Immunology - Transplantation Flashcards
What is an isograft?
A transplant from a twin
What is an allograft?
A transplant from the same species
What is a zenograft?
A transplant from a different species
What is a split graft?
A transplant shared by two recipients (e.g. liver)
What can a living donor donate?
- Bone marrow
- Kidney
- Liver
What can a deceased donor donate?
Solid organs:
- Kidney (most commonly transplanted organ)
- Heart
- Pancreas
- Lungs
- Liver
Other:
- Small bowel
- Free cells (BM, pancreas islets)
- Temporary (blood, skin, burns)
- Cornea
- Framework (bone, cartilage, tendons, nerves)
- Composiet (hand, face)
What is a transplant rejection + its three stages?
The immune system mounting a response to “foreign” (Non-self) antigens)
Stages:
- Recognition
- Activation
- Effector function
What cells are involved in immune recognition?
- T cells: recognise antigen presented via MHC (I/II) on APCs
- B cells: recognise just antigen
What are the different HLA classes and where are they expressed?
HLA Class I
- A, B, C
- Expressed on all cells
HLA Class II
- DP, DQ, DR
- Expressed on APCs
- Can be upregulated on other cells under stress
What factors are recognised during transplantation + their features?
Human Leukocyte Antigens (HLA):
- Most important: DR > B > A
- Coded by MHC complex on Chr 6
- Cell surface proteins
- Present foreign antigens to T cells leading to activation
Minor HLA
- Other polymorphic self peptides
ABO Blood Antigens
How can foreign antigens be recognised during transplantation?
Direct:
- Donor APC presents foreign antigen +/or MHC to recipient T cells
- Seen in ACUTE REJECTION
Indirect:
- Recipient APC presents donor antigen to recipient T cells
- e.g. Immune system working normally, as it would for an infection
- Seen in CHRONIC REJECTION
What components are involved in transplant rejection
- T cell mediated
- Antibody mediated
What are the events of T cell activation?
- Proliferate
- Produce cytokines
- Provide help to activate CD8+ cells
- Help antibody production
- Recruit phagocytic cells
What are the three phases of T cell mediated response in regards to transplant rejection?
- Recognition of foreign antigens
- Activation of antigen-specific T lymphocytes
- Effector phase of graft rejection
What happens during the effector phase of T-cell mediated response in regards to transplant rejection?
- Graft infiltration by allreactive CD4+ cells
- Cytotoxic T cells: release toxins (granzyme B), punch holes in target cells (perforin), apoptotic cell death (Fas ligand)
- Macrophages: phagocytosis, release of proteolytic enzymes, production of cytokines, production of oxygen + nitrogen radicals
- Abs bind to graft endothelium
Organ damage = Cytotoxic T cells + Macrophages
What are the three phases of antibody-mediated response in regards to transplant rejection?
- Recognition of foreign antigens
- Proliferation + maturation of B cells with Ab production
- Abs bind graft endothelium leading to intra-vascular disease (+organ damage)
What are some features of the proliferation + maturation phase of the antibody-mediated response in regards to transplant rejection?
- Anti-HLA Ab not naturally occurring - preformed due to transplant, pregnancy, transfusion OR post-formed (arise after transplant)
- Anti-A/B Abs naturally occur as per blood group
What is the mechanism of a hyperacute transplant rejection, its time onset, pathology + treatment?
Mechanism:
- Preformed Ab which activates complement
Time:
- Mins - Hrs
Pathology:
- Thrombosis + Necrosis
Tx: (Prevention)
- Crossmatch (ABO groups)
- HLA-matching
What is the mechanism of an acute (cellular) transplant rejection, its time onset, pathology + treatment?
Mechanism:
- CD4 activating a Type IV reaction
Time:
- <6mths
Pathology:
- Cellular infiltrate
Tx:
- T-cell
- Immunosuppression
What is the mechanism of an acute (Ab-mediated) transplant rejection, its time onset, pathology + treatment?
Mechanism:
- B cell activation: Ab attacks vessels
Time:
- <6mths
Pathology:
- Vasculitis
- C4d
Tx:
- Ab removal
- B cell immunosuppression
What is the mechanism of a chronic transplant rejection, its time onset, pathology + treatment?
Mechanism:
- Immune + non-immune mechanism
- RFs: multiple acute rejections, HTN, hyperlipidaemia
Time:
- >6mths
Pathology:
- Fibrosis
- Glomerulopathy
- Vasculopathy (ischaemia)
- Bronchiolitis obliterans (lungs)
Tx:
- Minimise organ damage
What is the mechanism of a GVHD transplant rejection, its time onset, pathology + treatment?
Mechanism:
- Donor cells attacking host
Time:
- Days-wks
Pathology:
- Skin (rash)
- Gut (D+V, bloody stool)
- Liver (jaundice) involvement
Tx:
- Prevention/immunosuppression-corticosteroids
What is an acute vascular rejection?
- After xenograft
- Similar to hyperacute, but 4-6 days after transplant
What are the possible number of HLA mismatches + what are the likelihodds in different circumstances?
- 6
- Parent-child = 3/6
- Sibling-sibling = 25% 0/6, 50% 3/6, 25% 6/6
- Stranger = 1 in 100,000
What processes are considered pre-transplant in terms of matching?
- Determine donor + recipient blood group + HLA: tissue typing (PCR analysis of DNA)
- Check recipient’s pre-formed Ab against ABO + HLA: 3 assay types
- Cross-match: via CDC + FACS (tests if serum from recipient is able to bind/kill donor lymphocytes - +ve crossmatch is CI for transplantation)
- Screening is done twice pre-transplant, once before + once after specific organ assigned
What processes are considered post-transplant in terms of matching?
- Repeat assays to check for new Abs against graft
- Weekly - monthly checks for rejection
What is a cytotoxicity assay and what does it look for?
- Complement dependent cytotoxicity
- Does recipient serum kill donor lymphocytes?
What is a FACS test and what does it look for?
- Flow cytometry
- Does recipient serum bind donor lymphocytes?
What does a solid phase/Luminex test look for?
- Does recipient serum contain Abs to individual HLA molecules?
What are some immunosuppressive regimes?
- Induction (pre-transplant): Suppress T cell response (e.g. anti-CD52 Alemtuzumab or anti-CD25 Basiliximab or OKT3/ATG)
- Baseline immunosuppression (e.g. SNI + MMF/Azathioprine +/- steroids)
- Tx for acute rejection as needed
What is the treatment for acute rejection?
Cellular:
- Steroids (3X methylprednisolone pulses + oral taper)
- OKT3/ATG
Ab-mediated:
- IVIG
- Plasma exchange
- Anti-C5
- Anti-CD20
What is the process of a haematopoeitic stem cell transplant?
- Elimiate hosts immune system (total body irradiation, cyclophosphamide, other drugs)
- Replace with own (autologous) or HLA-matched donor (allogenic) bone marrow
What are some indications for a haematopoeitic stem cell transplant?
- Life threatending primary immunodeficiency (SCID, leucocyte adhesion defect)
- Haematological cancer
What is graft versus host disease and its symptoms?
- Occurs in allogenic HSCT
- Donor lymphocytes recognise + attack host HLA
- Related to degree of HLA-incompatibility
Sx:
- Skin desquamation
- Rash
- GI disturbance (nausea, vomiting, abdominal pain, diarrhoea, bloody stool)
- Liver failure (jaundice)
- BM failure
What is the prophylaxis and treatment for graft versus host disease?
Prophylaxis:
- Methotrexate/cyclosporine
- Irradiate blood components for immunosuppressed pts
Tx:
- Corticosteroids
What are some post-transplant complications?
Infection:
- Increased risk of conventional infections: bacterial, viral, fungal
- Opportunistic infections: CMV, BK virus, pneumocystis carinii
Malignancy:
- Viral associated (X100): Kaposi’s sarcoma (HHV8), lymphoproliferative disease (EBV)
- Skin cancers (X20)
- Other cancers (e.g. lung, colon) (X2-3)
Atherosclerosis:
- HTN
- Hyperlipidaemia
- X20 increased risk in death from MI compared to age-matched general population
