Immunology Flashcards
Give circumstantial evidence supporting immune system control of tumours which express antigens absent from the corresponding normal tissue.
Autopsies of accident victims have microscopic cancer cell colonies with no symptoms.
People have donated organs where the recipients quickly developed tumours.
Deliberate immunosuppression, e.g. with transplantation, increases the risk of malignancy.
Men have twice the chance of dying from malignant cancer (women mount stronger responses).
Describe the cancer-immunity cycle.
Release of cancer cell antigens (due to cancer cell death) leads to cancer antigen presentation by APCs which primes and activates other immune cells, including T lymphocytes. T lymphocytes then travel to the tumour and infiltrate (tumour infiltrating lymphocytes, TILs)) where they recognise the cells and kill them.
As such, there is an immune selection pressure placed upon these tumour cells.
What are the requirements for an anti-tumour immune response.
Local inflammation - DAMP signals - leading to an innate response.
Expression and recognition of tumour antigens, leading to an adaptive anti-tumour response.
Why may an anti-tumour immune response not be mounted?
It can take a while for tumour growth to cause inflammation and cause an innate response.
Antigenic differences are very subtle (often arising from a small number of point mutations).
What is the principle immunotherapy is based on?
In the absence of requirement for ‘spontaneous’ activation of the adaptive anti-tumour immune response, we can ‘teach’ the adaptive immune system to selectively detect and destroy tumour cells.
Explain the basis of the HPV vaccine.
HPV causes cervical cancer: the resultant tumour cells contain viral antigens, E6 and E7 oncoproteins which induce and maintain the cancer. The vaccine alerts the immune system to these intracellular antigens. Often used preventatively but can be used to therapeutically boost immune response.
What are tumour associated antigens?
Normal cellular proteins which are aberrantly expressed (timing, location, quantity).
Since they are self-proteins, tolerance may need to be overcome.
What are the problems with targeting tumour associated antigens (TAAs) in immunotherapy?
Auto-immune response against normal tissue (since they are normal cellular proteins).
Must overcome immunological tolerance.
Describe monoclonal antibody-based immunological therapy.
Antibodies against tumour antigens.
‘Naked’ antibody e.g. herceptin agaisnt HER2
‘Conjugated’ with a radioactive particle or drug e.g. HER2 with cytotoxic drug.
‘Bi-specific’ - genetically engineered to combine 2 specificities e.g. anti CD3 and anti CD19 in B cell tumours.
What are the 4 types of immunotherapy?
Antibody-based therapy
Therapeutic vaccination
Immune checkpoint blockade
Adoptive transfer of immune cells.
Describe Provenge as a therapeutic prostate cancer vaccination.
T-cell response elicited against prostatic acid phosphatase (PAP).
Describe the principle of therapeutic vaccination in immunotherapy and its future personalised vaccination potential.
Principle: Eliciting a T-cell response against tumour-specific or tumour-associated antigens.
Whole exome sequencing (WES) may lead to personalised vaccinations through identification of somatic mutations between tumour cells and normal cells.
Describe immune checkpoint blockade.
Seeks to remove negative regulatory controls of T-cell responses - a GENERAL approach.
Targets CTLA-4 (cytotoxic T-lymphocyte associated antigen 4) and PD-1 pathways.
Uses antibodies to block these regulatory pathways.
Describe adoptive transfer of cells (ATC)
Isolate tumour infiltrating lymphocytes (T-cell source), expand in vitro and re-infuse into the patient.
Contrast life-saving vs life-enhancing transplantation.
Life-saving: when other life-supportive methods have reached their end of use, e.g. a left ventricular assist device (LVAD) in heart failure, total parenteral nutrition (TPN) in short bowel syndrome.
Life-enhancing: other life-supportive methods are less good; the organ is not vital but improves quality of life, e.g. with dialysis and insulin injections.
Give the 5 types of transplant source.
Autograft: within the same individual
Isograft: genetically identical individuals of the same species
Allograft: between different individuals of the same species
Xenograft: between individuals of different species
Prosthetic graft: synthetic material
Describe living donation.
Allografts (usually) - can donate bone marrow, kidney, liver. Genetically related (spouse) or unrelated (altruistic).
What is DBD (donor after brain stem death)?
The majority of deceased donation.
Brain injury has caused death before terminal apnoea has resulted in cardiac arrest and circulatory standstill, e.g. intracranial haemorrhage, RTC.
Circulation established through resus.
Death confirmed by neurological criteria.
Organs perfused until removed, harvest and cooled to reduce ischaemic damage.
Describe DCD (donor after circulatory death).
Donation after death confirmed by cardio-respiratory criteria.
What sort of things do you want to exclude from a donated organ?
Disease of the organ Infection of the organ Malignancy Drug abuse Poisoning
How long do cooled and perfused organs last?
Cornea 96h (longer if cryopreserved) Kidney about 60h max Other organs much shorter.
Describe transplant selection and allocation.
Selection: waiting list at a transplant centre after multidisciplinary assessment.
Allocation: evidence-based computer algorithm based on equity (accounts for time on waiting list and urgency of transplant).
How can we increase the number of organs available for transplant?
More acceptance of marginal donations (DCD, elderly, comorbidities).
Transplant across compatibility barriers, exchange programmes for better matching.
More xenotransplantation in the future? Stem-cell research.
Why are ABO antigens important in transplanted organs and how may ABO incompatible transplantation be permitted?
ABO antigens not just present on the RBCs but also the endothelial lining of the blood vessels in the transplanted organs.
In an incompatible transplantation, you can remove the antibodies in the recipient (plasma exchange) with good outcomes.
Describe HLA matching.
HLA is a group of highly variable cell surface proteins important in the defence against infections and neoplasia.
Class I (A,B,C) and II (DR, DQ, DP). They present peptides to T-lymphocytes.
A, B, DR most highly polymorphic, hence most commonly discussed in matching.
Each individual has 2 types of each HLA (maternal and paternal).
Expresses as mismatch (MM) 1:2:0 (A,B,DR) so 3/6.
What is rejection, how is it diagnosed and managed?
Rejection is the most common cause of graft failure, resulting from foreign HLA molecules on the transplanted organ being recognised as foreign epitopes and eliciting an immune response. This can result in graft damage and failure.
Diagnosed by histological examination of biopsy.
Managed by immunosuppression.
Describe T-cell mediated rejection.
Graft infiltration by autoreactive CD4+ cells.
Cytotoxic (CD8+) T-cells release toxins to kills targets, induce apoptosis and create holes in target cells.
Describe antibody-mediated rejection.
Antibodies against HLA and AB antigens raised.
If these arise preimplantation - they are sensitised antibodies.
If they arise post-implantation, they are de novo.
How do you monitor post transplant function?
Gold standard: biopsy.
Monitor, for example, creatinine, fluids and B.P. for a kidney graft, LFTs and coagulation for a liver graft, angioedema and breathlessness for a lung graft.
How is rejection prevented?
Maximising HLA compatibility
Life-long immunosuppression.
