L14 - Transplantation immunology Flashcards
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
Define the HLA gene locus and what it codes for?
chromosome 6 short arm
HLA-A, -B and -C region genes»_space; MHC -I molecules, present on all nucleated cells
HLA-D region genes (HLA-DP, -DQ and -DR subregions) »_space; MHC-II, present on antigen presenting cells
How does HLA type relate to transplant survival?
Well matched HLA predicts better transplant survival
less so for solid organ transplant e.g. liver
Define the cytokines needed for Th to trigger B and CD8 T cell response?
APC»_space; activate Th:
1) IL-2,4,5 to stimulate Ab production in B cells»_space; ADCC
2) IL-2, IFN -γ to CD8+ CTL for cytotoxic activation»_space; Cell-mediated cytotoxicity
Which types of immunity mediate allograft rejection?
Cell-mediated Immunity （T cells）
Humoral Immunity （B cells）
NK cells
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
List the 2 signals for T cell activation?
MHC-peptide bind to TCR = signal 1
Co-stimulator = signal 2
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
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
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
List 2 major co-stimulation pathways for T cell activation?
B7(APC) - CD28/CTLA4 (T cells)
CD40 (B cells) -CD40L (T cells)
Describe the effects of B7- CD28 signalling exam
Robust T cell expansion
Maximal cytokines
Respond to low antigen concentration
Sustained response
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»_space; dominantly inhibits both TCR- and CD28-mediated pathways
> > Anergy/ apoptosis
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)
Which tempo of tissue rejection is the most common?
Acute rejection
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»_space; inhibit NFAT»_space; inhibit IL-2 transcription**»_space; No T cell expansion
Renal damage + narrow therapeutic window
MoA of FK506 (tacrolimus) ?
binds to FKBP»_space; inhibits calcineurin»_space; inhibit NFAT»_space; 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»_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»_space; 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?
- Clonal deletion (central tolerance)
- Anergy by co-stimulatory blockage
- Immunologically privileged sites (e.g. eyes, testis)
- 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)
