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Renal and Urology > Immunology of Transplantation > Flashcards

Immunology of Transplantation Flashcards

1
Q

What are the normal immune functions?

A
  • Recognition of ‘non-self’ or ‘abnormal self’
  • Protection from pathogens (bacteria, viruses etc)
  • Surveillance for tumours
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2
Q

What are the components of the innate immune system?

A
  • Macrophages
  • Neutrophils
  • Complement & natural antibodies (IgM)
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3
Q

What are the components of the adaptive immune system?

A
  • Dendritic cells (antigen presentation)- regulate
  • T cells (helper and cytotoxic T cells)
  • Natural Killer (NK) cells - cytotoxic
  • B cells (antibody generation & memory)
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4
Q

What are the MHC molecules?

A
  • Major Histocompatibility complex
  • MHC in humans called Histocompatibility Locus Antigen (HLA)
  • These molecules imprint ‘individuality’ on cells and are pivotal in the generation of immune responses
  • HLA genes are very polymorphic i.e. there are many different variations possible at each gene locus
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5
Q

Describe HLA Class 1

A

-Class I molecules: HLA-A, -B and -C
-Expressed by most somatic cells of body
-Used to present peptides from internally processed proteins (check cells are healthy)- peptide groove
= If Class 1 HLA molecule is associated with virus-derived protein then the cell is recognised as infected
=Infected cell will be killed by cytotoxic T cells

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6
Q

Describe HLA Class 2

A

-Class II: HLA-DP, -DQ and –DR
-Expressed by Antigen Presenting Cells (DCs etc) that constantly ’sample’ their microenvironment
-Used to present antigenic peptides derived from digested material by Antigen Presenting Cells (including pathogens, abnormal or foreign cells)
=Cell surface expression of a peptide derived from a pathogen or foreign cell will stimulate a T cell immune response

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7
Q

Describe T ell receptor complex and co-stimulation

A
  • T cell synapse
  • Other molecules engaged have to be strong enough to stimulate T cell to be active
  • Range of receptors that have to be brought together
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8
Q

How does the cytotoxic T cell kill?

A

-Cell that is abnormal (allogenic cell)
=Fas ligand (induce cell death)
=TNF
=Perforin and granzyme B punches through membrane

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9
Q

Describe briefly how T cell activation occurs

A
  • DC finds abnormal pathogen/ cell
  • Take up material, process and APC
  • T cell response that is antigen specific
  • IL-2= proliferation of T cells= clonal expansion
  • Circulate through body, exert function
  • Die through cell death but memory when infection cleared
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10
Q

What are the key principles of Transplant Immunology?

A
  • Rejection of Tx is directed at specific proteins called antigens
  • Rejection is donor specific
  • Rejection may be both Cell or Antibody mediated
  • Rejection exhibits ‘memory’ i.e. a 2nd similar Tx is rejected MORE RAPIDLY and this results from the rapid generation of cytotoxic antibodies that recognise the Tx
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11
Q

What is HLA profiling?

A

-Performed using molecular biological and serological techniques
=HLA-A1 and A3,
=HLA-B44 and B44
=HLA-DR7 and DR15
-The HLA tissue types of all patients on the Kidney Transplant waiting list is held on a central UK database and the ‘best match’ chosen when kidneys become available

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12
Q

How is HLA Profiling used?

A

-Used to allocate kidneys but less important for other organs such as liver (less immunogenic)
-If all HLA-A, -B and –DR loci are the same the it is a 0-0-0 mismatch
-If they are all different then it is a 2-2-2 mismatch
=less long-term survival

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13
Q

What are the immunosuppression treatments?

A

-Corticosteroids
=Kill lymphocytes
=Interfere with T cell activation and gene transcription
=Powerful anti-inflammatory agents

-Calcineurin inhibitors (CNI) – Tacrolimus/ cyclosporine
=Inhibit T cell activation by interfering with intracellular signalling pathways

-Anti-proliferative agents - mycophenolate mofetil (MMF)
=Inhibit clonal expansion of T cells

-Various monoclonal and polyclonal antibodies directed against:
=IL-2 receptor blockers (IL-2 stimulates clonal expansion of T cells)
=T cells (cytotoxic complement fixing Abs)
=Co-stimulatory molecules

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14
Q

What are the Transplantable organs/ tissues?

A
  • Kidney
  • Pancreas (complete organ or pancreatic islets)
  • Liver
  • Lung
  • Heart
  • Small Bowel
  • Cornea
  • Faces, arms etc
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15
Q

What is included in patient assessment for transplant?

A
  • Age important (biological vs chronological!)
  • Primary cause of renal failure e.g. polycystic kidneys versus conditions which can recur in a Tx (e.g. aHUS, FSGS)
  • Comorbid disease e.g. cardiovascular disease (IHD, PVD), diabetes etc
  • History of infections (immunosuppressant)
  • History of tumours (need tumour free period)
  • Urological disease e.g. bladder dysfunction
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16
Q

What investigations are included in patient assessment for transplant?

A
  • CARDIAC - exercise ECG, myocardial perfusion studies
  • Angiography (need decent vessels for the anastomosis)
  • Urodynamic studies
  • Tumour markers, imaging etc
17
Q

What are the types of transplantation?

A

-Cadaveric Tx (commonest) e.g. subarachnoid haemorrhage
=DCD = donated after cardiac death
=DBD = donation after brain death

-Living related donor Tx
=Sibling, spouse, altruistic
=Typically a kidney Tx
=better long term outcome

18
Q

Describe the surgery of transplantation

A

-Plumbed in pelvis
-Attached to iliac vessels and bladder
-Assessment of vessels important
=How many vessels?

19
Q

What is the criteria for a kidney transplant to go ahead?

A

-Blood group (ABO) compatible (RIE now has an ABO incompatible programme)

-Immunological ‘X-match negative’
=assay to see what antibodies are present that would react with donor organ
=serum from potential recipient + donor cells +vital dye and complement
=flow cytometry

20
Q

What is sensitisation/ production of HLA antibodies?

A
  • If a person is exposed to a foreign HLA molecule, they can produce an HLA antibody against this e.g. patient is A1, A24 and with exposure to A31 generating an anti-A31 antibody
  • Approximately 30% patients on renal waiting list have anti-HLA antibodies
  • The ‘specificity’ of these antibodies has to be defined (e.g. A31, B8, DR3 etc)
21
Q

Where are the HLA antigens in sensitisation derived from?

A

-Highly sensitised patients exhibit high levels of cytotoxic Abs to many HLA antigens that may be derived from:
=Previous transfusions (WBC filtered)
=Pregnancies (paternal antigens in foetus)
=Previous Transplantation

22
Q

How do we assess the presence of antibodies and level of antibodies in potential recipients?

A
  • Hundreds of microbeads with different molecules
  • Mix beads with patient serum and wash
  • If antibody present, add anti-human immunoglobin= fluorescent signal
  • Graph= how much antibody against antigens
23
Q

Why do anti-HLA antibodies matter?

A
  • Make a successful X-match less likely (long wait for Tx)
  • Can lead to antibody mediated rejection
  • Consider desensitisation/antibody removal or paired exchange Tx
24
Q

What are the types of rejection?

A
  • Hyperacute rejection (should not happen)
  • Acute rejection
  • Chronic rejection
25
Q

Describe Hyperacute rejection

A
  • Occurs when the Tx carries antigens to which the recipient is already sensitised
  • Cytotoxic antibodies bind endothelial cells and induces complement activation, platelet aggregation and intravascular thrombus formation
  • The Tx is often destroyed ‘on the operating table’
26
Q

What are the features of acute rejection?

A

Cell or antibody mediated

  • Rise in creatinine (often only indication)
  • Reduced urine output
  • Tender transplant
  • Fever
27
Q

What features need to be excluded to diagnose acute rejection?

A
  • Dehydration (clinical examination, BP, weight)
  • Renal obstruction (ultrasound)
  • Vascular catastrophe (Doppler)
  • Drug toxicity (tacrolimus levels in immunosuppressance)
28
Q

How do we look at antibody rejection?

A 
-When antibody binds endothelium
=activates complement
=deposits C4d
=Footprint (indicates where previous antibody has bound)
=capillaritis
29
Q

What is the treatment for acute rejection?

A
  • High dose methyl prednisolone (anti-inflammatory, kills lymphocyte etc)
  • Change to more potent immunosuppressive agent or an increased dose
  • ‘Anti-T cell’ antibody (increased risk of infection, tumours)
  • Plasma exchange (severe acute Ab mediated rejection)
30
Q

What are the features of chronic rejection?

A
  • Progressive renal dysfunction
  • Interstitial fibrosis (fibrillar collagen) and vascular disease on renal biopsy (smouldering lymphocyte infiltration, antibody deposition)
31
Q

What do we need to exclude to diagnose chronic rejection?

A
  • Recurrent disease (membranous, MCGN)
  • Obstruction (ultrasound)
  • Renal artery stenosis (Doppler of renal artery +/- MRI angiography)
  • Recurrent crescentic nephritis
  • Recurrent diabetic nephropathy
32
Q

Describe the pathogenesis of chronic rejection

A

Multifactorial: immune and non-immune mechanisms:

=Increased HLA mismatch (1-2-1 vs 0-0-1)
=Previous acute rejection
=Poor drug compliance (low tacrolimus levels)
=Prolonged cold ischaemia time of kidney prior to surgery (CIT of living donor &laquo_space;cadaveric donor)

33
Q

What factors promote graft failure?

A
  • Delayed graft function (doesn’t work for several days)
  • Cytomegalovirus (CMV) infection
  • Age of donor and ‘donor disease’
  • Poor blood pressure control
  • Proteinuria
34
Q

How is chronic rejection managed?

A
  • No specific treatment available
  • Most patients will eventually require dialysis and potentially a further Tx
  • Optimise immunosuppression
  • Proactive treatment of BP, lipids, proteinuria etc
35
Q

What are the infective risks of immunosuppression?

A

-Bacteria
=urinary tract infection, chest infection
=prophylactic cotrimoxazole

-Viral
=CMV, herpes virus, parvo virus, BK virus (causes renal dysfunction= reduce immunosuppression)
=prophylactic valganciclovir if recipient CMV –ve and donor CMV +ve

*TB (may require prophylactic treatment)

36
Q

What are the tumour risks of immunosuppression?

A

-Tumours
=Incidence of all cancers increased

-Skin cancers common (UV block, avoid sun, skin surveillance)

-Post Tx Lymphoproliferative Disorder (PTLD) – secondary to infection with Epstein Barr virus
(reduce immunosuppression, may need chemotherapy)

37
Q

What are the side effects of immunosuppressive drugs?

A
  • Calcineurin inhibitors are nephrotoxic! Plasma levels of tacrolimus are measured regularly
  • Increased risk of diabetes (steroids and tacrolimus)
  • Hypertension (steroids and CNI)
  • Osteoporosis (steroids)
38
Q

What could be future treatments?

A
  • Xenotransplantation using genetically engineered (humanised) pigs
  • Tolerance induction – much better than immune suppression (interest in regulatory T cells)
  • Artificially engineered kidneys using stem cell technology, organoids and biological scaffolds

Renal and Urology (43 decks)

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