Tumor and Transplant Flashcards
What are the three phases of immunoediting?
Elimination, equilibrium, and escape
What are the three therapeutic usages of ab’s in regards to tumor treatment
Immunodepletion (inject pateint with mAB against tumor antigens like with ritixumab)
-Receptor blockade like anti-vegf to inhibit angiogenesis
Toxin/Drug/Radio- conjugated antibodies, deliver toxic substance like ricin to specific tumor antigen spots
What is T cell exhaustion?
Repeated stimulation of T cells results in anergy, mediated by CTLA-4 and PD-1
What is the anti-CTLA-4 drug called?
-used in metastatic melanoma
Ipilumamab (Yervoy)
What is the opposite of Ipilumab?
Abatecept, this is a mAB that binds to the a CTLA-4-ig that blocks T cell activity by acting like normaly CTLA-4 and binding to B7-1/2, thus this is lock a constant off switch. Used in autoimmune disease like RA
What is the ligand for PD-1?
PD-L1 and PD-L2 expressed on Dendritic cells
What is the anti-PD-1 drug and what is it used for?
This is Nivolumab (Opdivo)
-this blocks PD-1 so therefor is like inhibits the off switch.
used in melanoma and non-small cell lung carcinoma
Describe a tumor vaccine and how it works?
Goal is to lead to active immunity, you inject a tumor antigen with adjuvants inorder to promote the immune system against that antigen, this induces inflammation and leads to an immune response
-there are also other type of vaccines
What is the Dendritic cell vaccine?
Sipuleucel-T
- used in metastatic castrate resistant prostate cancer
- works by taking APCs out of the patient, activating them in vitro, and putting them back into the patient and illiciting an immune response.
- stimulate the DCs with PAP (Prostatic acid phosphatases) and GM-CSF
What is a bi-specific antibdoy?
This has two targets
- Tumor antigen
- Immune receptor like CD3 or CD16 (NK cells)
- also can use the Fc region to target Fc receptors (tri-specific)
- goal is to bring immune cells in close proximity to tumor cells and make them recognize them.
How would you manipulate a T cell to respond independent of MHC and what would it be used for?
You take a T cell and put a BCR on it.
-example is for use in B cell leukemias/lymphoas with CD19 as the target
What is an scFc?
Single chain antibody.
-has a heavy a light chain connected by a peptide
What is the signaling portion of the scFv?
It is the zeta chain on the T cell, which alone is enough to promote T cell activation. They attach to scFv on to this.
Dfine Syngenic
geneticall identical
Define Congenic?
genetically identical exepct for a single locus (e.g. knock-out mouse line)
Define allogenic
Different members of the same species
Define Xenogeneic
Members of different species
What is autologous transplantation?
transplant within the same individual
example is skin grafts and HSCT
What ae the two mechanisms of transplant rejection?
Antibodies, and T cells (especially CTLs)
What are the two ways to increase TCR-MHC affinity?
Thymic selection orrr
T cell activation where you can can alter peptide or alter MHC
-any change to MHC with change the affinity for the TCR
Compare direct and indirect allorecognition and explain what they are?
- Direct allorecognition : Recipient T cells recognize Donor cells
- Indirect allorecognition: Recipient APCs present donor antigens via cross presentation
What is the mixed lymphocyte reaction used for and how does it work?
Recipient T cells are mixed with irradiated donor cells, if recipient cells response, they proliferate
-used to screen for T-cell mediated rejection
What is the hyperacute phase of allograft rejection?
- preexisting antibodies agaisnt graft endothelial cells
- could have originated from prior transfusions
- activates complement and clotting mechaisms
- should never happen with modern day screening
What is acute phase of allograft rejection?
Takes days to weeks
CTLs may target graft or blood vessells within graft
-antibodies may also contribute to vascular component of rejection
What is the chronic phase of allograft rejection?
Take months to years
-Th1 mediated (CTL, macrophages)
antibodies and complement
- progressive loss of graft function,
- fibrosis of graft and graft arteriosclerosis (narrowing of the graft vessels)
What are some of the drugs used in rejection prevention?
Steroids, cyclosporine/FK506
rapamycin
mycophenolate mofetil
thymogloublin (generate horse antibodies and deplete the patient of their own, then inject them with the horse antibodies
What is the MOA of cyclosporine?
It is a calcinuerin inhibitor and blocks the PLCgamma1 from phoshporylating it
What is the MOA of rapamycin?
It inhibits mTOR by preventing PI3-K from phosphorylating it
Why does xenotransplantation usually fail?
Because the complement regulatory proteins dont work (they do not cross-inhibit) so complement runs wild
Describe HSC transplant
first isolate the CD34 (HSC) cells from the blood of G-CSF treated donors, can get this from the bonemarrow or cord blood
- then prior to injection, clear the recipeients bone marrow to prepare space for incoming cells
- when this goes wrong it is the donors immune system that is attacking the recipient
What are some adverse health outcomes post -HSCT?
- graft failure
- delayed engraftment leads to hemorrhage and anemia
- opprtunistim infections
- GvHD (acute and chronic) 30-70% of patients will experience and mortality is near 50%
- tumor recurrence; secondary malignancy
Compare rejection to GvHD
Rejection is recipient rejects donor
GvHD is the donor immune system is attacking the recipient
What are billinghams postulates?
- graft must contain working cells
- recipient must express tissue antigens that are not presint in the transplant donor
- recipient must be incapable of mounting an effective respoinse to destory the transplanted cells
What are the two categories of GvHD
Acute and chronic, do not confuse these with the phases of rejection
Describe the three phases of Acute GvHD
What are the three categories of chronic GvHD?
these must be 100 days post transplant
What are the mechanisms of chronic GvHD?
- T cell mediated (Th1, CTL, macrophages)
- B cell mediated
- manifests in skin, GI, liver, lung , bonemarrow, thymus
What are some therapies for GvHD?
Steroids
methotrexate
cyclosproine
mycophenylate
anti-CD25 (Daclizumab/Zenapax)
What is the anti-CD25 drug called?
Daclizumab (Zenapax)
