Lecture 21: Transplantation Immunology I Flashcards
Autografts
Grafts exchanged from one part of an individual to another part of the same individual
Isograft
Grafts exchanged between different individuals of identical genetic make up (identical twins)
Allografts
Grafts exchanged between non identical members of same species
Xenografts
Grafts exchanged between members of different species
HLA Ags are _______ expressed
Co-dominantly
What Ags are particularly strong barriers to transplantation
HLA-A
HLA-B
(Class I HLAs)
The three most important Class II HLAs in transplantation are
HLA-DR
HLA-DP
HLA-DQ
Direct pathway of allorecognition
T cell receptors on recipient T cells directly recognize donor MHC molecules
Indirect pathway of allorecognition
Recipient T cells recognize donor MHC molecules that have been processed into peptides by recipient APCs
This pathway is important during chronic rejection (when number of donor APCs is too low to stimulate direct immune response)
Onset and cause of hyperacute rejection
Immediate onset caused by accidental ABO blood type incompatibility. Presents while still in surgery
-Could also occur when the recipient has been sensitized to donor MHC by previous transplants, blood transfusions or pregnancy
Onset and cause of acute rejection
Weeks to months
T cell mediated response directed against the foreign MHC. (Donor DCs migrate to lymph nodes and stimulate primary recipient response) Leukocytes infiltrate graft vessels
Onset and cause of chronic rejection
Months to years
T cell mediated process resulting from the foreign MHC “looking like” a self MHC carrying an antigen. Occurs due to occlusion of blood vessels and ischemia of organ. Macrophages infiltrate and smooth muscle proliferation is often seen
Onset and cause of graft vs host disease
Variable onset
Donor T cells in the graft proliferate and attack the recipients tissues. Most common in bone marrow transplants
Main pathway of allorecognition in Acute vs chronic rejection
Acute- mainly direct, but indirect can also play role
Chronic- Mainly indirect (Abs can also be involved, depositing complement into graft tissues)
Non immunologic allograft rejection
Damaged graft tissues release mediators which trigger several cascades leading to immediate tissue damage
- Clotting cascade generates fibrinopeptides, attracting neutrophils and macrophages
- Kinin cascade makes bradykinin causing vasodilation, increased vascular permeability
First step in the donor-recipient match work-up
ABO blood group compatibility
In which grafts/transplants is ABO compatibility not important
Corneal transplant
Heart valve transplant
Bone/tendon grafts
Stem cell transplants
What is cross-matching used for
To test the recipient serum for preformed Abs against donors HLAs
-Needed to prevent hyperactive Ab dependent rejection of graft
What is tissue typing used for
To identify class I HLA Ags and make sure they match
What is class II HLA typing used for and what is another name for it
Mixed lymphocyte reaction (MLR) - used to determine if the donor cells stimulate proliferation of the recipients lymphocytes -If class II MHC Ags are the same, no proliferation will occur
What percent of the host T cells are capable of recognizing and responding to a single foreign MHC
Up to 2%
What cytokine/Helper T cell levels would be increased in the case of a humoral host vs graft rejection
Th2
IL-4, IL-5, IL-10
What cytokine/helper T cell levels would be increased in the case of a cellular host vs graft rejection
Th1
IL-2, IFN-y
Acute graft vs host disease symptoms and cause
Epithelial cell death in the skin, liver and GI
Caused by reaction of grafted mature T cells in the tissue transplant with allo-ags of host
Reaction is directed against miHAs of recipient (HLA Ags are usually matched
Chronic graft vs host disease causes
Fibrosis and atrophy of affected organ
May obliterate small airways
Steps in evolution of GVHD
Donor APCs activate donor CD8+ T cells by cross presentation of MHC I molecules
-Or donor APCs activate donor CD4+ T cells through MHC II molecules
Donor APCs can also activate naïve donor CD8+ T cells against new, non hematopoietic Ags
Two facts about patients on immunosuppressive drugs*NB
They are more prone to opportunistic infections and have a raised incidence of malignancy
Cyclosporin A and Tacrolimus mechanism of action
Inhibits IL-2,3,4,5, IFN-y, TNF-a gene transcription by blocking NFAT translocation to nucleus
Anti-CD3 MAB (OKT 3) action
T cell activation, opsonization and depletion
-Blocks function of CD3 molecule in membrane of human T cells
Anti-CD25 MAB action
Inhibits IL-2 function
Sirolimus action
Inhibits cytokine-mediated signaling
Corticosteroid action
Inhibits T cell proliferation
Transcription inhibition of pro-inflammatory genes
Induction of lymphocyte apoptosis
What cells play an important role in triggering acute rejection
Donor DCs, they migrate to lymph nodes draining the organ and stimulate primary recipient response
Does chronic rejection respond to immunosuppressive therapy
No
What is the microcytotoxicity test used for
To test for the presence of preformed Abs reactive with various allogenic HLA Ags, which can cause hyperactive graft rejection
How does the microcytotoxicity test work
Recipients serum is mixed with cells of a donor- if there is no cell damage, then a potential donor is identified
