20: Transplantation Immunology Flashcards
(26 cards)
Autografts
Grafts exchanged between one region to another region on SAME individual
Isografts
Grafts exchanged between different people with same genetic constitution
IDENTICAL TWINS
Allografts
Grafts exchanged between two DIFFERENT individuals of SAME SPECIES
Xenografts
Graft exchanged between two members of DIFFERENT SPECIES
- -Extra susceptible to immune rejection/attack
- -Inserting human genes into genome of donor of different species increases likelihood of tissue survival
3 Conclusions from Evidence proving Rejection is Immune Reaction:
- -Graft rejection shows MEMORY & SPECIFICITY (2 feat. adaptive immunity)
- -Graft rejection is mediated by lymphocytes
- -Graft rejection can be mediated by T lymphocytes
Cells express HLA class I and HLA Class II
Class I (HLA-A, HLA-B)–> ALL nucleated cells
Class II (HLA-D; HLA-DR, HLA-DP, HLA-DQ) –> APCs
Which HLA class is stronger barrier to transplantation & why?
Class I HLA (HLA-A, HLA-B)
–Exponentially greater amount of Class I HLA allele polymorphisms compared to Class II HLA allele polymorphisms or mutations
Direct Allorecognition
MHC molecules on Donor APC –> lymph node –> recognized and activate Recipient T cell
–Recipient activated T cell –> proliferates & matures to effector T cells specific to allograft tissue –> Recipient T cells attack Donor allograft
Indirect Allorecognition
Recipient APC processed & expresses donor alloAg –> lymph node –> activates naive T cells
–Main recognition pathway CHRONIC REJECTION
Key concepts that determine transplant outcome:
- condition of allograft / non-immunological factors (quality of graft)
- donor-host antigenic disparity
- strength of host anti-donor response
- immunosuppressive regimen
What are some non-immunological factors? What is an important determinant of allograft quality?
– Mechanical trauma & ischemia-reperfusion injury
– Cold ischemia time is an important determinant to be considered in preservation of an allograft. Time an organ is without blood circulation & kept cold; Time the organ was removed to the time the organ is transplanted.
Consequences of transplantation of damaged graft tissues?
Transplantation results in release of mediators that cause immediate tissue damage via stimulation of 2 pro-inflammatory processes:
–clotting cascade (fibrinopeptides) –> endothelial & mast cell activation = increased vascular permeability & chemoattraction of neutrophils & macrophages
–kinin cascade (bradykinin) –> vasodilation, smooth muscle contraction, vascular permeability
List 4 components of Donor-Recipient compatibility
1) ABO blood Ag compatibility
2) Tissue typing to identify class I HLA expressed (microcytotoxicity test)
3) Cross-reactivity test is recipient has pre-existing Abs against donors HLAs (modified microcytotoxicity test)
4) Class II HLA typing via mixed lymphocyte reaction (MLR)
Recipient T cells attack donor organ or graft
Host-vs-Graft Disease
Recipient APC activates donor bone marrow T cells –> donor T cells widespread attack of recipient tissues
Graft-vs-Host Disease
Hyperacute Rejection
– IMMEDIATE rejection; begins DURING THE TRANSPLANT PROCEDURE
– preformed Abs against donor tissue (ABO incompatibility, preexisting Abs to donor MHC/previously sensitized)
– Thrombosis & occlusion graft vessels
– HVG
Acute Rejection
– WEEKS to months onset
– T cell mediated directed against foreign MHC (DIRECT allorecognition)
– Inflammation & leukocyte infiltration of graft vessels
– Most common type of tissue rejection
–HVG
Chronic Rejection
–Months to years onset
– T cell mediated indirect allorecognition
– intimal thickening & fibrosis of graft vessels & graft atropy
– HVG
Graft vs. Host Rejection
– onset varies
– Donor T cells in graft proliferate & attack recipients tissue
– most commonly occurs in BONE MARROW TRANSPLANTS
– clinical manifestation: diarrhea, rash, jaundice
What are primary side effects of immunosuppressive drugs?
–More prone to opportunistic infections (infections in general) & increased risk for malignancy
Mechanism of action: Steroids (corticosteroids)
Anti-inflammatory
–inhibits activation of TF NF-kB –> thus, transcription of pro-inflammatory molecules & IL-2
Mechanism of action: Cyclosporine A (CsA)
Inhibits IL-2 gene transcription / T cell activation & proliferation
– Inhibits NFAT activation –> inhibits production of IL-2, IL-3, IL-4, IL-5, IFN-gamma, TNF-alpha, GM-CSF (T cell specific cytokines - inhibit activation)
**NEPHROTOXIC EFFECTS – can lead to tissue rejection if kidney transplant
Mechanism of action: Anti-CD3 mAb (OKT 3)
Inhibits T cell activation & depletion
–blocks TCR transduction of first activation signal from the extracellular domain to cytosol (CD3 component of all TCR cytosol signaling molecules)
Mechanism of action: Tarcolimus
Inhibits IL-2 gene transcription / T cell activation & proliferation
–Blocks activation NFAT (Ca2+-dependent pathway of T cell activation) –> inhibits production of IL-2, IL-3, IL-4, IL-5, IFN-gamma, TNF-alpha, GM-CSF (T cell specific cytokines - inhibit activation)
**NEPHROTOXIC EFFECTS – can lead to tissue rejection if kidney transplant
