Transplant Immunology Flashcards
What is the most important factor for graft acceptance/rejection?
Genetic variation
- stimulates an immune response for graft rejection if the genetic components are not the same
- *this is why monozygotic (identical) twins can transplant easily
- *Graft rejection is mediated by the adaptive immune system (CD-4 and B/plasma cells)
- this is because the adaptive immune system shows SPECIFICITY and MEMORY as well as is mediated by lymphocytes (two cardinal features of adaptive immunity)
Types of grafts
1) Autografts = autologous grafts from one individual to the same individual
- highest acceptance rates*
2) syngeneic graft (isograft) = grafts done between genetically identical twins
3) allogeneic graft (allograft) = grafts done between two genetically different individuals of the same species
- most common graft done**
4) xenogenic graft (xenograft) = grafts done between two genetically different individuals of different species
- lowest acceptance rates*
How does the immune response to transplant occur?
1) trauma from the actual transplant occurs, brining in pro inflammatory cytokines and inflammatory cells into the graft tissue itself
2) alloantigens are shown to recipient T cells/APC cells.
* this is where rejection occurs if it is going to
3) T-cells activate if the graft is going to be rejected (alloantigens produce response from T-cells)
- activates TCR signaling and cytokine generations
4) TH1/TH2/TH17 immune responses are activated inside the graft and outside
5) recruits macrophages, CD-8, CD-4 Tcells and antibodies to transplant organ and begins destruction
What are most of the transplants done today?
Allografts
- have different MHC on graft vs recipient
- induces reactive lymphocytes and antibodies unless the immune system is hindered/suppressed
the major limitation to transplantation success is the presence of alloreactive T and B cells
MHC
Major HistoCompatability antigens (also called HLA)
When mismatched betweengraft and recipient, elicits a large immune response which is destructive all the time
- *Most common and important are HLA- A/B/C and DR (class 1= A/B/C; class 3 = DR/DQ)
- class 1 = CD-8 t-cells
- class 3 = CD-4 T-cells
- large amount of different combinations of these MHC, which accounts for the majority of the genetic variability (HLA-B alone has 8000 different combinations)
What is a haplotype
A set of MHC alleles on each chromosome
- each individual has two of these
- genetic identical twins have the exact same haplotypes
- *if not genetically identical, siblings have a 25% chance of matching HLAs (since they get 50% from dad and 50% from mom)
- however parents have less of a chance of being a match to their children
What are the two pathways for recognition of alloantigens
Indirect presentation
- recipient APCs uptake allogeneic (donor) MHC molecules, process them into allogeneic peptides and present them to recipient T-cells
- *recipient T-cells recognized processed peptide of the allogeneic MHC on the recipient APCs
Direct presentation
- donor APCs present peptides to the donor MHC molecules
- *recipient T-cells recognize unprocessed allogeneic(donor) MHC molecules on donor APCs
What is a hyper acute rejection
Massive immune response to a graft organ that occurs within minutes-hours
- preexisiting antibodies against alloantigens (usually based on ABO blood typing and MHC molecules on vascular endothelial cells) in the recipient are present. These antibodies activate complement and PMNs quickly which release lytic enzymes that damages the endothelium vessels and some of the tissue itself
- **primarily inflammation of the vessels of thrombi formation to cut off blood supply to the tissue and make it ischemic
- Antibodies/PMNs and complement mediated**
this needs to be monitored for in patients have previously had blood transfusion, multiple pregnancies or previous transplants. These cases present increased risk of hyper acute rejection*
How to screen for hyper acute rejection?
ABO typing and cross matching with MHC antibodies
usually the first time you transplant or transfuse a patient with non matching tissues, it’s okay. But the second time will elicit a hyper acute response
Acute rejection
Occurs as early as 7-10 days but usually within 2 months
Caused by T-cells responding to alloantigens on endothelial and parenchyma cells
- cause direct lysis of graft cells (caused by CTL (CD-8/TH-1) cells and their presence is the hallmark of acute rejection)**
- also recruits T-helper (TH-1) cells which mediate hypersensitivity to the graft tissue
Sometimes shows complement activation but this rare and requires a humoral response
to prevent = HLA type and cross match before transplanting to lower the risk
Chronic rejection
Takes months-years to occur post transplant
- **CD4-T cells, TH1 and macrophages mediated
- CD-8 and complement also play a small role - overall leads to irreversible fibrosis and occlusion of small arteries and arterioles which leads to ischemia and cell death overtime
Also induces smooth muscle proliferation in the vascular intima layers
Graft vs host disease
Donor tissue contains immunocompetent cells which attacks the host tissues
- **can be fatal!
**Most commonly seen in stem cell and liver transplants, but is an issue in all transplants
Symptoms
- skin rashes
- liver failure and jaundice
- diarrhea and GI bleeding
- lung issues
caused by donor reactive T-cells which attacks host when they bid to host MHC which naturally will have host proteins in them*
**causes a combo of acute and chronic rejection
How to fight graft vs host disease?
Widespread immunosupression
- especially T-cells of all classes
Issues with this
- increases infection side effects and makes it difficult to fight them
- prolongs wound healing
- increases risks of cancer
What is the most important cytokine in T-cell formation?
IL-2
T cell activation signals
Signal 1 = CD20 receptor binding to allogeneic peptides
- **ritixumab hits this
Signal 2 = TH1/2 : CD28 receptor binding
- produces calcium and activates calcinuerin which promotes NFAT and IL2 transcription
- **cyclosproine and tacrolimus inhibt calcinueirn
- **corticosteroids prevent NFAT from producing IL-2
Signal 3 = IL-2 receptor activation
- promotes cyclin and CDK production and fully activates the T-cells
- Basliximab prevents IL-2 activation
- **mycophenolate and Azathiopurine prevents cell cycle activation
