Manipulation of the Immune Response Flashcards
Why are multiple vaccinations “boosters” needed?
Vaccines often don’t stimulate the immune system strongly enough to confer protective immunity. Each booster leads to a greater and longer lasting response by the immune system
What is the composition of DTaP?
Diphtheria toxoid, tetanus toxoid and an inactivated pertussis bacteria
What is the advantage of combining the pertussis bacteria with the diphtheria and tetanus toxoids?
The presence of the bacteria stimulates an improved response to the toxins (presumably by upregulating B7 expression by antigen presenting cells).
Side effect: it produces more inflammation and discomfort at the site of injection
Name 4 different antigen sources for vaccines
Killed/inactivated pathogen
Toxoid
Viral subunits
Live attenuated virus
What type of immunity must be produced for intracellular infections?
Cell mediated immunity
What type of cytokine must be produced for fungal infections?
IL17
What type of response must be generated against toxins and organisms that resist phagocytosis?
B cell responses
What type of response must be generated against viruses?
Both T and B cells should coordinate to fight off viruses
What are the pros and cons of dead/inactivated pathogens?
Pros: safe, more stable than attenuated antigens
Cons: Weaker cell mediated response, boosters required + sometimes contaminants are present
What are the pros and cons of live attenuated pathogen vaccines?
Pros: better cell-mediated responses
Cons: Reversion- risk of infecting immunocompromised people, less stable
What are the pros and cons of using molecular components for a vaccine?
Pros: no living pathogen, very stable
Cons: fewer epitopes, weaker cell mediated response
What is the “basic tenet of tumor immunology”?
Malignant cells are “different” and can be recognized by immune cells. Malignant cells can be attacked by immune effectors thru recognition of tumor associated antigens which are; mutant proteins, overexpressed proteins or modified “altered-self” proteins
If the immune system can recognize and destroy tumor cells, then why does cancer grow?
Either 1) the tumor cell is not recognized by the immune system or 2) it has developed a mechanism to thwart activation of an immune response to it
What makes up tumor antigens?
Tumor antigens are usually self-proteins modified or selectively over-expressed by a tumor
What is GP-100?
GP-100 is the melanocyte specific antigen- antibodies against GP-100 will eliminate all melanocytes (both melanoma and healthy melanocytes)
Name three vectors for the delivery of tumor-specific antigens
1) Retroviral
2) Conventional adjuvants (alum)
3) Dendritic cells
Tumor cells are poorly immunogenic so immunogenicity must be increased. Name three methods to increase the immunogenicity of tumors
1) Addition of adjuvants
2) Use of gene-engineered tumor cells - cytokines
3) Co-stimulatory molecules B7
What are the cell mediated immune responses against tumor cells?
CD4+ T cells: produce cytokines and help CD8+ T-cells and B cells with their effector function
CD8+ T cells: direct lysis/killing of antigen-expressing cells
What are the B cell -mediated immune responses against tumor cells?
Ab production
What are the granulocyte-mediated immune responses against tumors?
Ab-dependent cytotoxicity (ADCC)
What are the macrophage-mediated immune responses against tumors?
Cytokine-induced killing
Antibody-dependent cytotoxicity
What are the natural-killer cell-mediated immune responses against tumors/
Direct lysis of tumor cell targets
Ab-dependent cytotoxicity
What are the cytokine-mediated immune responses against tumors?
Direct tumor killing (TNF-alpha)
What are the antibody-mediated immune responses against tumors?
coating of tumor cells –> Antibody-dependent cytotoxicity
How does “antigenic loss” allow tumors to escape immune killing?
Downregulation of recognizable antigen targets means that CD4+ and CD8+ T cells cannot recognize the tumor any longer and mount a response against it
Other than downregulation of specific antigens, how can a tumor cell evade recognition by the immune system?
Loss of MHC class I/antigen processing
- MHC class I expression
- TAP etc (for processing/loading)
- Loss of CD8+ T cell recognition
What can tumor cells secrete to avoid the immune system?
Inhibitory cytokines
-TGFbeta, IL-10, DCs, T regs
What is Rituximab?
Anti-CD20 monoclonal antibody
Eliminates B-cell lymphoma cells expressing CD20. Works synergistically with chemo or radiation
Recognizes B cell marker regulating B cell activation, induces growth arrest and apoptosis in vitro
What is herceptin?
Anti-Her2 monoclonal antibody
Works synergistically with radiation therapy
Recognizes EGF-like receptor regulating cellular proliferation (ERBB2) and induces growth arrest and apoptosis in vitro
What are TILs?
Tumor infiltrating lymphocytes
How are TILs generated?
Culture lymphocytes with tumor fragments to sensitize them against the tumor antigens, infuse back into patient
You are infusing the patient’s own T-cells so reactivity is not a problem
TILS are most effective against what type of tumors?
Highly immunogenic tumors- melanoma in particular
What is the main drawback of TILs?
Lack of persistence of transferred cells –> only confers passive immunity
What are the four components of a CAR T cell?
Variable region of the heavy chain
Variable region of the light chain
CD8+ transmembrane region
CD3+ signaling component (zeta subunit)
These are all combined in a retroviral vector
Describe the production of CAR T cells
1) Leukocytes are collected from donor blood
2) T cells are transfected with the chimeric receptor retrovirus and activated
3) Cells are grown/expanded
4) Cells are selected for a re-transfused into the patient
How do CAR-T cells kill their target cells?
CAR’s recognize antigen on the tumor cells, are activated and induce apoptosis through the death receptor pathway, release pro-inflammatory cytokines, and release cytotoxic granules
What are the two immune checkpoints that tumors have co-opted to down regulate the immune response to a tumor?
CTLA-4 and PD-1
How can antibodies against CTLA-4 and PD-1 help in tumor destruction?
Tumor cells express CTLA-4 and PD-1 to block the activation of T-cells.
Antibodies against CTLA-4 and PD-1 block this and the T cells are activated normally now
What are CTLA-4 and PD-1 usually used for?
They are checkpoints to prevent over-reaction
They act on T cells and NK cells
What is PD-1? Where is it normally expressed?
PD-1 = Programmed cell death protein-1
Expressed on T-cells
What is the normal purpose of PD-1? How is co-opted by tumor cells?
PD-1 binds two ligands- PD-L-1 and PD-L-2
PD-1 functions as an immune checkpoint, playing an important role in down regulating the immune response by preventing the activation of T-cells and by promoting apoptosis
Normal homeostasis, PD-1 reduces autoimmunity and promotes self tolerance. However, tumors can upregulate PD L1/2 on their surface, neutralizing cytotoxic T cell tumor attack
What is Nivolumab
Mab against PD-1
