Exam Flashcards
Causes of cancer
Radiation
Chemicals
Viruses
Aging
Mutation in gene
Tumour specific antigens
overexpressed by tumour
can lead to anti-tumour immunity
Tumour specific antigen used for
used in diagnosis
target in immunotherapies
Immune system aware of developing tumour
yes, have tumour specific antibodies and T cells
Immune surveillance of tumours
immune system survey body for development of malignancy and eliminate tumours as they arise
immuno suppresed develop tumors quickly
Melanoma kidney
Cancer in transplant
Transplant patient has higher rate of cancer then general public
lady free from cancer, kidney transplanted, both got cancer
immune system fight aginst tumour cells
some tumour regress sudennly
In lab, cytotoxic t cells and NK cells kill tumour cells
how cytotoxic T cells attack tumour
Tumour antigen in MHC class I
perforin, granzyme and FAS ligand interaction
In cancer
Why immune system ineffective
tumour antigen not presented (ignorance)
T- cell unresponsive (anergised)
too little too late
unable to enter tumour
cytokines secreted by tumour
TGFbeta - immunosupressive
VEGF - development of BV
cytokines secreted by regulatory cell
TGFbeta
IL-10
how does cancer evad immune system
immunosuppressive
hide via no MHC class I
dosnt release danger signals to start inflammation
3 E’s of immunoediting
Elimination
Equilibrium
Escape
immunoediting
Elimination
innate cells recognise tumour
DC transport antigen to LN
tumour specific T-cell eliminate tumor cells
immunoediting
Equilibrium
cant completely eliminate tumour
tumour cells left avoid killng by genetic altration
lose tumour antigen
downreg MHC class I
secrete soluble factor
immunoediting
Escape
Tumour cell completely avoid immune killing
aim of immunotherapy + types
boast immune system to kill cancer
-vaccination
-cytokines
-checkpoint blockade
Cytokine therapy
Interferons: stim NK, T cells and macrophages
TNF: directly kill tumour (used in conj w/ IFNy)
IL-2: Promote cytotoxic T, NK and macrophages
Cancer vaccine
tumour antigen
specific types of cancer, underwhelming
CAR
Chimeric antigen receptor
DC vaccines
expose to antigen, genetically modify and activate.
But tolerance occur if im DC given to patient
Anti-tumour antibody
monoclonal antibody that target tumour antigen.
have trouble getting into tumour
Rituximab for B-cell lymphoma CD20
cancer pov
Checkpoint molecules
Prevent excessive inflammation
tumours can take advantage of this
first checkpoint molecule
Cytotoxic T lymphocyte-associated molecule 4 (CTLA-4)
inhibit T-cell activation and proliferation
compete with CD28 for B7 on APCs
Anti-PD-1 vs Anti CTLA4
PD-1: less toxic, long term remission, possible cure
stem cell vs progenitor cells
stem cells divide for lifetime
progenitor is already more specific
Source of stem cells
Adult: largest reservoir BM
Cord blood: umbilical cord (small amount)
Embryonic: fertilized embryos, early phase
different graft source
Autologous: patient own
Syngeneic: idential twin
Allogeneic: someone else
Autologous
must not have evidence of disease
mortality low
Relapse high
no GVSHD but also no GVST
Allogeneic
Matched unrelated
- high mortality
- GVHD
- lower relapse due to GVST
Matched related
Matched related donor chances of being related
25%
the more siblings, the better the chance
key event for stem cell transplant
- Donor selection: typing 6-10 HLA antigen
- Harvest stem cell from donor
- Preparative regimen for patient: chemo + radiation
- Stem cell intravenous infusion into patient
- Pos transplant suppotive care: auto 100 days, allo 180 days
Preparative regimen for patient
- Myeloablation (high dose of chemo +/- radiation)
- eliminate malignancy
- generate immunosupp to allow engraftment
- decrease host vs graft - Stemcell infusion
- Maintain with immunosuppressant drugs
non-myeloablative conditioning
for low dose chemo
- better for slow growing cancer or older patients
- immunosuppress enough to allow engraftment
- less injury to organs
- higher relapse
Mixed chimerism
2 set of genetically different cells co-existing
Donor prep
BM: Given granulocytes colony stimulating factor (G-CSF) to amp stem cell
PB: growth factor
Cord: umbilical cord and placenta
what happends to transplated cells
“reverse migration” goes back to BM which in empty after chemo
recognise adhesion molecules and growth factor in stroma
proliferate untill BM full
Factors for GVHD
immunologically competent donor graft
histo-incompatibility
immunologically incompetent host
where does GVHD occur
starts in skin first, rash to dermatitis, blisters to necrosis
gastrointestinal shows diarrhra, malaise and vomiting
MHC antigen
main antigen in graft rejection
* upregulation of class I and II on APC and tissue during inflammation
* becomes target antigen by allo-specific T cells
* casue fast and strong rejection by allo-specific T cells
minor histocompatibility antigen
slower and weaker rejection
* ABO group antigen
* Tissue specfic antigen (vascular endothelial cells)
graft vs cancer malignancy effects
lower relapse in patients who got GVHD
higher relapse in those withiut GVHD (twin donation, T depleted BM)
Direct presentation
Donor APC
Indirect presentation
Recipient APC
what cytokines released by tissue due to chemo and other infection
IL-1, IL-6 & TNFa
DAMPS
Model for GVHD
tissue damage from chemo: IL1&6 > inflammation >IL12 and IFNy > tissue damage
infection > inflammation > tissue damage
Primary immunodeficiencies
abormalities of immune system
genetic causes
Bruton’s disease
X-linked agammaglobulinaemia, mutation in bruton tyrosine kinase > stop development in pre-B stage
* few B cell in blood or lymph
* decrease immunoglobin
6 Main type of immune related functional deficiency
- Phagocytic deficiencies
- Complement def
- T cell mediated (cellular) def
- B cell mediated (antibody) def
- combined immunodeficiencies
- disorders of immune dysregulation
65% antibody def
Phagocytic deficiencies
Neutrophils
any age
e.g. Chronic granulomatous disease and leukocytes adhesion deficiency
Chronic granulomatous disease
impact neutrophil phagocytosis and dectruction of pathogen
IGAM in CoV19
IgM: First responder
IgA: in mucous secretion (where CoV enters)
IgG: isotype switching occurs later
3 different spike protein
RBD
S1
Ectodomain(S2P)
spleen and Lymph nodes in COVID-19
germinal centres lost in lymph and spleen (isotype switch)
loss of white pulp in spleen (where T&B cells are )
Biphasic course for COVID 19
- viral 2. host inflammatory
