40. Immune Deficiency & Immunosuppression Flashcards
State some characteristics of cancer cells.
Self-sufficient Pro-angiogenic Insensitive to anti-growth signals Non-senescent Anti-apoptotic Pro-invasive and metastatic Evades the immune system
What are the standard treatments for colorectal cancer?
FUFU = 5-fluorouracil + folinic acid Bevacizumab
What type of drug is 5-fluorouracil?
Anti-metabolite
What is the main mechanism of action of 5-FU?
Inhibition of thymidylate synthase This is important in the generation of THF (tetrahydrofolate), which is required for the generation of nucleotides for the growing DNA chain
What is the mechanism of action of Bevacizumab?
It is a monoclonal antibody against VEGF (ligand) It inhibits angiogenesis and so strangles the blood supply of the tumour
What is the standard treatment for non-small cell lung cancer?
PLATINUM treatment + another drug Cisplatin + Etoposide Carboplatin + Gemcitabine
What type of drug is cisplatin and what is its mechanism of action?
Alkylating-like agent It cross-links guanine residues in DNA and forms adducts These adducts inhibit DNA synthesis and repair leading to apoptosis
What type of drug is etoposide and what is its mechanism of action?
Topoisomerase II inhibitor Topoisomerase II cuts a bit of DNA to allow it to unwravel so that substrates required for DNA replication can gain access to the DNA Etoposide will lead to strands being cut and unable to re-ligate –> no replication
What type of drug is gemcitabine and what is its mechanism of action?
Antimetabolite Inhibits ribonucleotide reductase Inhibits DNA polymerase Incorporates into DNA causing chain termination
What is the treatment of advanced non-small cell lung cancer?
PLATINUM therapy in combination with a TAXANE or VINCA ALKALOID If EGFR mutations are present = ERLOTINIB also recommended
Name a taxane.
Docetaxel
Name a vinca alkaloid.
Vinorelbine
What feature of microtubules is essential for its role as mitoticspindles?
Dynamic instability – the ability to grow from one side and shrink from the other allows the spindle to rapidly lengthen and shrink
Describe the difference in the mechanism of action of taxanes andvinca alkaloids.
Taxanes – inhibit microtubule DISASSEMBLY Vinca alkaloids – inhibit microtubule ASSEMBLY
What is the overall effect of these drugs?
They inhibit spindle formation meaning that the chromosomes can’t separate during mitosis and the cells can’t divide
What type of drug is Erlotinib?
Small molecule inhibitor
What receptor does Erlotinib target?
EGFR (selective inhibitor)
Describe the mechanism of action of Erlotinib.
It binds to the intracellular domain of EGFR and prevents auto-phosphorylation This prevents intracellular signaling of EGFR and hence reduces cell proliferation
What are the three main treatment options for breast cancer?
Hormone therapy TAC regimen Trastuzumab
Which drugs make up the TAC regimen?
Doxorubicin Docetaxel Cyclophosphamide
Describe the mechanism of action of cyclophosphamide.
It is an alkylating agent/nitrogen mustard It forms covalent bonds with DNA and RNA, which prevents DNA replication and transcription It cross-links guanine residues in the DNA
Describe the mechanism of action of doxorubicin.
Intercalates DNA and poisons topoisomerase II This inhibits DNA synthesis and replication –> cells are unable to divide
What is trastuzumab used to treat?
Her-2 enriched breast tumours
What does the Her-2 receptor form a dimer with?
EGFR
Describe the mechanism of action of trastazumab.
It is a monoclonal antibody that binds to the extracellular region of the Her-2/neu receptor and prevents the intracellular actions of the Her-2/EGFR heterodimer
What is the difference between life-saving and life-enhancing transplantation?
Life-saving – other life-supportive methods are not fully developed or other life-supportive methods have reached the end of their possibleuse Life-enhancing – other life-supportive methods are less good e.g. Kidneys and dialysis – the organ is not vital but it improves the quality of life
What are the different types of transplants?
Autograft – within the same individual Isografts – between genetically identical individuals of the same species Allograft – between different individuals of the same species Xenograft – between individuals of different species Prothetic graft – artificial material e.g. plastic, metal
Give an example of an autograft.
Coronary artery bypass graft
What tissues can xenografts be used for?
Heart valves Skin
What are the two types of deceased donor?
Donor after brain death – brain dead but heart-beating Donor after cardiac death –non-heart beating donors
What must be confirmed with DBD donors?
Irremediable structural brain damage of known cause Apnoeic coma that is NOT due to depressant drugs, hypothermia, neuromuscular blockers etc. Must be able to demonstrate a lack of brain stem function (e.g. pupils both fixed to light)
What must be excluded before harvesting organs from a deceased donor?
Viral infection Malignancy Drug abuse, overdose or poison
How are the organs maintained once they’ve been removed?
They are rapidly cooled and perfused NOTE: absolute maximum cold ischaemia time for the kidneys is 60 hours
What is the difference between transplant selection and transplant allocation?
Selection – access to the waiting list Allocation – access to the organ
What is the nationwide system of transplant allocation based on?
Equity – fairness Efficiency – what is the best use of the organ in terms of patient and graft survival?
What are the 5 tiers of patients on the organ transplant waiting list based on?
Paediatric or adult Highly sensitised or not
What are the 7 elements that are used to decide upon organ allocation?
Waiting time HLA match and age combined HLA-B homozygosity HLA-DR homozygosity Donor-recipient age difference Location of patient relative to donor Blood group match
What are the main obstacles to donation?
Contraindication for use of that organ Family not approached for consent Family declined consent
Describe some other strategies for increasing transplantationactivity.
Use marginal donors e.g. elderly and sick Transplantation across compatibility barriers Exchange programmes – organ swaps for better tissue matching Future – xenotransplantation + stem cell research
What are the main antigens that must be considered when determining the compatibility of an organ for transplant?
ABO HLA
On which chromosome is the HLA gene encoded?
Chromosome 6
What are the two classes of HLA and which HLA subtypes are in each class?
HLA Class I – A, B and C = present on all cells HLC Class II – DP, DQ, DR = present on specialised immune cells
What are the most important HLA subtypes in organ compatibility?
A B DR NOTE: the fewer the number of mismatches, the better the outcome for the recipient
What are the two types of organ rejection?
T cell-mediated rejection Antibody-mediated rejection (B cells)
How is rejection diagnosed?
Histological examination of graft biopsy
How is rejection classified based on the time of onset?
Hyperacute Acute Chronic
How may organ rejection present?
Deteriorating graft function e.g. rise in creatinine with kidney transplant Pain and tenderness over graft Fever
How can rejection be prevented?
Maximise HLA compatibility Life-long immunosuppressive therapy
List some treatments for Antibody-mediated rejection.
Anti-CD20 antibodies Bortezomib (proteasome inhibitor) Anti-complement antibodies Plasma exchange IVIg Splenectomy
What is normally used for baseline immunosuppression following transplantation?
Signal transduction blockade: usually a calcineurin inhibitor (tacrolimus or cyclosporin) Antiproliferative agent (e.g. azathioprine) Corticosteroids
Describe the treatment of episodes of acute rejection.
T cell mediated: steroids and anti-T cell agents Antibody mediated: IVIg, plasma exchange, anti-CD20, anti-complement
What is a major risk of the extensive immunosuppressive therapythat is given to patients following transplantation?
Increased risk of infection (including opportunistic infection)
