WK 6- TRANSPLANTATION IMMUNOLOGY Flashcards
What does auto… mean
The donor is the recipient
What does allo… mean
The donor and the recipient are genetically different but belong to the same species
What does xeno… mean
The donor is another species
What is the graft versus leukemia effect
Allogeneic preparations of haematopoietic stem cells contain donor T cells that recognize minor histocompatibility antigens or tumor-specific antigens expressed by the host leukemic cells→ leading the donor cells killing the leukemic cell (therapeutic)
What is graft versus host disease
condition that occurs after an allogenic transplant and is due to donor bone marrow or stem cells (such as T cells) viewing the recipients antigens as foreign and attacking the recipient’s cells
- causes severe inflammatory disease characterised by rashes, diarrhea, and pneumonitis
- Symptoms generally begin developing after 7-10 post-surgery.
What are the 3 requirements for a transplant
- ABO compatibility
- Tissue typing (HLA typing)→ involves 6 antigen matching→ 2x HLA- A, -B, -DR. If 6 HLA’s are different then MHC won’t match
- Cross matching → presence of antibodies to HLA. HLA antibody levels can change following events such as blood transfusions, previous transplants, pregnancies/miscarriages and even surgeries
Why is immunosuppression important in preparing a patient who is going to receive a transplant
stops T cell function and prevents T cells from attacking the graft→ stops rejection)
What are examples of immunosuppressive agents
irradiation, cyclosporine, antibodies, corticosteroids, cytotoxic agents
What is the method by which cross matching is conducted
- combining recipient serum (potentially containing donor-specific anti-HLA antibodies) with donor lymphocytes (B and T cells) and complements
- if there are donor specific anti-HLA antibodies present in serum they will bind to the lymphocytes and activate complement
- Binding of complement causes cell lysis and indicates a positive cross match result
When would a syngeneic transplant occur
Syngeneic= graft between individuals with identical MHC
-occurs in identical twins
What is a first set rejection
Grafts differing at the MHC are rejected around 10–13 days after grafting
What is a second set rejection
due to memory cells being present from the original presentation- occurs faster with an MHC specific response
What is a hyperacute rejection
Occurs from min-hours
-occurs due to recipient already have Ab to donor antigens, which are often blood group antigens or HLA Ag
What happens to the graft following a hyperacute rejection
When the donor organ is grafted into recipients, Ab bind to vascular endothelium in the graft→ initiating the complement cascade (causing inflammatory cell recruitment and MAC development on endothelial cells (causing endothelial damage and exposing VWF))→ damage initiates the clotting cascade→ causes blood vessels in the graft to become obstructed by clots and leak, causing hemorrhage of blood into the graft→ causes death of graft
What is an accelerated rejection
AKA 2nd set rejection
- Reactivation of sensitised T cells followed by cell and humoral immune responses
- takes 2-5 days
What is an acute rejection
Most common- occurs from days-weeks after transplant
-Activation of naive T cells
= 1st set skin graft rejection
-naive T cells are primed against donor antigens, proliferate and then attack donated graft
What is a chronic rejection
Takes months-years
-Multifactoral: Ab, immune complexes T cell activation, immunosuppressants, original disease process
What is allorecognition
Ability of an individual organism to distinguish its own tissues from those of another. It manifests itself in the recognition of antigens expressed on the surface of cells of non-self origin.
How do dendritic cells contribute to the alloimmune response (attack graft)
- DCs migrating from the graft display peptides from the graft on their surface (via MHC)→
- after travelling to lymph node, these APCs encounter naive T cells specific for graft antigens, and the DC stimulate these T cells to divide→ 3. the resulting activated effector T cells migrate via the thoracic duct to blood and move to grafted tissue, which they rapidly destroy.
What are the two ways of presenting alloantigens to recipient cells
Direct and Indirect
What is the direct method of presenting alloantigens
involves presentation of donor peptide directly to T cells by donor APC/MHC
What is the indirect method of presenting alloantigens
involves presentation of peptides from the graft organ by self APC (dendritic cells) directly to T cells
What does the effector stage encompass
Response of the immune system towards the presentation of foreign antigens
What is the function of T cells during the effector stage
-CD8 promotes cytotoxicity (apoptosis) by acting on MHC1
-CD4 promotes release of cytotoxic and regulatory cytokines through acting on MHC2
→ cytokines promote macrophage infiltration, endothelial cell activation, more T cells→ amplification of response
What is the function of other APC/sensor cells during the effector stage
Macrophages, Natural killer cells and B cells→act to cause cytotoxicity by perforin, granzymes, ADCC, cytokines and complements
-NK cells distinguish allogenic cells from self > potent cytolytic effector mechanisms
What is the function of other APC/sensor cells during the effector stage
Macrophages, Natural killer cells and B cells→act to cause cytotoxicity by perforin, granzymes, ADCC, cytokines and complements
-NK cells distinguish allogenic cells from self > potent cytolytic effector mechanisms
If the graft is MHC-identical, why can rejection still occur?
There can be other alloantigens bound to graft MHC molecules→ Even though MHC genotype might be matched exactly, there might be polymorphism–> these are minor histocompatibility antigens-> trigger T cell responses
What is an example of a minor histocompatibility antigen- eg. what would be present in a set of fraternal twins boy/girls that would cause the identical MHC to be rejected
As females do not have genes that have a loci on the Y chromosome the female will view it as foreign→Female anti-male minor H responses occur
What are some of the absolute requirements for kidney transplants (4)
- ABO identity or compatibility
- Negative T cell cross match
- No previous Ab against donor HLA Ag
- No shared incompatibilities with previous donor(s)
How many MHC molecules/HLA have to be matched in order for the transplant to go ahead
6 matches- HLA-A, HLA-B, HLA-DR
When are bone marrow transplants done
be used to correct immunodeficiencies caused by defects in lymphocyte maturation-> leukemia
What are the 3 requirements for a BMT
- HLA Matching: Matching of MHC class I & II genes between donor and recipient
- Cross Matching: Used to determine whether Antibodies are present in the recipient’s serum that may cross-react with the donor cell surface Antigens
- Mixed lymphocyte culture (MLC): Involves mixing lymphocytes from two individuals→different histocompatibility antigens on the surface of donor lymphocytes will activate the recipient lymphocytes and vice versa
What are the 3 steps of the immunosuppresive protocol
- Immunosuppression of recipient & histocompatibility matching (make T cell non-responsive will mean T cell will not attack the graft)
- Induction of specific tolerance
- Pretreatment of allograft prior to transplant (removing certain types of cells/blocking APC coming from graft)
What is serological HLA typing
- leucocytes from potential donors and recipient are distributed into series of wells on microtiter plate→ 2. Ab specific for various class I and class II MHC alleles are added to different wells→ 3. After incubation, complement is added to the wells→ 4. if antibody is bound and complement is added it will cause the cells to leak (from MAC) and take up dyes→
- cytotoxicity is assessed by the uptake or exclusion of various dyes (e.g., trypan blue or eosin Y) by the cells
What is an induction regimen in regard to immunosuppression
Brief use of potent immunosuppressive agents in immediate post-transplant period to reduce the immune response of T cells to the transplanted organ. Individual agents either deplete T cells, or interrupt T cell activation and proliferation
