2: Transplantation Flashcards
What are the different types of transplantation (refering to donor-recipient relation)
- Autografts
- within the same individual
- Isografts
- between genetically identical individuals of the same species
- Allografts
- between different individuals of the same species
- Xenografts
- between individuals of different species
- Prosthetic graft
- plastic, metal
What are the different types of donors that can donate in allograft transplantations?
Allograft= recipiant is different individuum from same species
Donors can be
- Deceased
- DBD (donor after brain stem death)–> neurological criterial for death
- DCD (donor after circulatory death) –> circulatory criteria for death
- Living donor
What are the criteria that need to be met for being an organ donor?
Once death has been confimed
- Excluding of Infections (e.g. HIV, HBV)
- malignany
- drug abuse, overdose or poison
- disease of the transplanted organ
What would happen if an organ with the blood group of A woud be transplanted to someone with blood group B (and anti-A antibodies
Antibodies would bind to endothelial A antigens and cause
- complement activation
- Blood clotting and thrombus formation
- immediate loss of organ due to vascular damage (no perfustion possible)
How are AB0 incompatible transplants performed today?
Remove the antibodies in the recipient (plasma exchange)
- Good outcomes (even if the antibody comes back)
- Kidney, heart, liver
What are the three importatnt Class I and Class II HLA antigens for transplantation?
- Class I (A,B,C)– expressed on all cells
- Class II (DR, DQ, DP) (on Antigen-Presenting cells, but can be upregulated on other cells under stress )
What are the three mainantigens that are involved in performing HLA matching)
Main three (in order of importance) (but others are also important) are
- HLA-DR
- HLA-B
- HLA-A
Explain the concept of (mis)matching of antigens in transplantations
Three molecules are taken into consideration:
- HLA-A, HLA-B, HLA-DR
Every HLA: 2 Alleles (one from each parent)
so: A maximum of 6 Mismatches can be there (2 for each HLA gene)
What is the main problem in transplantations?
What is the overall mechanism behind it?
Rejection
- Exposure to foreign HLA molecules results in an immune reaction to the foreign epitopes
- The immune reaction can cause immune graft damage and failure = rejection
How is organ rejection after transplantation diagnosed?
Mainly: Via histological examination of a graft biopsy
- Clinical signs (e.g. monitor kidney function, liver enzymes etc.)
- Hear only possible with biopsy
What are the two ways you can classify rejections?
- Time-linked classification
- Hyper-acute (directly when organ is implanted)
- Actue (weeks to months)
- Chronic (years-happens in almost all recipients)
- Type of immune reaction
- T-cell mediated
- Antibody mediated
What happens during T-cell mediated rejection?
What are the three phases?
- Phase 1: Antigen-Presenting cells present the foreign HLA molecules (on their own HLA molecules) to T-cells in lymphocytes
- Phase 2: Get activated and cause migration into tissues and
3: Phase 3: Recrtuitement of pro-inflammatory cells that cause tissue damage (with release of cytotoxic things)
Interstitial inflammation
Which inflammatory cells are invove in T-cell mediated rejection?
What is their respective role?
- CD4+ -T-cells
- infiltrate the graft
- CD8+
- cytotoxic: kill cells in graft
- Macrophages
- phagocytosis and proteolysis of cells
When can antibodies that are involved in organ rejection form?
How do you call them?
They can be there pre-transplantation (in “sensitised” patients)
Or after transplantation (de novo)
Explain the process of antibody-mediated organ rejection
Antibodies against HLA and AB antigens
Phase 1: Recogniton of foreign antigens
Phase 2: Prliferation of B cells with Ab production
Phase 3:
- antibodies bind to antigens presnent on endothelial donor cells
- leading to complement and macrophage activation and
Intra-vascular pathology
What are the different time-frames that you can Sub-devide Transplant rejection in?
- Hyperacute (Min-h)
- Acute (under 6m)
- Cellular (CD4 Type IV hypersensitivity)
- Antibody-mediated (B-cell mediated)
- Chornic (>6m)
Graft-Versus host disease
What is usually the pathophysiology of hyperacute transplant rejection?
How can the risk be minimised?
Proformed Antibody in recipient attack the graft and activate complements –> Theombosis and necrosis of tissue
Pervention by Crossmatch (ABO groups) and HLA-Matching
What is the Mechanism and pathology seen in chornic transplant rejection?
Differnt immune and non-immune mechanisms after more of 6 months of transplant
Risk factors
- Multiple acute rejections
- Hypertension
Shows with
- fibrosis
- glomerulopathy, vasculopathy, ischaemia
- bronchilitis obliterans (lung)
What are the targets of the immunosupressant drugs given in acture and preventative treatment of organ rejection
- Targeting T cell activation and proliferation
- mainly signaling pathways that lead to activation or interaction between antigen presenting cell and T-cell
- Targeting B cell activation and proliferation, and therefore antibody production
- anti-CD20 antibodies –> destroy B cells
- Plasma exchange (get rid of antibodies)
What are the targets for immunosupressant drugs pre-transplantation?
•Induction agent (T-cell depletion or cytokine blockade)
What are the treatments in the base-line immunosupressing of tranplant patients? (after recieving an organ)
- Signal transduction blockade, usually a CNI (calcineurin) inhibitor: Tacrolimus or Cyclosporin; sometimes mTOR inhibitor (Rapamycin) –> inhibits activation of T cells
- Antiproliferative agent: MMF or Azathioprine (T-cell antiproliferative)
- Corticosteroids
What are the main risks that are associated with immunosupression in patients that have recieved an organ transplant?
- Drug toxicity
- Development of malignancies
- Increased risk of infections
What kind of infections are people on immunosupressive therapy after recieving an orgn transplant more suseptible to?
- Increased risk for conventional infections
- Bacterial, viral, fungal
- Opportunistic infections – normally relatively harmless infectious agents give severe infections because of immune compromise
- Cytomegalovirus
- BK virus
- Pneumocytis carinii (jirovecii)
What are the common types of post-transplation malignancies?
- Skin cancer
- Post transplant lymphoproliferative disorder – Epstein Barr virus driven
- others
What are the most important antigenic determinants of rejection in transplant practice?
- MHC matching/ HLA matching
- (ABO blood group no longer as much as problem)
How does the T-cell activation work in T-cell mediated transplant rejection?
Effect
T cell activation leads to
- Proliferation of cells
- Production of Cytokines
- Activation of B-cells
What histopathological findings can be seen in T-cell mediated host rejection?
- Lymphocytic and Monocytic infiltration
- Intimal arteritis (inflammatory cells in intima of arteries
3.
What are the histopathological findings of antibody-mediated rejection?
Mainly: Intra-vascular (capillary) pathology
Swollen endothelial cells -→ glomerulitis
Capillary infiltration of B-cells
What is the clinical difference between antibody and t-cell mediated rejection?
Clinically same presentation
BUT
T-cell mediated rejection usually can be controlled
Antibody-mediated rejection is a lot harder to control and often leads to slow decline
How is donor-recipient matching done?
- Serum
- Flow cytometry
- Solid phase assays
What is the process of Flow-citometry donor-recipient crossmatch?
Does recipient serum bind to donor lymphocytes?
What is the process of Solid phase assay donor-recipient cross-match?
Does recipient serum bind to dono
How is acute antibody-mediated rejection treated?
- Plasma exchange: remove of antibodies)
- B-cell depletion: rituximab (anti-CD-20)
- Inhibition of antibody production
- IVIG: Inhibition of Antibodies
- anti-C5 (complement inhibition)
How is acute T-cell mediated rejection treated?
- Steroids (3x 60mg/kg IV, then oral)
- ATG/OKT3
What treatment regiment is usually prescribed as induction and baseline rejection prevention?
Induction Agent
- T-cells depleting agents: OKT3/ATG, anti CD-52
- B-cell: anti-CD25 (anti-IL2R)
Baseline immunosuppression:
CNI inhibitor + MMF or Aza (immunosuppression), with or without low-dose steroids
How are drug-related complications in transplant medicine managed?
Is possible
- Decrease drugs
- treat complication (e.g. chemotherapy)
What is the treatmen of acute B-cell mediated transplant rejection?
IVIG, plasma exchange, anti-C5, anti-CD20
