Tumors and Transplants Flashcards
1
Q
3 Possible Tumor Antigens
A
- Products of mutated genes that have no other role in tumor (passenger mutations)
- Products of oncogenes or mutated tumor suppressor genes; drive malignant transformation (driver mutations)
- Proteins of normal structure but aberrant expression (ex- expression of fetal proteins in adults or proteins only expressed in germ cells or overexpression)
2
Q
How do tumor cells evade immune system?
A
- Stop expressing antigen (antigen loss variants); if antigen is not involved in malignant growth than tumor keeps evolving
- Stop expressing MHC class I molecules so cannot present to CD8+ cells; NK cells may take over at this point (NK cells attack cells w/o MHC)
- Tumors engage pathways that inhibit T cell activation
- Express PD-1 ligands (inhibitory receptors)
- Down-regulate B-7 on APCs —> engagement of CTLA-4 over CD28
- Secrete immunosuppressive cytokines (like TGF-beta)
- Induce regulatory T cells
3
Q
Passive Cancer Immunotherapy (3)
A
- Antibody therapy - can cause phagocytosis and complement activation OR antibody against VEGF (Avastin) OR antibodies to block growth factor signaling (anti Her2/Neu)
- Adoptive cellular therapy - get T cells from tumor w/in patient, expand # w/ growth factors then inject back into pt (these T cells are assumed to be tumor-specific CTLs)
- Chimeric antigen receptors - genetically introduce tumor antigen receptor into pt’s T cells then grown ex vivo and injected back into pt
4
Q
Active Cancer Immunotherapy (3)
A
- Vaccination - inject tumor cells or tumor antigens w/ adjuvant; inject patient’s own dendritic cells that are expanded and exposed to tumor antigen in vitro then injected (so they are ready to cross present when they encounter tumor)
- Checkpoint Blockade - block normal inhibitory signals for lymphocytes; antibodies against PD-1, CTLA-4 and PD-1’s ligand; chance of autoimmunity
- Cytokine Therapy- w/ cytokines that enhance activation of T cells (ex- IL-2)
5
Q
Transplant Waitlist Considerations (6)
A
- ABO blood group
- HLA matching
- Immune status of candidate -antibody screening and crossmatching (look to see if there are pre-formed antibodies in recipient blood that react w/ donor cells)
- Geo distance b/n donor and recipient
- Degree of medical urgency
- Length of time on waiting list
6
Q
Which transplants require matching?
A
- Solid organs - HLA A, B and DR
- Bone Marrow - HA A B C and DR (most needed)
- Liver and cornea - none
7
Q
2 Paths of Presentation of Graft Antigen
A
- 1- Direct Allorecognition- T cells recognize donor allogenic MHC on dendritic cells of the donor organ —> activates CTLs against cells of graft
- Peptide- independent - T cell just recognizes allogenic MHC as foreign
- Peptide-dependent - T cell recognizes the foreign MHC and bound peptide complex as foreign allogenic
- 2- Indirect Allorecognition - host dendritic cells ingest alloantigens then present them to T cells on donor’s own MHC molecules —> activates mainly CD4+ cells —> release cytokines
8
Q
3 Classes of Graft Rejection
A
- Hyperacute (w/in min) - thrombosis of graft vessels and ischemic necrosis of graft tissue; antibodies bind antigen on graft endothelium —> activate complement and clotting cascade; antibodies are pre-formed (IgM “natural antibodies” or from previous blood transfusion, transplant or pregnancy)
- Usually does not happen b/c cross match before operation; cant be treated
- Acute (w/in days or weeks) - can be due to antibodies (complement damages vessels of graft) or CTLs or CD4+ cytokines/inflammation
- Principle cause of early graft failure; most immunosuppressives try to prevent T cell activation
- Chronic (w/in months or years) - progressive loss of graft function; fibrosis, gradual narrowing of graft vessels (graft atherosclerosis); T cells secrete cytokines —> fibroblasts and smooth muscle cell proliferation —> vessel occlusion
- Does not respond to current treatments so now this is the main problem
**Rejection time is faster upon second exposure - shows that immune response to transplant shows memory and specificity
9
Q
Blood Transfusion Antigens
A
- Blood group antigens (ABO antigens)
- Expressed on RBCs, endothelial cells, epithelial cells and others
- Carbs on membrane glycoproteins or glycosphingolipidsl core glycan w/ poss terminal sugar
- A/B - have different terminal sugars (AB blood has mix of both)
- O- no terminal sugar
- Others (minor blood groups)
- Ex- RhD antigen- protein is on RBC membrane; Rh antibodies made 0 high immunogenicity; if mom is Rh negative but baby has Rh from dad then mom may make Rh antibodies against baby (IgG so cross placenta)
- RhD antibodies made for first exposure but only create reaction w/ 2nd exposure
- Ex- RhD antigen- protein is on RBC membrane; Rh antibodies made 0 high immunogenicity; if mom is Rh negative but baby has Rh from dad then mom may make Rh antibodies against baby (IgG so cross placenta)
10
Q
Why is there no T cell response in blood transfusion?
A
No T cell response (only antibodies) b/c antigen is sugar NOT peptide
11
Q
Possible Transfusion Reactions (5)
A
- Acute hemolytic - incompatible RBCs
- Febrile non-hemolytic - alloantibodies react to HLA antigens
- Allergic non-hemolytic - preservatives or plasma proteins
- Acute lung injury from anti-WBC antibodies
- Graft v host disease if graft includes donor WBCs
12
Q
Bone Marrow Transplant Issues
A
- Must remove some host bone barrow to make room for new; leads to dec immune cells - immune suppression (w/ chemo and radiation)
- Strong reaction against heme stem cells so must HLA match
- Graft v host disease - if donor T cells come w/ marrow and attack host’s tissues
13
Q
Cyclosporin and Tacrolimus
A
- block calcineurin which blocks NFAT transcription factor from producing cytokines
14
Q
Mycophenolate Mofetil
A
- inhibits guanine nucleotide synthesis in leukocytes; no proliferation
15
Q
Rapamycin
A
- inhibits mTOR and IL-2 signaling to block lymphocyte proliferation
