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YR5 Immunology > Transplantation > Flashcards

Transplantation Flashcards

1
Q

What is an allograft?

A

Transplant of an organ, tissue, or cells from one individual to another individual of the same species who is not an identical twin.

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2
Q

Which parts of the body can be transplanted in an allograft?

A

Solid organs: Kidney, liver, heart, lung, pancreas

Small bowel

Free cells: BM stem cells, pancreas islets

Temporary: Blood, skin (burns)

Privileged sites: Cornea

Framework: Bone, cartilage, tendons, nerves

Composite: Hands, face

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3
Q

How can transplant outcomes be improved?

A

Patient survival + graft survival

Improved surgical technique

Improved pre- + post-transplant patient management: Drug levels, Infections, cardiovascular disease, diabetes

Better understanding of transplant immunology: Prevention, dx + tx of graft rejection

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4
Q

What are the different stages of immune response to a transplanted graft?

A

Phase 1: Recognition of foreign antigens.

Phase 2: Activation of antigen-specific lymphocytes.

Phase 3: Effector phase- all cells that will cause injury to graft have coordinated recruitment

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5
Q

What are the relevant protein variations in clinical transplantation?

A

HLA (human leukocyte antigens).

ABO blood group (for ABO-incompatible transplantation)

Others: minor histocompatibility genes.

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6
Q

What is the immunology of transplantation?

A

The immune system recognises someone else’s organ as foreign.

2 major components to rejection (may occur simultaneously):

  • T cell-mediated rejection
  • Antibody-mediated rejection (B cells)
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7
Q

What is HLA?

A

Major Histocompatibility complex (MHC) (chr 6).

Discovered after 1st attempts at transplantation (animal models + humans).

Cell surface proteins.

  • 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 up-regulated on other cells under stress.

Both have peptide binding groove to present antigen

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8
Q

What is special about HLA?

A

Highly polymorphic: 100s of alleles for each locus (e.g. A1, A2, A3–A372…).

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

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9
Q

How does HLA contribute to infections and neoplasia?

A

To maximise diversity in defense against infections/ neoplasia, each individual has a variety of HLA.

Each individual’s HLA are derived from a large pool of population varieties.

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10
Q

How does HLA affect transplantation?

A

The variability in HLA in the population provides a source for immunisation against the transplanted organ.

“Mismatches”

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11
Q

What is the nomenclature for HLA mismatches?

A

Work out number of mismatches based on differences

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12
Q

What is the relationship between HLA mismatches and transplant outcome?

A

Minimising HLA differences between donor + recipient improves transplant outcome.

The more mismatches, the worse the graft outcome

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13
Q

How is tissue typing (determining HLA in individuals) conducted?

A

PCR-based DNA sequence analysis for HLA alleles determines the individuals genotype

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14
Q

What is T cell mediated rejection?

A

Phase 1: Presentation of donor HLA by a professional antigen presenting cell (APC), in the context of recipient HLA.

Phase 2: T-cell activation, inflammatory cell recruitment.

Phase 3: Effector phase (organ damage).

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15
Q

Explain T cell activation.

A

Proliferation

Production of cytokines (IL-2, IL-15)- autocrine effect increasing activation

Activation of CD4 helper + CD8 cytotoxic T cells

Help for antibody production by B cells

Recruit monocytes/macrophages

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16
Q

What cells are involved in the effector phase of T cell mediated rejection?

A

Cause inflammation in interstitium

“Cytotoxic” T cells:

  • Release of toxins to kill target: Granzyme B
  • Punch holes in target cells: Perforin
  • Apoptotic cell death: Fas -Ligand

Monocyte/macrophages:

  • Phagocytosis
  • Release of proteolytic enzymes
  • Production of cytokines
  • Production of oxygen radicals + nitrogen radicals
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17
Q

What can result from T cell mediated rejection?

A

Interstitial inflammation + tubulitis

Arteritis

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18
Q

What drugs can be used to manage T cell mediated rejection?

A

Target T cell activation pathway

Corticosteroids: anti proliferative

Daclizumab: Anti-CD25 monoclonal antibody

Mycophenolate mofetil: MPA inhibitor

Alemtuzumab: Anti-CD52 monoclonal antibody

OKT3, ATG: Anti-CD3 monoclonal antibody

Calcineurin inhibitors: Cyclosporine, tacrolimus

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19
Q

What are the phases of antibody mediated rejection?

A

Phase 1: B cells recognise foreign HLA.

Phase 2: Proliferation + maturation of B cells with anti-HLA antibody production.

Phase 3: Effector phase; antibodies bind to graft endothelium: intra-vascular disease.

20
Q

How are anti-HLA antibodies formed?

A

Anti-HLA antibodies are not naturally occurring.

  • Pre-formed: Transplantation, pregnancy, transfusion.
  • Post-formed: Arise after transplantation.

Other antibodies:

  • Anti-A or anti-B antibodies (naturally occurring)
  • Non HLA antibodies
21
Q

What are ABO blood groups?

A

A + B glycoproteins on RBCs but also endothelial lining of blood vessels in transplanted organ.

Naturally occurring anti-A + anti-B antibodies.

22
Q

When is screening for anti-HLA antibodies conducted?

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.

23
Q

What are three types of assay to test for anti-HLA antibodies?

A

Cytotoxicity assays

Flow cytometry

Solid phase assays

24
Q

What is being tested for in a cytotoxic crossmatch?

A

does the recipient serum kill the donor’s lymphocytes in the presence of complement? – detection of cell death using vital dyes.

25
Q

What is being tested for in flow cytometry?

A

Does the recipient’s serum bind to the donor’s lymphocytes (bound antibody detected by fluorescently-labelled anti-human Ig)?

26
Q

What is being tested for in solid phase assays?

A

Does the recipient’s serum bind to recombinant single HLA molecules attached to a solid support such as beads (bound antibody detected by fluorescently-labelled anti-human Ig)?

27
Q

How can antibody mediated rejection be managed?

A

Remove antibodies with plasma exchange

Intravenous Ig

B cell depletion: Rituximab

Complement inhibitors

28
Q

How is rejection detected?

A

Monitor transplant function (creatinine) + screen for antibodies.

If creatinine goes up: take a biopsy to confirm and classify rejection.

29
Q

What does this show?

A

Drug toxicity

Calcineurin inhibitors at high doses can cause tubular injury

Decrease immunosuppressive drug

May present with rise in creatinine

30
Q

What does this show?

A

Viral infections

Opportunistic infections related to baseline immunosuppression

Decrease immunosuppressive drug

BK nephropathy is a frequent complication

31
Q

What does this show?

A

Vascular disease

BP control + Vascular stent

32
Q

What does this show?

A

Post-transplant Lymphoproliferative Disease

Reduce immunosuppressive drug

Chemotherapy

33
Q

What does this show?

A

Recent glomerulonephritis

34
Q

What is the most important antigenic determinant of rejection in a patient for kidney transplantation?

A

HLA/ MHC

35
Q

Why is ABO blood group now much less a concern for rejection?

A

Techniques can remove naturally occurring antibodies before + after transplantation

36
Q

Why are previous mismatches recorded in a transplant recipient patient?

A

If seen foreign HLA before, will have memory cells which can be rapidly + vigorously activated if exposed again

37
Q

Describe antigen presentation in organ transplantation

A

Both host + donor APCs can present antigens to T cells

APCs circulate in secondary lymphoid organs with HLA molecules they have picked up from the transplanted organ

Naive + memory T cells also circulate there

If appropriate match occurs- T cell activation

T cells recirculate to graft for effector phase

38
Q

Describe the effector phase of antibody mediated rejection

A

Intravascular

Antibodies fix onto HLA molecule on endothelial surface, leads to complement activation, creation of holes in endothelium, coagulation, necrosis

Recruitment of mononuclear + NK cells

39
Q

What is a defining histological feature of antibody mediated rejection?

A

Glomerulitis

Capillaries stuffed with inflammatory cells + swollen endothelial cells that are damaged

40
Q

Which type of rejection has greater impact on organ function acutely?

A

Both present with rise in creatinine

T cell: tubular-interstitial infiltrate causes tubular dysfunction

Antibody: cells in glomerulus clog glomerulus- reduce GFR

Need biopsy to determine T cell, antibody or combination

41
Q

Which type of rejection has greater impact on organ function in the long term?

A

T cell: responds quite well to therapy, creatinine returns to normal

Antibody: hard to treat, often doesn’t completely go away, a/w slow degradation

42
Q

What footprint signature of antibody mediated rejection is sometimes identifiable with a stain?

A

Complement activation on endothelial cell surface with stain for C4d

43
Q

Describe the antibodies and antigens present in each blood group

A

A: A antigen + Anti-B antibody in plasma

B: B antigen + Anti-A antibody in plasma

AB: A+B antigens, no antibodies

O: No antigens, anti-A + anti-B antibodies in plasma

44
Q

What can be given prior to transplant to reduce risk of rejection?

A

Induction agent

Stronger agent of immunosuppression

T cell depleting e.g. OKT3/ATG or anti-CD52

Cytokine blocking agent e.g. anti-CD25

45
Q

What should be monitored in a patient post kidney transplant?

A

Creatinine + screen for antibody development

If creatine rises or antibodies detected- biopsy

46
Q

A patient has an episode of acute T cell mediated rejection 2 months post transplantation. What additional drug would most commonly be administered?

A

Methylprednisolone on 3 consecutive days

47
Q

Which is the main cell that is injured in the effector phase of antibody mediated rejection?

A

Endothelial cell

YR5 Immunology (14 decks)

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