11-immune Respone Against Tumors And Transplants Flashcards
Xenograft. Rejected or no?
Donor and recipient are from different species
Rejected unless immune privelaged site
Allograft. Rejected?
Donor and recipient are from same species, but differ at MHC loci
Rejected unless immune privelaged site
Syngraft. Rejected?
Donor and recipient are MHC identical
Not rejected
Autograft. Rejected?
Donor is recipient
Not rejected
Rejecting transplants is a ______ cell based rejection
T cell
Quickness of xeno and allograft rejection?
Very quick
Xeno within minutes
Allo takes more time: because it is human
7-10/10-12 is adaptive response
What lead to discovery of MHC? Aka?
Transplant rejection initial work led to discovery
HLA: human leukocyte antigen
Hyperacute graft rejection. Time? Cause? Effects?
Due to preformed antibodies
Alloantigen(blood group) of endothelial cell binds circulating alloantigen-specific antibody in blood vessels
Happens in less than a day
Leads to compliment activation, endothelial damage, inflammation, thrombosis
Chronic graft rejection. Cause? Time? Effects?
Takes decades to form, chronic inflammatory reaction in vessel wall. Internal wall proliferation leads to vessel occlusion
Two ways:
1) MHC is a couple amino acids different, takes 10-20 years for body to notice the difference (MHC not usually used as an antigen in immune response)
2) solid organ transplant: something happens to physiology during transplant process–>blood vessel occlusion. NOT antigen specific issue, vascular issue w/ non specific inflammatory responses, but STILL classified as rejection
A) vascular collapse triggers response in body leading to blood vessel occlusion: layers of tissue added, eventually not much blood can get through (perfusion dec)
Most solid don’t last for 30 years. 10-15 best of them
Usually other rejection before this can take effect
Acute graft rejection
Human-human, but MHC mismatched
Closer you are matched at each class 1 and 2 loci, slower rejection takes
T cell response (type 4 reaction)
Causes parenchymal cell damage, interstitial inflammation, endothelialitis
Immunosuppressants balance
Suppress enough so it doesn’t kill graft, but now so much that they are immunodeficienct and cannot fight infections
Especially used for acute graft rejection
Direct vs indirect allorecognition?
Two ways to activate against a graft
1) direct: graft tells new host it is foreign: graft APCs go to nearest to lymph node and activate host T cells–> we respond against foreign MHCs the most
2) indirect: host has to figure it out for itself: host APCs infiltrate new graft, pick up antigens, and carry them back. Usually host APCs can pick up entire cells, break them down, full MHC breakdown and present it
Both cases: body treats it as foreign antigen
Same relative timing
What is GVHD
Graft versus host disease
Follows allogenic or xenogenic bone marrow transplant
Have to remove everything else (the cancerous stem cells) before BMT (stem cell transplants)
Tissue and organ damage; wasting; death
Occurs in immuno-compromised recipients of grafts containing immune cells
What are immune privelaged sites?
Can tolerate grafting without provoking immune response
Ex: corneal transplants are not rejected unless damaged barrier: results in inflammation and vascularization occurs
Mechanisms unclear: reduced MHC expression, active suppression by FasL or cytokines such as TGF-B
Fetus as the original allograft, what factors?
Fetus, with placenta, creates environment where it is not susceptible to moms immune response (fetus is half foreign)
Fetal RBCs can cross placenta
Site protected by nonimmunogenic tissue barriers
Local immunosuppressive response in mother
Mothers immune response slightly weakened during
***How does the placenta sequester fetus away from mother’s T cells?
Needs to because mother makes Ab against father’s MHC and RBC Ag
Trophoblast (outermost layer) has no MHC I or II, presents no classical HLA class I, which binds to inhibitory receptors on NK cells (they won’t attack)
Also, nutrient deprivation (Tryp): if cells activate they can’t divide
***How does fetus suppress TH1 of mother?
Fetus secretes cytokines at the interface that turn down/off inflammatory responses
Remember about transplantation:
It’s complicated, tricky, NOT a permanent lifelong fix: adds years of life, but cannot last for decades, transplants are ALWAYS rejected eventually
What is key for anti-graft rejection treatments?
Do it too much=immunosuppressed
Too little=rejection
Treatments for graft rejection: what do they do?
Corticosteroids:
Rapamycin:
Anti-IL2:
CTLA4:
Corticosteroids:broad anti inflammatory
Rapamycin: blocks lymphocyte proliferation by inhibiting IL-2 signaling
Anti-IL2: stops proliferation response for T cells
CTLA4: negative equivalent of CD28
Transplant summary
Transplant rejection occurs b/c graft antigens are seen as foreign
Severity of rejection is influenced by how foreign the graft is compared to the host
Nearly all transplants are rejected (usually immune, vascular collapse also)
Generalization about tumor rejection
It happens, much evidence to support
Inhibiting tumor growth, IS protects against tumor growth
Why is the CD8 tumor response important?
IS is good at recognizing pre-cancerous cells
As they mutate and develop abilities, we usually catch them
Need both CD8 and CD4: really want Cd8 to actually kill tumor cells
How does CD8 tumor response work?
If you can get APC (dendritic) to take in a cancerous cell, if cancerous cell has specific antigen to cancer–> can trigger immune response
Altered-self: changed enough that we are not screened against it
CD8 activated then, can seek out and destroy any cell with tumor antigen
CD4s activated can stimulate CD8s to differentiate, etc.
Different types/sources of tumor antigens?
- mutated self
- if you want immune response to deal with the cells, you need a unique antigen, but many rumors don’t have an antigen we can target
- aberrently expressed self protein: tissues have unique antigens: if one is found in the wrong place (testicular in lungs for example) we can recognize cancer
- potential viral antigen (HPV)
- oncogenic
Mechanisms of tumor escape?
Cancer cells develop ways to avoid tumor control:
- self antigens (lose tumor antigen variant)
- turn on and turn off MHC (mutate genes for antigen processing)
- turn on atypical MHC: such as with placenta to suppress CD8 and NK response
- secrete immunosuppressive cytokines
***what is tumor immunogenicity? (A tumor therapy)
Artificial lymph node outside of person, forcing the issue
Four main methods of tumor immunotherapy?
1) vaccination (can have a problem with tolerance)
2) Monoclonal antibodies***
3) cytokines injections
4) tumor immunogenicity
***How are monoclonal antibodies a method of tumor immunotherapy?
(MAb)
Conjugate them to toxins and isotopes for specific response
Creating tumor specific T cells/antibodies and give through passive immunity transfer
How are cytokines injections a method of tumor immunotherapy?
Increasing immunogenicity and inflammatory response
Ex: IFN-a for hairy leukoplakia: reactivation Epstein Barr virus, hit with cytokines to get IS to reactivate
Couple versions of tumor immunogenicity?
1) adoptive immunotherapy: clonal expansion of CTLs and NKs
2) gene transfer
3) pulverize cancer cells: give to dendritic and give them incentive to take them up, hit with right cytokines and they express costimulators–> then have B7 to trigger adaptive response
Need costim before exposure to naive T cells so they don’t go to anergy
Cancer summary
Cancer cells develop antibodies over time due to mutations
Immune cells can recognize pre-cancerous and cancer cells if they express altered-self antigens or adherent my expressed self-antigens
Once cancer becomes malignant and detectable it has escaped immune control
Will a newborn child test positive for ELISA at birth?
Yes, because they would have their mothers IgG HIV antibodies and ELISA tests for antibodies against the virus
Would take 6 months to clear and test HIV-
3 methods of tumor immunotherapy?
1) passive immunity by transfer of tumor-specific T cells or antibodies
2) active T cell immunity enhanced by dendritic cell “vaccines” (forced to take in tumor antigen and express with costim)
3) active immunity enhanced by antibody blockade of T cell inhibitory molecules (if cancer cells are expressing inhibitory costimulation)
