Real World Manipulation of the Immune Response Flashcards
What is acquired immunity?
active immunity that provides long lasting protection from the infectious agent (immunological memory)
What can acquired immunity be a consequence of?
an active infection or an intentional vaccination
What is passive immunity?
transfer of immunity by Ab
How is passive immunity different from acquired immunity?
provides immediate protection but does not provide for long lasting immunity (no immunological memory)
What are some examples of passive immunity?
protection from intestinal infection from mothers milk and colostrum
transfer of Ab for immediate protection from e.g. spider or snake venom
What does a protective level of immunity require?
multiple immunizations with vaccines
What does inactivation of the pathogen by heat or chemical means do?
the pathogen is not capable of reproduction in the host, but the epitopes still remain against which the host can mount an immune response
In addition to provoking a protective immune response, what must effective vaccinations include?
be safe
high proportion of population must be protected
immunity must be long lasting
inexpensive
offer herd immunity
What is herd immunity?
lowering the number of susceptible individuals lowers the number of possible infections, which reduces transmission.
When is herd immunity effective?
if vaccine coverage is high
What are antigen sources?
killed/inactivated pathogen
toxoid
viral subunits
live attenuated virus
What must be known about a pathogen in order to devise an effective vaccine?
cell mediated immunity for intracellular infections
IL17 for fungal infections
B cell response for toxins and organisms that resist phagocytosis
T&B responses for viruses
What must a vaccine do in all cases?
generate memory cells
What are the pros of dead pathogens?
may be safer, more stable than attenuated
What are the cons of dead pathogens?
weaker cell mediated response
boosters require contaminants
What are the pros of live attenuated pathogens?
provide a better cell mediated response than dead
What are the cons of live attenuated pathogens?
reversion - low risk of infection in immunocompromised patients
What are the pros of molecular components?
no living pathogen present
very stable
What are the cons of molecular components?
fewer epitopes
weaker cell mediated response
How can malignant cells be attacked by immune effectors?
via recognition of tumor associated antigens
What are tumor associated antigens?
mutant proteins, over expressed proteins, altered-self proteins
What are typical tumor antigens?
usually self proteins modified or selectively over expressed by a tumor
What are some examples of cell-type specific tumor antigens?
melanoma (essentially melanocyte specific): MART-1, tyrosinase, Gp-100
B cell lymphoma (essentially B cell specific): CD20
AML (essentially myeloid specific): CD33
Prostate Cancer: PSA (prostate specific antigen
What are some examples of shared tumor associated antigens?
MAGE-3 (e.g. melanoma)
Carcinoembryonic antigen (CEA): colon and rectal cancer
HER2/neu: over expressed in breast cancer
What are some examples of tumoral viral antigens?
HPV
What does vaccination do as immunotherapy against tumors?
therapeutic: boosts ‘ineffective’ T cell responses
What are some examples of specific antigen vaccines
synthetic peptide fragments: Gp100 209-217
recombinant proteins: Gp100 AA 209-217
DNA/RNA: nucleotides encoding Gp100 AA 209-217
What are some examples of delivery vectors for specific antigen vaccines?
conventional adjuvants
viral (retroviral) delivery
dendritic cells - feed tumor Ag to a DC to stimulate response
How is immunogenicity increased against a tumor by using whole tumor vaccine techniques?
use adjuvants
use gene engineered tumor cells that will result in cytokines or upregulation of co-stimulatory molecules such as B7
What are the anti-tumor effects of CD4+ T cells
produces cytokines and provides help for CD8+ T cells and C cells
What are the anti-tumor effects of CD8+ T cells?
direct lysing/killing of Ag expressing cells
What are the anti-tumor effects of B cells?
produce Ab
What are the anti-tumor effects of granulocytes?
Ab-Dependent Cytotoxicity (ADCC)
What are the anti-tumor effects of macrophages?
cytokine-induced killing
ADCC
What are the anti-tumor effects of NKs?
direct lysing of tumor cell targer
ADCC
What are the anti-tumor effects of cytokines?
direct tumor killing (eg via TNF-alpha)
what are the anti-tumor effects of Ab?
coating of tumor cell (ADCC)
How do tumor cells escape the immune system?
antigenic loss variants and immune inhibition
What are the antigenic loss variants that allow a tumor to evade the immune system?
loss of antigen targets: loss of CD4 and CD8 epitopes, loss of binding to CD20
loss of MHC class I/Ag processing: mutation of TAP - prevents Ag from entering the ER
What do tumor cells produce that can inhibit the immune system?
TGF-beta, IL-10, induction of Tregs
What is Rituximab, and what does it do?
anti-CD20
recognizes B-cell marker and activates B cells
induces growth arrest/apoptosis in vitro
What is Herceptin?
anti-HER2
recognizes EGF like receptors regulating cellular proliferation (ERBB22)
induces growth arrest/apoptosis in vitro
What are TILs and what do they do?
Tumor infiltrating lymphocytes
generates effector T cells
Take tumor fragments, cultivate with TILs and allow to expand, transfuse TILs into patient
What is passive (adoptive) immunotherapy?
patients own T cells are activated in vitro and retransferred
provides an exogenous source of anti-tumor T cells
How is tumor specificity generated for passive immunotherapy?
using defined tumor specific antigen
using TILs
What is a CAR and how is it produced?
chimeric antigen receptor
take Vh and Vl and combine it with the TCR zeta signaling complex via a CD8 transmembrane unit
How can CAR be used to eliminate a tumor?
create a CAR against a specific tumor antigen, expand and infuse into patient so that the transduced T cells can mount a T cells response against the tumor
How does CAR lead to killing of a tumor?
production of granzyme, perforin, and other apoptotic signals
release of pro-inflammatory cytokines IL-2, IFN-gamma, TNF-alpha
What are some inhibitory signaling molecules that tumors can use to inactivate the immune system?
CTLA-4 ligands, PD-1 ligands
act on T cells and NK cells
What is the function of CTLA 4?
immune checkpoint that downregulates the immune response
On what cells is CTLA 4, and what does it bind?
on the surface of T cells, binds B7 on APC cells and acts as an off switch
When are CTLA4 receptors upregulated?
following T cell stimulation - prevents an overactive immune response
What is the binding affinity of CTLA4 for B7
high - higher than CD28, which allows CTLA4 to stop the immune response
What does Ipilimumab do?
Tumor cells can produce CTLA 4
Ipilimumab blocks CTLA4 which allows the costimulation by CD28 to continue
What is PD-1 and on what cells is it found?
Programmed cell death protein-1
found on T cells
What does PD-1 bind?
PD-L-1 and PD-L-2
How can tumor cells co-opt PD-1 to evade the immune system?
tumor cells can upregulate PDL-1/2 on their surface, neutralizing the cytotoxic T cell response (cause death of T cells that express PD-1)
How does ivolumab reinstate the T cell response?
mAb against PD-1 receptor on T cells which prevents binding by PD-L1 on tumor cells
