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MBBS II HIS > L14 - Transplantation immunology > Flashcards

L14 - Transplantation immunology Flashcards

1
Q

Define the 4 types of transplantation?

A

Autograft: from one part of the body to another

Isograft: between genetically identical individuals

Allograft: between members of the same species

Xenograft: between members of different species

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2
Q

Define the HLA gene locus and what it codes for?

A

chromosome 6 short arm

HLA-A, -B and -C region genes&raquo_space; MHC -I molecules, present on all nucleated cells

HLA-D region genes (HLA-DP, -DQ and -DR subregions) &raquo_space; MHC-II, present on antigen presenting cells

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3
Q

How does HLA type relate to transplant survival?

A

Well matched HLA predicts better transplant survival

less so for solid organ transplant e.g. liver

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4
Q

Define the cytokines needed for Th to trigger B and CD8 T cell response?

A

APC&raquo_space; activate Th:

1) IL-2,4,5 to stimulate Ab production in B cells&raquo_space; ADCC
2) IL-2, IFN -γ to CD8+ CTL for cytotoxic activation&raquo_space; Cell-mediated cytotoxicity

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5
Q

Which types of immunity mediate allograft rejection?

A

Cell-mediated Immunity （T cells）
Humoral Immunity （B cells）
NK cells

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6
Q

Describe the selection of T cells in thymus?

A

Thymus cortex:
Positive selection of cells whose receptor binds MHC molecules

Thymus medulla:
Negative selection and death of cells with high-affinity receptors for self-MHC

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7
Q

List the 2 signals for T cell activation?

A

MHC-peptide bind to TCR = signal 1

Co-stimulator = signal 2

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8
Q

Describe the difference in location, functions, CD, and MHC expression between immature and mature dendritic cells?

A

Immature DC:

  • Blood stream
  • Phagocytosis to capture Ag
  • Low CD40, 80, 86
  • High intracellular MHC-II

Mature DC:

  • Lymph nodes
  • Present antigen, non-phagocytotic
  • High CD40,80,86
  • High surface MHC-II
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9
Q

What is meant by MHC restricted?

A

Antigen recognition by TCR is MHC restricted: need self MHC to present a foreign peptide for T cell to be able to recognize

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10
Q

Describe the 2 pathways for alloantigen presentation?

A
  1. Direct: donor APC presents donor MHC/peptide to TCR of recipient T cells
  2. Indirect (major): recipient APC presents self MHC II/non-self peptide (donor antigen) to TCR of recipient T cells
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11
Q

List 2 major co-stimulation pathways for T cell activation?

A

B7(APC) - CD28/CTLA4 (T cells)

CD40 (B cells) -CD40L (T cells)

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12
Q

Describe the effects of B7- CD28 signalling exam

A

 Robust T cell expansion
 Maximal cytokines
 Respond to low antigen concentration
 Sustained response

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13
Q

Describe the effects of B7- CTLA4 signalling

A
  1. Blocks IL-2 receptor expression, suppresses IL-2 production, arrests cell cycle
  2. Much higher affinity to B7 than CD28&raquo_space; dominantly inhibits both TCR- and CD28-mediated pathways

> > Anergy/ apoptosis

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14
Q

List the 4 diff. rates of tissue rejection after transplantation? Define the speed of rejection?

A 
Hyperacute  rejection (7mins)
Xenograft  rejection (7min)
Acute  rejection (8-11 days) 
Chronic  rejection (3m to 10y)
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15
Q

Which tempo of tissue rejection is the most common?

A

Acute rejection

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16
Q

Describe the mechanism of hyperacute rejection of transplanted organ?

A

Pre-existing antibodies*** to donor tissue bind to graft endothelium

> > activate complement**

> > microhemorrhages, rapid thrombotic occlusion of vessels **

17
Q

Which type of transplant commonly results in hyperacute rejection?

A

ABO incompatibility & xenotransplantation

18
Q

Describe the mechanism of acute rejection of transplanted organ?

A

CD4-controlled, CD8 mediated cytotoxicity (Major)
+
CCTL-mediated lysis, macrophage-mediated lysis (DTH), NK-mediated lysis

> > Necrosis of parenchymal cells + lymphocyte, macrophage infiltration

19
Q

Describe the mechanism of chronic rejection of transplanted organ?

A

Mixed CD4 and antibody mediated

> > “Delayed type hypersensitivity (DTH)-like”

> > Can be Antigen-dependent or -independent

20
Q

Histological features of chronically rejected organs?

A

 Perivascular inflammation (macrophages)
 Fibrosis
 Arteriosclerosis (smooth muscle cells)

21
Q

List 3 laboratory tests for tissue matching?

A

(a) ABO antigens testing
(b) Lymphocytotoxicity test
(c) Molecular HLA-typing by PCR

22
Q

Purpose of ABO antigen testing?

A

ABO antigens are present on RBC and vascular endothelium of the graft.

> > prevents hyperacute rejection

23
Q

Purpose of Lymphocytotoxicity test?

A

serological detection of MHC class I and class II for both recipient and donor

24
Q

Purpose of Molecular HLA-typing?

A

PCR test of genomic HLA in donors and recipient

Important in bone marrow transplantation

25
Q

HLA mismatch is tolerable in bone marrow and solid organ transplant. T or F?

A

False

may accept HLA mismatch in solid organ transplantation

can’t accept in bone marrow transplantation

26
Q

List 3 drugs for non-specific immunosuppresion after transplant?

A
  • Cyclosporin A (CsA)
  • FK506 (Tacrolimus)
  • Monoclonal antibodies against lymphocyte surface molecules e.g. Rituximab
27
Q

MoA of cyclosporin A? ADR?

A

Binds to inhibit calcineurin&raquo_space; inhibit NFAT&raquo_space; inhibit IL-2 transcription**&raquo_space; No T cell expansion

Renal damage + narrow therapeutic window

28
Q

MoA of FK506 (tacrolimus) ?

A

binds to FKBP&raquo_space; inhibits calcineurin&raquo_space; inhibit NFAT&raquo_space; inhibit IL-2 transcription *****

100X more potent than CsA

29
Q

Which non-specific immunosuppressant is used commonly?

A

FK506(tacrolimus)

30
Q

MoA of Monoclonal antibodies against lymphocyte surface molecules?

A

Blockage of:
CD3,4,8, IL-2 receptor …etc

> > Eliminate cells / block lymphocyte function

31
Q

3 ADR of long term immunosuppression?

A

Risk of opportunistic infections

Risk of malignancy e.g. lymphoma, PTLD (post-transplant lymphoproliferative disease)

Pharmacological side-effects

32
Q

Pathogenesis of PTLD?

A

3 hit:
1) Calcineurin inhibitors (cyclosporine, tacrolimus) induce IL-6, TGF-B&raquo_space; increase B cell proliferation

2) Calcineurin inhibitors protect EBV-transformed cells from apoptosis
3) EBV latency protein LMP-1 mimics natural form of CD40 in B cells&raquo_space; upregulates B cell proteins

33
Q

What metric is used to monitor onset of PTLD after transplant?

A

EBV viral load increase = start preemptive therapy

34
Q

List the treatment options for PTLD?

A
  • Reduce ongoing immunosuppression (i.e. lower dosage of CsA)
  • Rituximab: Anti-CD20 monoclonal antibody
  • Interferon-alpha
  • HLA-matched, EBV-specific CD8 CTL infusion
35
Q

List 4 innate mechanisms of immune tolerance?

A
  1. Clonal deletion (central tolerance)
  2. Anergy by co-stimulatory blockage
  3. Immunologically privileged sites (e.g. eyes, testis)
  4. Regulatory cells (Treg)
36
Q

Name the 2 phenomenons that proof immune tolaerance can be transferred by regulatory immune cells?

A

Infectious tolerance

Linked suppression

37
Q

Describe the CD and surface receptors expressed by Tregs?

A

 CD4+, CD25+, FoXP3+

 Express CTLA4 (block IL-2 pathways, outcompete CD28 for B7 = limit T cell expansion)

MBBS II HIS (30 decks)

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