Term
|
Definition
a graft or transplant from one area to another on the same individual
the graft is recognized as self and the immune system does not attack the graft
ex) skin graft when someone burns themselves severely |
|
|
Term
|
Definition
a transplantation of cells, tissue, or organ from one individual to another that is genetically identical (identical twins)
the donor's cells are still recognized as self to where the immune system does not attack |
|
|
Term
|
Definition
a graft or transplant from one individual to a genetically dissimilar individual of the same species
all individuals except identical twins are genetically dissimilar no matter how closely they are related (including fraternal twins)
the graft is recognized as NOT being self and the transplant is rejected
this is the main type of graft immunosuppressants are used for |
|
|
Term
|
Definition
a graft between a donor and recipient from different species
the transplant is recognized as foreign and the immune system proceeds to destroy it |
|
|
Term
hyperacute rejection
acute rejection
chronic rejection |
|
Definition
| 3 major types of allograft rejection |
|
|
Term
occurs within minutes to hours of transplantation
MOA: destruction of the transplant is caused by preformed antibodies = antibody dependent cellular cytotoxicity and complement
examples: previous pregnancies or transplantation; blood type mismatch
pharmacologic treatments are not effective |
|
Definition
hyperacute allograft rejection:
time to occurrence
mechanism
examples
pharmacologic treatments |
|
|
Term
begins after a few days, leading to loss of transplant function within weeks to months
MOA:
cell mediated immunity by T-cells is the primary cause of acute rejection
the key initiating event in graft rejection is the direct activation of the recipient's CD4+ T cells with non-self MHC II class antigens, which results in the release of IL-2 and the stimulation of proliferation of both CD4+ and CD8+ T-cells, in addition to recruitment of macrophages
common type of rejection experienced by those who the tissue is a mismatch and DO NOT RECEIVE ADEQUATE IMMUNOSUPPRESSANT THERAPY |
|
Definition
acute allograft rejection:
time to onset
mechanism |
|
|
Term
occurs months to years after transplanted tissue has assumed normal function; major cause of late graft loss
MOA: is caused by both antibody and cell-mediated immunity although the precise MOA remains unclear
not reversible; not reversed with immunosuppresion |
|
Definition
chronic allograft rejection:
time to onset
mechanism |
|
|
Term
1) APC take up foreign antigen and present them on self-MHC molecules to CD4+ and CD8+ T-cells resulting in their activation
2) through MHC molecules:
foreign MHC molecules are highly potent transplantation antigens
MHC I - expressed on every nucleated cell in the body and always there; CD8+ cells (cytotoxic T cells) interact with MHC I in conjugation with the antigen
MHC II - expressed constitutively on dendritic cells, B-cell, thymic epithelial cells; CD4+ cells (helper T cells) interact with MHC II
THE KEY INITIATING EVENT IN REJECTION IS ACTIVATION OF CD4+ T-CELLS BY DONOR MHC II |
|
Definition
| 2 immune system mechanisms of allograft rejection |
|
|
Term
the recognition of a foreign peptide (allopeptide) by recipient T-cells is key to the initiation of the rejection pathway
direct pathway:
activation of T-cells involves the recognition of intact foreign MHC molecules on the surface of donor cells, including donor derived APCs
indirect pathway:
processed allopeptides are presented to T cells by self MHC molecules on the surface of self APCs
direct = acute rejection
indirect = chronic rejection |
|
Definition
| direct and indirect pathways of allorejection |
|
|
Term
| the TH1 pathway activates macrophages and leads to further proliferation of CD4+ T-cells and the key initiating event in rejection is activation of CD4+ T-cells by donor MHC II |
|
Definition
| why is the TH1 pathway critical in acute rejection? |
|
|
Term
1) the alpha and beta chain of the CD4+ T-cell receptor complex interacts with antigen in addition to MHC II of the APC or the donor organ
2) this leads to signal transduction of the CD3 molecule
3) this leads to increased intracellular Ca
4) increased intracellular Ca then activates calcineurin
5) activated calcineurin then dephosphoryates NFAT, leading to the active form of NFAT
6) activated NFAT influences transcription leading to generation of pro-inflammatory cytokines such as IL-2
7) IL-2 then binds to the IL-2 receptor which then activates mTOR
8) mTOR then stimulates G1 to S transition initiating the cell cycle
9) DNA synthesis occurs in the S phase, followed by G2 and then mitosis, leading to cellular proliferation of T cells |
|
Definition
| stages of T-cell activation |
|
|
Term
polyclonal antibodies: combination of immunoglobulin molecules secreted against a specific antigen, each identifying a different epitope
example drugs: ATG, ALS
prepared by inoculating rabbits or horses with human lymphocytes, to where antibodies are made by the animal's B-cells against human lymphocytes; blood is taken from the animal, centrifuged to get serum and purified IgG fraction contain antibodies directed against many cell surface molecules expressed on T-cells (CD3, CD4, CD8, CD25)
MOA: antibody response generated against T-cells to where lymphocyte count is reduced by 85-90% |
|
Definition
polyclonal antibodies:
definition
example drugs
manufacture
MOA |
|
|
Term
first dose reaction: febrile reaction
antibodies can be made against the polyclonal antibodies: antigenic, prohibits multiple dosing
variability between batches: preparation potency, product properties (efficacy and toxicity can vary) |
|
Definition
| ADRs of polyclonal antibodies (ATG, ALS) |
|
|
Term
muromonab is a monoclonal antibody directed against CD3 molecules of human T-cells
after a T-cell binds to MHC,CD3 transfers a signal to the T-cell resulting in increased intracellular Ca
CD3 also plays a role as a chaperone in transporting the T-cell receptor to the cell surface
MOA:
inhibits intracellular signal transduction resulting from the T-cell receptor interacting with non-self antigen
rapid internalization of the T-cell receptor which prevents subsequent antigen recognition
reduces function of remaining T cells |
|
Definition
|
|
Term
minutes: profound lymphodepletion due to T-cell lysis
3-5 days: T-lymphocytes can be detected but do not express CD3 and are immunologically incompetent (cannot signal that a substance is foreign) |
|
Definition
| time-line of muromonab's effects (monoclonal antibody against CD3) |
|
|
Term
initial binding results in T-cell activation and release of cytokines (antibody is made of mouse, and mouse is foreign to the immune system) leading to:
cytokine release syndrome - 1st dose reaction
generation of anti-mouse antibodies
humanized anti-CD3 monoclonal antibodies developed to minimize occurrence of anti-antibody response; do not cause 1st dose cytokine release syndrome |
|
Definition
| ADRs of muromonab (monoclonal antibody against CD3) and drugs developed to prevent these |
|
|
Term
humanized monoclonal antibody against the CD52 receptor in mature T-cells
primarily an anti-cancer drug
used in bone marrow and kidney transplants
CD52 found on B-cells, T-cells, and macrophages and alemtuzumab causes the death of these lymphocytes |
|
Definition
|
|
Term
inhibitors of calcineurin and T-cell activation
cyclosporin and tacrolimus bind to the immunophilins (cyclosporin binds to cyclophilin while tacrolimus binds to FKBP12) forming a complex that binds to calcineurin which inhibits calcineurin
the end result of inhibiting calcineurin is that it blocks the production of pro-inflammatory cytokines such as IL-2 and inhibits T-cell activation and proliferation |
|
Definition
| MOA of cyclosporin and tacrolimus |
|
|
Term
composed of 3 distinct subunits:
alpha chain - does not transmit intracellular signals, but confers high affinity binding of IL-2 to the receptor
beta chain - transduces intracellular signals
gamma chain
none of the chains have intrinsic enzymatic function; rather, they associate with intracellular tyrosine kinases (JAK1 and JAK3)
the kinases phosphorolate multiple tyrosine residues on the beta chain activating the mTOR pathway (leading to cellular proliferation of T-cells) |
|
Definition
| composition and signaling of the IL-2 receptor |
|
|
Term
monoclonal antibodies against the IL-2 receptor
basiliximuab and daclizumab bind to CD25 (IL2R alpha) and inhibit IL-2 mediated activation and proliferation of T-cells
because they are humanized, they do not trigger strong human anti-mouse antibody response; do not produce 1st dose reaction/cytokine release syndrome |
|
Definition
| MOA of basiliximab and daclizumab |
|
|
Term
bind to the immunophillin FKBP12 forming a complex
FKBP12 is the same protein that tacrolimus binds to but the FKBP12 complex with serolimus or everolimus does not inhibit calcineurin
instead the complex inhibits mTOR (kinase involved in cell cycle progression - G1 to S transition)
cellular proliferation in response to IL-2 is inhibited |
|
Definition
| MOA of serolimus and everolimus |
|
|
Term
wound healing problems due to their inhibitory effects on fibroblast growth factor
effects on insulin and growth factor production |
|
Definition
| side effects of serolimus and everolimus |
|
|
Term
azathioprine is an inhibitor of B-cell and T-cell proliferation
azathioprine is a prodrug of 6-mercaptopurine (glutathione-S transferase activity is required)
metabolism of 6-mercaptopurine:
1) conversion by xanthine oxidase to 6-thiouric acid (inactive)
2) metabolism by thiopurine methyltransferase (TPMT) to an inactive compound; in humans TPMT activity can be low or normal; low activity can lead to profound myelosuppression
3) conversion by HGPRT to 6-thioinosinic acid; further metabolized by IMPDH to 6-thioguanine nucleotides
these nucleotides are incorporated into DNA, halting replication leading to non-functional DNA and RNA cytotoxicity
azathioprine can also inhibit the first enzymatic step in de novo purine biosynthesis
also inhibits metabolic conversion of IMP to adenosine or IMP to xanthosine monophosphate (forms guanosine)
T-cells and B-cells depend on de novo purine synthesis for cell division and now lack a salvage pathway for purine production -> blocks T and B cell proliferation |
|
Definition
| metabolic fate of azathioprine and MOA |
|
|
Term
prodrug that is rapidly metabolized to the active drug, mycophenolic acid
mycophenolic acid is a selective inhibitor of inosine monophosphate dehydrogenase (IMPDH)
IMPDH is the enzyme involved in the rate limiting step in converting IMP to guanosine monophosphate
IMPDH is a key enzyme in the de novo pathway of guanine nucleotide synthesis
B and T cells are highly dependent on this pathway for cell proliferation, as they lack a salvage pathway for guanine
mycophenolate inhibits lymphocyte proliferation and antibody formation |
|
Definition
| MOA of mycophenolate mofetil |
|
|
Term
effects:
suppresses prostaglandin synthesis
impairs monocyte and lymphocyte function
decreases the number of circulating CD4+ T-cells
decreases transcription of pro-inflammatory cytokines
has inhibitory influences on gene transcription by NFAT and decreases transcription of pro-inflammatory cytokines through one of 2 ways:
1) transactivation:
prednisone increases transcription of a gene
prednisone binds to the glucocorticoid receptor in the cytoplasm; travels to the nucleus; GR dimerizes and binds to the DNA to influence transcription
2) transrepression:
prednisone binds to GR and translocates to the nucleus, deacetylates histone leading to repression of inflammatory gene transcription such as NFAT genes -> leads to decreased transcription of pro-inflammatory cytokines such as IL-2 |
|
Definition
|
|
Term
Tu = tumors
Li = immune system
O = mouse
A = rat
Zu = human
Xi = chimeric
Mab = monoclonal antibody |
|
Definition
| abbreviations: Tu, Li, O, A, Zu, Xi, Mab |
|
|
