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

25
Q

Is HLA matching in organ transplantation important always?

A

HLA matching is an important part of organ allocation procedure for:

  1. Bone marrow
  2. Kidney

HLA matching not as important for:
Heart
Lung

26
Q

How is donor and recipient HLA type determined?

A

PCR-based DNA sequence analysis determines the individuals genotype

27
Q

Main cell injured in antibody mediated rejection is _____?

A

is endothelium

28
Q

when do we Screen for antibodies for transplant?

A

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

29
Q

How is Screening for anti-HLA antibodies conducted?

A

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

30
Q

what are the 3 signals of t cell activation?

A

MHC from APC
Co-stimualtion from APC
Interleukin-2

31
Q

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

A

Corticosteroids

Mycophenolate mofetil

Calcineurin inhibitors: Tacrolimus, Cyclosporine

the umab’s - monoclonal antibodies to CD’s expressed on surface of T cells eg CD25

32
Q

what are calcineurin inhibitors?

A

calcineurin is downstream of T cell receptor activation

meaning these drugs work to inhibit immune attacks

33
Q

What is the MOA of Mycophenolate mofetil?

A

Target the cell cycle and nucleotide synthesis

34
Q

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

A

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
35
Q

how does IVIG work?

A

reduces production of antibodies via negative feedback

other mechanisms

36
Q

when are steroids used in the context of transplants?

A

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

37
Q

what are the preferred drugs for baseline immunosuppression?

A

Calcinuerin inhibitors; Tacrolimus, Cyclosporine
+
Mycophenolate mofetil / Azathioprine

38
Q

what is used for treatment of acute episodes of immunosuppresion?

A

DEPENDS IF T OR B cell (determien by biopsy)

if antibody mediated:
IVIG, plasma exhange, anti-CD20, anti-CD5

39
Q

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

A

Skin: rash
Gut: nausea, vomiting, abdominal pain, diarrheoa, bloody stool
Liver: jaundice

GVHD prophylaxis: Methotrexate/Cyclosporine
Treat with corticosteroids

40
Q

what are common Post transplantation infections?

A

Increased risk of Opportunistic infections

Cytomegalovirus
BK virus
Pneumocytis carinii

and other infections too

41
Q

what are common Post transplantation malignancy?

A

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)
42
Q

when might graft vs host disease occur ?

A

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.

43
Q

what is the mechanism behind acute rejection?

which system in the graft is affected most usually?

type of reaction?

A

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

44
Q

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?

A

chronic rejection

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

45
Q

GvHD is what kind of reaction?

A

type 4 hypersensitivity

46
Q

what causes hyperacute rejection?

what kind of reaction?

A

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

Path - Immuno (11 decks)

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