Immuno 4 - Transplantation Flashcards
(38 cards)
HLA classes
Expression
HLA Class I (A, B, C) - expressed on all cells
thought to be the most immunogenic
HLA Class II (DR, DQ, DP) - expressed on APC but also upregulated on other cells under stress
3 commonest transplanted organs
1 - kidney
2 - liver
3 - heart and lung
Phases of T cell mediated Immune Response to Transplanted Graft
+ where do they occur
Phase 1_ recognition of foreign antigens
Lymph node
Phase 2_ activation of antigen-specific lymphocytes
Lymph node
Phase 3_ effector phase of graft rejection
In the graft
Which are the most relevant protein variations in clinical transplantation?
ABO blood group
HLA - coded by the MHC on chr 6
o Two types of rejection
Direct
• Donor APC presenting antigen and/or MHC to recipient T cells
• acute rejection mainly involves direct presentation
Indirect
• Recipient APC presenting antigen to recipient T-cells – i.e. the immune system working normally as it would for an infection
• Chronic rejection mainly involves indirect presentation
Most important HLAs to match and why
o Most important to match = DR > B > A
o These are the HLA molecules with the most variation and therefore the most immunogenic
Major determinant of the risk of rejection
number of mismatches
Number of mismatches in siblings
25% 6MM
50% 3MM
25% 0MM
Parent to child - matches
> = 3/6 matched
how do we express differences between recipients and the HLA donor ?
o HLA-A: HLA-B: HLA-DR
How do we determine an individuals HLA genotype?
PCR based DNA sequence analysis for HLA alleles
How do alloreactive T cells get activated?
Presentation of foreign HLA antigens by APCs (i.e. the donor’s HLA molecule) both donor and host APC cells are involved
Co-stimulatory signals – particularly of the IL-2 receptor in T cells through the release of IL-2
what happens to the T cell during phase 2 of the transplant rejection?
Phase 2_ activation of antigen-specific lymphocytes
o Proliferation
o Product cytokines (IL2 is important)
o Provide help to CD8+ cells
o Provide help for antibody production by B cells
o Recruit phagocytic cells (monocyte/macrophage lineage cells)
Targets for immunosuppressive drugs targeting T cell/cellular activation
Most drugs target T cell activation
calcineurin
MTOR pathways
co-stimulatory pathways
targeting the 3 signals that activate T cells:
APC MHC - TCR
APC CD80/CD86 - T cell CD28
Cytokine IL-2 - T cell CD25
Key points of the phase 3 -effector response in rejection
graft infiltration by alloreactive CD4+ cells
and start attacking the tubules which express the donor HLA molecules
recruitment of CD8+ T cells + monocytes
o Cytotoxic T cells:
Granzyme B (toxin)
Perforin (punch holes)
Fas-ligand (apoptosis)
o Macrophages: Phagocytosis Proteolytic enzymes Cytokine release O2 and N2 radicals
o Antibodies bind to graft endothelium
Histological features of acute T cell mediated rejection
o Lymphocytic interstitial infiltration
Immunohistochemistry – some are CD4+ cells, some are CD8+ cells, others are macrophages lineage
o Arteritis
(also see tubulitis in kidney graft rejection - inflammatory cells within the tubule)
DDx for rejection in a transplanted kidney
• Calcineurin inhibitor toxicity
o Presentation - raised creatinine
o Nephortoxic
o Mx – reduce immunosuppressive drug
• Viral infections (reactivation of latent viruses e.g. polyoma viruses)
o BK nephrotpathy
o Mx – reduce immunosuppressive drugs
• Vascular disease o Arterial intermural thickening o Small lumen o Hypertension o Mx -BP control, vascular stent if larger arteries are affected
• Post transplant lymphoproliferative disease
o Some of this is virally driven
o Mx - immunosuppressive drug
o Depending on the malignancy of the infiltrate they might need chemo
• Recurrent
glomerulonephritis
o Depends on nature GN
Phases of antibody mediated Immune Response to Transplanted Graft + where do they occur
o Phase 1: B cell exposure to foreign antigen/HLA epitope
Lymph nodes
o Phase 2: proliferation and maturation of B cells with antibody production + start producing anti-HLA ab
Lymph nodes
o Phase 3: effector phase – antibodies in the circulation fix on the endothelial cell surface (bind to graft endothelium) + cause damage + recruit inflammatory cells to the endothelium (capillaries of glomerulus and around tubules)
Graft
Main difference between T cell mediated rejection + antibody mediated rejection
T cells – crawl out of the circulation + go to interstitium + tubules of the kidney
B cell mediated rejection = intra-vascular disease
T cells interstitial damage
Antibodies endothelial damage
Anti-ABO ab
Anti-HLA ab
naturally occurring or not
Anti-ABO ab - naturally occurring
Anti-HLA ab - not naturally occurring
Action of antibodies in infection/ transplant rejection
o Neutralise toxins
o Opsonise (aid phagocytosis)
o Antibody-dependant cellular cytotoxicity
o Recruitment of inflammatory cells through complement independent mechanisms
o Complement activation: (complement fixes on the antibodies and then gets activated)
MAC lysis
Phagocytosis of microbes opsonized wit h complement fragments (e.g. C3b)
Inflammation
• Antibody mediated rejection histopathology
o Inflammatory cell infiltrate
o Complement fragments on the endothelial cell surface activation of the complement
o capillaritis Inflammatory cells in the microcirculation – a cardinal feature of antibody mediated rejection
Describe phase 3 of the antibody mediated rejection
o Antibodies bind to antigens (HLA) on the endothelium of the blood vessels in the transplanted organ
o Antibodies fix/activate complement which assembles to:
Form MAC endothelial cell lysis
Recruit inflammatory cells to the microcirculation
o Antibodies can
Crosslink the MHC molecules activating them
Directly recruit mononuclear cells, NK cells and neutrophils capillaritis
how can mismatch positive transplantation take place?
requires a lot of preparation
Plasma exchange to remove ab
IVIG
*IVIG reduce antibody production through feedback and displaces troublesome ABs so they cannot exert their harmful effects
