L14 - Transplantation immunology Flashcards by Benjamin Chan

Define the 4 types of transplantation?

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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Define the HLA gene locus and what it codes for?

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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How does HLA type relate to transplant survival?

Well matched HLA predicts better transplant survival

less so for solid organ transplant e.g. liver

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

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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Which types of immunity mediate allograft rejection?

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

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Describe the selection of T cells in thymus?

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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List the 2 signals for T cell activation?

MHC-peptide bind to TCR = signal 1

Co-stimulator = signal 2

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

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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What is meant by MHC restricted?

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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Describe the 2 pathways for alloantigen presentation?

Direct: donor APC presents donor MHC/peptide to TCR of recipient T cells
Indirect (major): recipient APC presents self MHC II/non-self peptide (donor antigen) to TCR of recipient T cells

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

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

CD40 (B cells) -CD40L (T cells)

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Describe the effects of B7- CD28 signalling exam

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

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Describe the effects of B7- CTLA4 signalling

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

> > Anergy/ apoptosis

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

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

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Which tempo of tissue rejection is the most common?

Acute rejection

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Describe the mechanism of hyperacute rejection of transplanted organ?

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

> > activate complement**

> > microhemorrhages, rapid thrombotic occlusion of vessels **

Which type of transplant commonly results in hyperacute rejection?

ABO incompatibility & xenotransplantation

Describe the mechanism of acute rejection of transplanted organ?

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

> > Necrosis of parenchymal cells + lymphocyte, macrophage infiltration

Describe the mechanism of chronic rejection of transplanted organ?

Mixed CD4 and antibody mediated

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

> > Can be Antigen-dependent or -independent

Histological features of chronically rejected organs?

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

List 3 laboratory tests for tissue matching?

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

Purpose of ABO antigen testing?

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

> > prevents hyperacute rejection

Purpose of Lymphocytotoxicity test?

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

Purpose of Molecular HLA-typing?

PCR test of genomic HLA in donors and recipient

Important in bone marrow transplantation

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

False may accept HLA mismatch in solid organ transplantation can’t accept in bone marrow transplantation

List 3 drugs for non-specific immunosuppresion after transplant?

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

MoA of cyclosporin A? ADR?

Binds to inhibit calcineurin >> inhibit NFAT >> inhibit IL-2 transcription******** >> No T cell expansion Renal damage + narrow therapeutic window

MoA of FK506 (tacrolimus) ?

binds to FKBP >> inhibits calcineurin >> inhibit NFAT >> inhibit IL-2 transcription ***** 100X more potent than CsA

Which non-specific immunosuppressant is used commonly?

FK506(tacrolimus)

MoA of Monoclonal antibodies against lymphocyte surface molecules?

Blockage of: CD3,4,8, IL-2 receptor ...etc >> Eliminate cells / block lymphocyte function

3 ADR of long term immunosuppression?

Risk of opportunistic infections Risk of malignancy e.g. lymphoma, PTLD (post-transplant lymphoproliferative disease) Pharmacological side-effects

Pathogenesis of PTLD?

3 hit: 1) Calcineurin inhibitors (cyclosporine, tacrolimus) induce IL-6, TGF-B >> 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 >> upregulates B cell proteins

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

EBV viral load increase = start preemptive therapy

List the treatment options for PTLD?

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

List 4 innate mechanisms of immune tolerance?

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

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

Infectious tolerance | Linked suppression

Describe the CD and surface receptors expressed by Tregs?

 CD4+, CD25+, FoXP3+  Express CTLA4 (block IL-2 pathways, outcompete CD28 for B7 = limit T cell expansion)

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L14 - Transplantation immunology Flashcards

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