Lecture 21 - Manipulation of Immune Responses Flashcards
What 3 areas of the immune system are most prone to polymorphisms?
- MHC - Antigen Presentation
- TLR
- activation determines type and intensity of response - Cytokine
- liked to differences in production (INCREASED)
MHC - Ag presentation dictates what?
What is no antigen displayed?
What if there is a polymorphic MHC?
- MHC-antigen presentation dictates how the immune system responds
a) If doesn’t display Ag, NO response
b) the antigen IS presented, the polymorphic MHC generates multiple unique antigen binding grooves that
guarantee almost INFINITE VARIETY on how the peptide is displayed by the DC
The duration and intensity of the response is dependent on “how much” a _____ is triggered.
What determines the affinity and number of these?
What is associated with SLE?
What is the trigger for labor?
- TLR
- Genetics!
- “hyperstimulation” of a DNA sensing TLR may be associated with SLE
- Level of fetal DNA in the mother
“different DNA” TLR senses fetal DNA level and induces labor
Cytokine Polymorphisms:
Patients who produce lots of ______ to a given stimulus do better after a bone marrow transplant because they suppress graft versus host reactions better than those who produce low amounts of this cytokine
Mutations in this cytokine are associated with IBD.
Is it hypo or hyper produced?
Patients transplanted with a specific TLR polymorphism had increased risk of a specific type of _____
- IL-10
- IL-10
HYPO - PRODUCED (less IL -10 to suppress inflammation)
- fungal infection
Bacteria manipulate our _____ to be tolerant of them
Bacterial populations in the gut dictate how we respond to various antigens by what?
What is the risk of altering gut bacteria with medical treatments?
- DC
- manipulating our Tregs
- change the ratio of Treg/Th17 - risk the development of autoimmune diseases!
What is epidemiology?
What does it provide us with?
The factors that influence the incidence, distribution and control of infectious diseases
- study of epidemics and epidemic diseases
2. Calculate mortality and morbidity
Why does infection result in a diverse set of clinical symptoms and disease outcomes?
Wide spectrum of :
- Antigen presentation
- TLR
- Cytokine activation
** same for vaccinogenetics**
Ground rules of Vaccinogenetics:
- _____ for intracellular infections
- _____ for fungal infections (need what type of cells?)
- mediated by toxins or organisms that cannot hide inside cells, stimulate _____
- Viral disease, prevent dissemination of virus and facilitate ____ responses to limit cellular infection
- TMMI for intracellular infections
- IL17 for fungal infections –> Th17 cells!!
- B cell response for
- T cell responses!
dissemination = act of spreading something
What is the most important thing in the vaccine? (rendering it helpful)
MEMORY
How can drug addiction vaccines be created?
ex: Cocaine
- causes effect by binding to dopamine transporters and blocking their ability to clear dopamine
ANTIBODIES created to bind to cocaine
= bigger complex that cannot fit through BBB
What is the purpose of adjuvants?
Enhance immunogenicity by creating a depot for the antigen so there is prolonged exposure to it as it is slowly released, or by activating innate immunity that “primes” APCs via TLR’s
- stimulate TLRs and trigger a tremendous TLR response
What are the 2 basic tenets of tumor immunology?
- Some but not all malignant cells look “different” to immune cells. (immune system will not pay attention to them)
- The ones that look different can be attacked by immune effector cells.
What are 3 ways the tumor cell can look different to the immune system?
- Mutation
- Overexpression
- Post-translational modification (DNA methylation)
What are 4 ways that a tumor cell can be killed?
- NK cell recognizes altered MHC
- CD8 cytotoxicity (from Nk and Cd4 cells)
- Complement activation by B cell plasma cells via Th2 response
- NK FcR ADCC
- crosslink fc receptors
The survival of a “recognizable” tumor cell implies that either it is not recognizable to the immune system or it has developed a mechanism(s) to thwart activation of ____ responses to it
cytotoxic
Tumor cells can secrete what to protect themselves?
What can they convert cells into?
TGF - B
IL - 4
IL - 6
IL - 10
Treg!!!
What chemokines do tumor cells secrete to covert a cell into a Treg?
What else secretes this chemokine?
What is the result?
CCL-21 (test!!!)
- fibroblasts secrete CCL-21 as well!
IMMUNOSUPPRESSIVE ENVIRONMENT FORMED
- promote Treg formation
RESULT: tumor evades the immune response
Tumors can also display a ligand that activates an inhibitory receptor on cytotoxic T cells.
What is it?
PD -1
What is the function of PD-1?
When is it unregulated?
How can tumors utilize it?
- Inhibitory T cell receptor, distinct from CTLA - 4
- When engaged with PD-L1 or 2 it PARALYZES OR KILLS T cell
- Unregulated during PROLONGED ANTIGEN exposure
- Tumore upregulate PD-1/2 ligands and NEUTRALIZE and cytotoxic T cells that attack the tumor
If a tumor can convert cytotoxic T cells to T regs, then the only defense left is what?
Will this cell be active if the tumor cell is displaying antigen on its surface, and not in context of MHC -1?
WHat 3 things are blocked?
- NK cells through Fcr!
- but there is no antibody bound to antigen!!!
- only way to kill it is if the tumor is presenting antigen to MHC - I
2. but if tumor itself is displaying antigen on the surface, the NK cells are not activated)
- B cell response
CD4 (TMMI)
CD8 cytotoxicity
Where is the PD -1 receptor found?
What happens when it is engaged with PD-L1?
How can tumors use it?
What will be neutralized?
- On T cells
- Inhibits/kills T cells when engaged with PD-L1 and/or 2
- Tumors can upregulate PD L1/2 on their surface
- Any cytotoxic T cell attacking the tumor will be neutralized
What can be used to inhibit the death signal initiated by PD-1 (via tumor) cell to allow the CD8 cell to kill?
Already several monoclonals available to inhibit the death signal and allow the CD8 cell to kill
- TX: monoclonals Anti-CTLA 4 and ANTI- PD-L1 = CD8 cells migrate INTO THE TUMOR
CD28 active, CTLA 4 blocked,
PD-1 blocked
= TUMOR RESPONSES ARE ASTOUNDING
What happens if a tumor blocks the CTLA4 receptor?
PROTECTING ITSELF
- cannot engage the receptor and thus the cell does not go into anergy
What is an inhibitory signal on T cells?
Negative regulation?
What can be developed to block tumor binding to either of these?
What is this therapy called?
- CTLA -4
- PD-1 (programmed cell death)
Anti - CTLA 4 monoclonals
&
Anti - PD -1 monoclonal antibodies to bind and present the tumor cell from binding
IMMUNE CHECKPOINT THERAPY
