transplantation and tumors Flashcards
autograft
one person to the same person
allograft
one person to a genetically different person
syngraft
-one person to a genetically identical person
xenograft
-graft to a different species
two mechs by which grafts are recognized by host t cells
- recipeient t cells recognize the peptides from donor MHC molecules which have been processed in host APC’s
- recipient t cells recognize unprocessed donor MHC molecules directly on the graft presenting cell (unprocessed)
hyperacute graft rejection
- minutes or hours
- due to preformed antibodies in the recipient
- compliment also binds to antibody
acute graft rejection
-mechanisms
- 10 to 14 days
- due mainly to cell mediated immunity but some injury is also antibody mediated
- diret contact with CD8 (perforin/granzyme and FAS L)
- locally released cytokines and chemokines (inflammation, macrophage activation, infiltration of phagocytic cells)
- antibody against donor HLA (complement binding and ADCC by NK cells)
- direct NK cell attack
- direct NK cell attack
stem cell transplantation
- how are they obtained
- what problem can occur
- can be obtained from peripheral blood if colony stimulation factor is given or from umbilical cord blood and bone marrow
- the major problem with bone marrow transplant is that competent T cells from the donor may be transplanted giving rise to graft versus host disease
graft versus host disease
- what is it
- what must occur to get this disease
- mechanism of cytokine storm
- a reaction of donor t cells against recipient MHC
- the graft must be contain live t cells (bone marrow/thymus)
- the recipient must be immunosuppressed
- the donor and recipeint must have different HLA types
- CD4 T cells in the graft are activated by allogenic molecules and produce a cytokine storm that recruits other T cells, macrophages, and NK cells to create the severe inflammation associated with this disease
cyclosporin and FK506
block a T cell phosphatase called calcineurin and inhibit cytokine production
corticosteroid
-also inhibit cytokine production
anti-CD3
monoclonal antibody that inhibits the binding of the coreceptor CD3
anti-IL-2 receptor
antibody that blocks the function of IL2
what is the problem with all forms of immunosuppressive therapy
-increases the risk of infection bu suppressing the bodies response to pathogens
types of antigens on the surface of tumor cells
- virally controlled antigens
- oncofetal antigens: alpha-fetoprotein (primary hepatocellular carcinoma) and carcino-embryonic antigen (CEA) (colon carcinoma)
- abnormal peptides made by tumor cells
- mutant antigens (Her2/neu - if positive can give herceptin)
- tissue specific differentiation antigens (PSA, B Cell and T Cell spec antigens)
- may lose HLA
flow cytommetry findings of b cell lymphoma
- normally a population of b lymphocytes will have some lambda and some kappa cells
- in b cell lymphoma, the cells are either all one or the other (monoclonal)
what happens if a tumor cell loses its HLA 1
- it will no longer be recognized by CD8 cells
- however, they will be killed by NK cells that recognize that they are HLA 1 negative
natural killer cells
- appearance
- function
- receptors
- how are they activated
- what do they produce
- large granular lymphocytes
- destroy infected malignant cells with absent or defective MHC 1 (this may occur after viral infection or malignant transformation)
- have Fc receptors that can bind IgG and give rise to ADCC
- can be activated by cytokines such as IL2, 12, and IFN gamma
- they produce a variety of cytokines
immune mechanisms of tumor rejection
- principal mechanism is by cytotoxic CD8 cells using granzyme and perforin, production of TNF, and expression of FasL on the CD cell
- killing of the tumor cells also takes place by activated macrophages and NK cells
how do tumors escape the immune system
- they release immunosuppressive factors like IL-10 and TGF-beta
- they release factors that activate TREG cells
- they select antigen-negative variants
cancer immunotherapy
- stimulation of the innate immuno mechanism
- checkpoint inhibitors: clock CTLA4 and PD-1/PDL-1 to remove the brakes from cytotoxic t cells
- immunization against oncogenic viruses such as hepB and HPV
- increase immunogenicity of tumors (B7, MHC2, cytokine genes)
- monoclonal antibodies: magic bullets with immunotoxins (ricin or radioactive isotopes)
ipilimumab
- anti CTLA4 monoclonal antibodies for the treatment of malignant melanoma
- AI disease and inflammation seen in 40% of patients treated with this
