Transplantation Flashcards
What is an allograft?
The transplant of an organ, tissue, or cells from one individual to another individual of the same species who is not an identical twin.
What can you transplant?
Solid organs (kidney, liver, heart, lung, pancreas)
Small bowel
Free cells (bone marrow stem cells, pancreas islets)
Temporary: blood, skin (burns)
Privileged sites: cornea
Framework: bone, cartilage, tendons, nerves
Composite: hands, face
Where do organs come from?
Live donor
Deceased donor
What are the most common transplants?
Kidney Pancreas Cardiothoracic Liver Intestinal
How do improve transplant outcomes?
Improved surgical technique
Improved pre- and post-transplant patient management and monitoring
Better understanding of transplant immunology
(Immunosuppression, graft rejection)
What are the 3 phases of graft rejection?
Phase 1: recognition of foreign antigens
Phase 2: activation of antigen-specific lymphocytes
Phase 3: effector phase of graft rejection
What are the important immunological considerations in transplant?
Foreign object!
Mostly ABO and HLA (Chr6MHC)
Other: Minor histocompatibility genes
What are the two major components to rejection?
T cell-mediated rejection
Antibody-mediated rejection (B cells)
What is HLA?
Discovered after first failed attempts at human transplantation
Cell surface proteins
Presentation of foreign antigens on HLA molecules to T cells is central to T cell activation
How are HLA variable?
HLA Class I (A,B,C)– expressed on all cells
HLA Class II (DR, DQ, DP) – expressed on antigen-presenting cells but also can be upregulated on other cells under stress
Highly polymorphic – hundreds of alleles for each locus (for example: A1, A2, A3 – A372 and rising…)
How are HLA antigens connected to infections and neoplasia?
To maximise diversity in defense against infections, each individual has a variety of HLA proteins
Each individual’s HLA proteins are derived from a large pool of population varieties
What is the relevance of HLA in transplantation?
The variability in HLA molecules in the population provides a source for immunisation against the transplanted organ
What may help improve transplant outcomes regarding HLA?
Minimising HLA differences between donor and recipient improves transplant outcome
What is T cell mediated rejection?
T cells require presentation of the foreign HLA antigens by a professional antigen presenting cell (APC), in the context of HLA, to initiate activation of alloreactive T-cells
What do T cells do?
Proliferate Produce cytokines Provide help to activate CD8+ cells Provide help for antibody production Recruit phagocytic cells
What is graft infiltration?
Graft infiltration by alloreactive CD4+ cells
What is the role of Cytotoxic T cells?
Release of toxins to kill target Granzyme B Punch holes in target cells Perforin Apoptotic cell death Fas -Ligand
What do macrophages do?
Phagocytosis
Release of proteolytic enzymes
Production of cytokines
Production of oxygen radicals and nitrogen radicals
What is the histology of acute cellular rejection?
Interstitial inflammation and tubulitis
What are the phases of antibody mediated rejection?
Phase 1 – exposure to foreign antigen
Phase 2 - proliferation and maturation of B cells with antibody production
Phase 3 – effector phase; antibodies bind to graft endothelium (capillaries of glomerulus and around tubules, arterial)
What are the naturally occurring antibodies?
Anti-A or anti-B antibodies are naturally occurring
Other Anti bodies may be wither naturally or non naturally occurring
anti-HLA antibodies are not naturally occurring
Pre-formed – previous exposure to epitopes (previous transplantation, pregnancy, transfusion)
Post-formed - arise after transplantation
How do cells come to the graft?
Endothelial cell activation and inflammatory cell recruitment and injury
What are the ABO groups?
A and B glycoproteins on red blood cells but also endothelial lining of blood vessels in transplanted organ
Naturally occurring anti-A and anti-B antibodies
What is rejection?
T-cell mediated, antibody-mediated or combined
Both cause graft dysfunction (e.g. raised creatinine, raised LFT)
Graft biopsy: management and outcome are different
How do you manage graft rejection?
Preventing rejection:
A. AB/HLA matching
B. Screening for anti-HLA antibodies
C. Immunosuppression: dampen the immune system of the recipient
Treating rejection:
More immunosuppression
Always balance the need for immunosuppression with the risk of infection/malignancy/drug toxicity
How do we control AB/HLA typing?
Part of the organ allocation procedure
Encourage living donation from “blood” relatives
How do we do HLA matching in organ transplantation?
HLA matching is an important part of organ allocation procedure Bone marrow Kidney HLA matching not as important Heart Lung Liver - ?
How can we determine HLA type?
PCR-based DNA sequence analysis determines the individuals genotype
When should we screen for antibodies?
Before transplantation
At time of transplantation: when a specific deceased donor kidney has been assigned to the patient
After transplantation, repeat measurements to check for new antibody production
How do we screen for anti HLA antibodies?
Cytotoxicity assays
Flow cytometry
Solid phase assays
What is a cytotoxic assay?
does the recipient serum kill the donor’s lymphocytes
in the presence of complement? – detection of cell death using vital dyes
What is flow cytometry?
does the recipient’s serum bind to the donor’s lymphocytes
bound antibody detected by fluorescently-labelled anti-human Ig
What are solid phase assays?
does the recipient’s serum bind to recombinant single HLA molecules attached to a solid support such as beads (bound antibody detected by fluorescently-labelled anti-human Ig)
What do we need to increase organs?
Transplantation across tissue barriers (ABOi, positive cross match transplantation) – esp. if blood group O, rare HLA genotypes, sensitised; improved immunosuppression
More donors
Encourage registration for organ donation
Marginal donors – donation after cardiac death, elderly, sick
Organ exchange programmes
What is the future of transplant?
Xenotransplantation
Stem cell research
How do we target T cells?
FK506 OKT3ATG Daclizumab Mycophenolate mofetil Alemtuzumab
What are modern transplant immunosuppression?
Induction agent ex. OKT3/ATG, anti-CD52, anti-CD25 (anti-IL2R)
Base-line immunosuppression: CNI inhibitor + MMF or Aza, with or without steroids
Treatment of episodes of acute rejection:
Cellular: steroids (MethylPrednisolone IV 3x 60mg/kg then oral), ATG/OKT3
Antibody-mediated: IVIG, plasma exchange, anti-C5, anti-CD20
What is a haematopoeitic stem cell transplantation?
Haematological and lymphoid cancers
Acquired (autoimmune) or inherited deficiencies in marrow cells such as errors of metabolism or immunodeficiencies
Why does GVHD occur in haematopoeitic stem cell transplants?
Eliminate hosts immune system (total body irradiation; cyclophophamide; other drugs)
Replace with own (autologous) or HLA-matched donor (allogeneic) bone marrow
Allogeneic HSCT leads to reaction of donor lymphocytes against host tissues
Related to degree of HLA-incompatibility
Also graft-versus-tumour effect
GVHD prophylaxis: Methotrexate/Cyclosporine
How does GVHD present?
Injury induced by
preparative regime
before HSCT –
GI tract
What does GVHD present with?
Skin: rash
Gut: nausea, vomiting, abdominal pain, diarrheoa, bloody stool
Liver: jaundice
Treat with corticosteroids
What infections may you get post transplant?
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 malignancies are linked to post transplant?
Viral associated (x 100) Kaposi’s sarcoma (HHV8) Lymphoproliferative disease (EBV) Skin Cancer (x20) Risk of other cancers eg lung, colon also increased (x 2-3)
How does HLA mismatch predict prognosis?
More mismatches has a higher chance of rejection
Where does T cell and Antibody rejection occur?
Antibody mediated = intra vascular (endothelial injury)
T cell = Extra vascular damage
How do we treat latent infection re activation post transplant?
Reduce immunosuppression
How do you manage vascular disease post transplant?
Better BP control
What do you do for post transplant lymphoproliferation?
Reduce immunosuppression
Start chemo
How do you treat post transplant recurrent Glomerulonephritis?
Kidney pathway
What is the most important antigenic determinant of rejection in current clinical practice for kidney transplantation?
HLA/ MHC
A potential donor is described as being 1:1:0 MM. What does this mean?
1MM at A
1MM at B
0MM at DR
What are the main effector cells in T-cell mediated rejection?
T cells and monocyte/macrophages
A patient has an episode of acute T cell-mediated rejection 2 months post transplantation. What additional drug would most commonly be administered?
IV Methylprednisolone (steroids)
Which cell is injured in the effector phase of antibody-mediated rejection?
Endothelium
Recipient: A2 A24 B75 B61 Cw8 Cw15 DR 11 DR12 DQ7
Potential donor: A11 A24 B61 B18 Cw15 Cw7 DR1 DR11 DQ5 DQ7
Recipient anti-HLA serology: anti-DR1 (MFI 2,800), DQ5 (2600 MFI)
You are given the HLA genotype of a potential live donor and a recipient, and the recipient’s anti-HLA serology. Do you agree?
The live donor could be the recipient’s son.
50% mismatch- could be related
Recipient: A2 A24 B75 B61 Cw8 Cw15 DR 11 DR12 DQ7
Potential donor: A11 A24 B61 B18 Cw15 Cw7 DR1 DR11 DQ5 DQ7
Recipient anti-HLA serology: anti-DR1 (MFI 2,800), DQ5 (2600 MFI)
You are given the HLA genotype of a potential live donor and a recipient, and the recipient’s anti-HLA serology. Do you agree?
A standard transplant procedure is likely to go smoothly
Disagree- anti HLA found
You are given the HLA genotype of a potential live donor and a recipient, and the recipient’s anti-HLA serology. Do you agree?
The recipient would benefit from treatment to remove the anti-DR1 and DQ5 before transplantation
Recipient: A2 A24 B75 B61 Cw8 Cw15 DR 11 DR12 DQ7
Potential donor: A11 A24 B61 B18 Cw15 Cw7 DR1 DR11 DQ5 DQ7
Recipient anti-HLA serology: anti-DR1 (MFI 2,800), DQ5 (2600 MFI)
Agree- can still find use
