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Transcript
Immunosuppressive
medications
Mechanisms
Usage
Side effects
Allograft rejection
T cell (CD4+) dependent
recognize intact MHC class II antigens of the
surface of transplanted cells
recognize processed antigens on self APCs
T cell receptors (TCRs)
major TCR a + b heterodimer
minor TCR g + d heterodimer
constant and variable portions
Allograft rejection
TCR engages presented alloantigen
T cell is activated
TCR-CD3 complexes transduce signal 1
TCR-CD3 complexes and CD4 co-receptors
are phosphorylated
Transcription factors induce expression
of new proteins involved in cell division
and proliferation
Allograft rejection
Activated CD4+ cells differentiate into two
distinct populations
Type 1 T helper cells (Th1 cells)
IL-2, IFN-g
mediate activation of macrophages, and delayed
hypersensitivity
Type 2 T helper cells (Th2 cells)
IL-4, IL-5, IL-10, IL-13
involved in B cells function
Allograft rejection
Activated CD4+ cells secrete cytokines
which activate CD8+ cytotoxic cells
CD8+ cells recognize HLA class I
molecules, and, if T helper cytokines
(IL-2, IL-4, IL-5) are present
differentiate, divide, and destroy cells
with the recognized markers.
Allograft rejection
CD8+ secretory mechanism
granzymes (serine esterases)
perforins
kill by DNA degradations and osmotic lysis
CD8+ contact mechanism
Fas (CD95) on target meets the Tcell Fas
ligand
engagement of Fas ligand triggers apoptosis
Allograft rejection
IL-2 from macrophages induces Th1 cells
IL-4 from other cells induces Th2 cells
Th2 cells down regulate Th1 cells (yin-yang)
All T cell responses require two initiating
factors: a TCR-MHC interaction and a “costimulatory” signal
Tolerance is related to 1/2 stimulation: TCRMHC but no second “hit” as in absent or
blocked CD40, B7 interactions
Allograft rejection
CD8 knockouts still reject transplants
CD4 knockouts do not reject
B cell responses are important in the
hyperacute rejection and IgG plays a
role in chronic rejection
Natural killer (NK) cells recognize
alloMHC directly and kill MHC negative
and alloMHC cells
Allograft rejection
APCs take up foreign HLA proteins; HLA
on a donor APC is recognized directly
Ag specific T cells are activated,
proliferate, and enter circulation
T cells move to tissue in response to
selectins or chemoattractants
selectins, ICAMs, VCAMs, etc
Transplantation: therapy
options
Avoid need - disease prevention /
modificatioin
Designer organs
Immune tolerance
Immunosuppression
Immunosuppresion: history
Prednisone
Azathioprine
Total body (lymph node) irradiation
Splenectomy
Anti lymphocyte globulin ---- OKT3
Cyclosporine, FK506, rapamycin
Mycophenolate mofetil
Daclizumab, Basiliximab
Immunosuppression timeline
Prednisone
Azathioprine
Cyclosporin
Mycophenolate
Tacrolimus
Sirolimus
60’s
80’s
90’s
00’s
Immunosuppression: induction
Steroids
Azathioprine
CyA, FK 506 (tacrolimus), and rapamycin
OKT3, ALG, ATG
Mycophenolate
Daclizumab
Basiliximab
Immunosuppression: rescue
Steroids
OKT3, ATG, thymoglobulin
Mycophenolate
? role of receptor-blockers ?
Steroids: phamacokinetics
Agent specific
Prednisone half life 18 - 36 hours
70% protein bound
Actions do not correlate with plasma
concentrations
Volume of distribution variable
Elderly have decreased clearance, as do
women. Obesity increases clearance
Prednisone: drug interactions
P450 inducers increase the rate of
steroid metabolism
Nephrotic patients have more toxicity at
the same dosage and level
CyA and FK-506 may interfere
Prednisone: mechanisms
Glucocorticoids act upon steroid receptors and
induce genes which shut off cytokine
production
AP-1 complexes formed of Jun and Fos proteins
are bound by steroid/GR complex
Similar reactions occur with Il-1, Il-3, Il-4, Il-6,
IGF-1, TNF, IFN-g, Il-8, RANTES, and MCAF
Prednisone: mechanisms
Downregulates: collagenases, elastases,
plasminogen activator complex
Decreases: WBC numbers
Upregulates: neural endopeptidase which
degrades neuropeptides such as
substance P and bradykinin
Alters: adhesion molecules (ICAMs)
Prednisone: mechanisms
Decreases: release of Il-1b, TNF
Locally inhibits: arachadonic acid
metabolism (blocks PLA-A2)
Inhibits: cytokine dependent COX
Inhibits: platelet activation factor
Prevents: synthesis of inducible NO
synthase
Prednisone: side effects
Immunosuppression
Bone and cartilage metabolism
Cushing’s syndrome
Gastric symptoms
Weight gain
Diabetes
Cataracts
Azathioprine
Imidazole purine analogue which is the prodrug
for 6-mercaptopurine (6MP)
Imidazole side group preserves purine structure
from degradation
Converted by HGPRT to a precursor of
thionuclides which inhibits PRPP synthase
Inhibits AMP and GMP formation
A methylnitroimidazole product may have
separate effects on Ag recognition etc.
Azathioprine
Absorbed in 2 hrs
Parent drug bioavailability is about 20%
Metabolite availability is >40%
Total availablity is > 60%
Oxidized by GSSH
Xanthine oxidase inhibitors increase toxicity, as
do genetic factors in Asians
Clonal mutation can lead to resistance
Azathioprine
Half lives of drug and active metabolite
are short (50 min, 75 min)
Renal elimination
Hepatic disease interferes with
metabolism and leads to accumulation of
drug
Azathioprine
Excessive marrow suppression
5 - 10 days to marrow recovery
Asians and patients taking allopurinol may
become very cytopenic
Liver disease: cholestatic disease and VOD
Interstitial pneumonitis
Increased malignancies
Cyclosporines
Norwegian soil fungus product
Monstrous macrolide antibiotic
? Calcineurin inhibitor ?
(E)-14,17,26,32-tetrabutyl-5-ethyl-8-(1hydroxy-2-methylhex-4-enyl) 1,3,9,12,15,18,20,23,27-nonamethyl-11,29dipropyl-1,3,6,9,12,15,18,21,24,27,30undecaazacyclodotriacontan2,4,7,10,13,16,19,22,25,28,31-undecaone
Cyclosporine A: mechanisms
Disrupts the calcium dependent cascade of
events which follows binding of antigen
to the T cell receptors and leads to
activation and proliferation.
Interferes with secondary messengers in
cell
Suppresses genes for c-myc, Il-2, Il-3, Il4, Il-5, IFN-g, and Il-2 receptors
Cyclosporine
CyA/Cyp inhibits calcineurin
This prevents the phosphorylation of nuclear
factor (NF-Atc) of activated T cells
The NF-ATc cannot enter nucleus to activate its
nuclear (DNA) subnunit
Prevents promotion of: Il-2 gene and thus Il-2,
Il-3, Il-4, IFN-g, TNF, also: AP-1, AP-3, OAP,
Oct-1 and NF-kb
Cyclosporine
Prodrug: only active after it binds to
intracellular ligands
Immunophilins are small proteins which
comprise 0.2 - 0.4% of cellular proteins
Cyclophilins A, B, C, and D
Complexes bind to calcineurin catalytic
subunit and render complex inactive
Inihibition stops activation of T cells
Cyclosporine
May upregulate TGF-b
TGF- b increases endothelin 1, and
extracellular matrix production
Cyclosporine
Inhibits B cells
CyA inhibits CD40 ligand expression by
inhibiting NF-ATC phosphorylation
The CD40 ligand is involved in T cell, B cell
interactions
Alters TNF a production by macrophages
Complex effects on bone marrow
Cyclosporine: Side effects
Nephrotoxicity
related to trough levels
patchy, striped, interstitial fibrosis
Hypertension
Cholesterol metabolism
Neurotoxicity
peripheral neuropathy
Lethality
> 1500
Cyclosporine: drug interactions
Far too many to recall
Interference by drugs which are
metabolized by the P450
Interactions at the P-glycoprotein pump
Cyclosporine-drugs : useful things
Erythromycin - itraconazole - ketoconazole
inhibit p450 and reduce CyA dosage (save
money)
reduce infections
Diltiazem - verapamil
(p-glycoprotein)
Interfere with metabolism, other effects
Nifedipine
(p-glycoprotein)
effect on transplant independent of CyA
FK-450, Tacrolimus (Prograf)
Japanese fungus product
Giant macrolide molecule
Not structurally related to CyA
Works much like CyA
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3S-[3R [E(1S ,3S ,4S )],4S ,5R ,8S ,9E,12R ,14R ,15S ,16R ,18S ,19S ,26aR ]]
-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a -hexadecahydro-5, 19-dihydroxy
-3-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14,16-dimethoxy
-4,10,12,18-tetramethyl-8-(2-propenyl) -15,19-epoxy-3H-pyrido[2,1-c] [1,4]
oxaazacyclotricosine-1,7,20,21(4H,23H) -tetrone, monohydrate
Tacrolimus
Well absorbed
Food slows absorption
Peak 0.5 to 8 hours post dose
Protein bound, variable volume of
distribution
Hepatic metabolism by P-450-3A4
Monitoring less critical than with CyA
Tacrolimus: mechanisms
Prodrug which binds to an immunophilin
FK-BP (high affinity receptor)
FK-BP not related to cyclophilins
Inhibits rotamase activity of FK-BP only
Does bind to rapamycin BP
Complex (FK-506/FK-BP) binds to and
inhibits a calcium/calmodulin-dependent
serine-threonine phosphatase
Tacrolimus: mechanism
Inhibition of the phosphatase prevents the
enzyme from dephosphorylating the
transcription factors for NF-AT, AP-3, Oct-1
and others which inhibits gene turn on
The result is less Il-2, Il-3, Il-4, TNF-a, IFN-g
Also affects a rapamycin inhibitable system
which is not calcium dependent
Tacrolimus
Clinically, tacrolimus is very close to CyA in
terms of effects, though the binding
proteins and the precise mechanisms
differ
Pharmacologically, the drug is 50 times
more active wt for wt
Blood levels are said to be much more
stable
Tacrolimus: toxicity
Nephrotoxicity
Similar to CyA
Mechanism of toxicity is unknown
Inhibits the P-glycoprotein multidrug
transporter
Tacrolimus: drug interactions
Pharmacological antagonist for CyA
Similar profile of drug interactions
Rapamycin
Yet another macrolide
Not nephrotoxic ?
Acts at a point beyond tacrolimus and CyA
Acts on the same binding protein as
tacrolimus, but the mechanisms differ
Some protocols use in combination with
CyA
(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S, 26R,27R,34aS)9,10,12,13,14,21,22,23,24,25,26, 27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]- 1-methylethyl]-10,21-dimethoxy6,8,12,14,20,26- hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone
Rapamycin
Binds to TOR (target of rapamycin)
Inhibits signal transduction downstream
from growth factor receptors (IL-2)
Blocks progression from G1 to S phase of
cell cycle
Antagonist of tacrolimus
Cooperative with cyclosporine A
Mycophenolate mofetil:
Inhibts inosine monophosphate
dehydrogenase (IMPDH)
Mycophenolate is the morpholino-ethyl
ester of mycophenolic acid (a penicillium
product)
Non-competitive inhibitor of IMPDH
Mycophenolate: mechanism
Inhibits IMPDH
IMPDH is a key enzyme in purine
nucleoside synthesis
IMPDH inhibition lowers GMP levels which
occupy a key step in T cell response
TCR /CD3 complex activity may need GMP
Thus cell activation is inhibited
Mycophenolate: mechanism
Lymphocytes do not have purine salvage
pathway enzymes
Lymphocytes depend on IMPDH for
purines
Lymphocyte proliferation is blocked by
MPA effect on purines
Most other cells have purine salvage
and are not affected
Mycophenolate: mechanisms
Effects can be reversed by administration
of guanosine nucleotide
Guanosine does not reverse AZA effects
IMDPH acts if given up to 24 hours after
T cell stimulation
Does not act on early response genes and
Ils
Arrests lymphocytes in G1 phase
Mycophenolate: toxicity
Leukopenia
Anemia
GI toxicity
Note: despite the “targeting” of the drug
to cells without a salvage pathway, the
toxicity tends to indicate all high
turnover cells are at risk…….. ? a rate
issue ?
Antibodies
ALG going
ATG going
MM AB gone
OKT3 only option
OKT3
Murine IgG2a directed against e chain of
CD3 molecule
Cells may be activated and then release
cytokines which cause acute toxic
responses
Block recognition site by internalization
Cells are then opsonized and sequestered
by macrophages
OKT3
Given IV only, 5mg a day for up to 14 days
First 2 to 3 doses may trigger severe
reactions which result in flu-like
symptoms, acute pulmonary edema, and
chemical meningitis
Wt must be within 3% of dry
Profound lymphopenia results
OKT3
Very high risk for viral infections
Use immune globulin for CMV
If dose excessive, high risk for
lymphoproliferative malignancy
Don’t exceed 70 mg
Antibodies may develop
Test for Ab titer before second dose
IL-2 receptor antibodies
IL-2 is a major factor in the proliferation of
activated Tcells in response to grafts
CyA, tacrolimus inhibit IL-2 production by
interfering with secondary messages which
lead to stimulation of the IL-2 promoter
Rapamycin inhibits secondary messenger
responses (by Tyr Kinase pathways) to IL-2
stimulation
Activation of T cells
APC
T cell
Presentation of Ag to Tcell Ag receptor
Proliferation/differentiation signal
Activation of T cells
APC
T cell
IL-2
rejection
IL-2 and tolerance
Since IL-2 stimulates Tcells in recursive
manner, it would seem that IL-2 inhibition
should block rejection and memory
But, IL-2 knockout mice reject heart
transplants
Anti IL-2 treatment slows but does not
prevent later rejection
IL-2 neutralizing antibodies reduce tolerance
IL-2 causes apoptosis of activated T cells
(clonal deletion role)
IL-2 effects
Activation of T cells
Induction of
“memory cells”
Induction of T cell
apoptosis
T cells and tolerance
T cell activation is required for tolerance to
develop
Complete suppression of T cell response (total
blockade of IL-2, for example) leads to
ignorance, and the host remains primed to
recognize and reject
Tolerance is preferable to ignorance
IL-2 inhibits the maintenance of memory cells
Memory cells
Naïve cells
Memory cells
Survival
Long (years)
Very long (life)
Homing
Circulate to
secondary
lymph sites
Slow
(high
threshold)
Circulate to
lymphatic and non
lymph tissue *
Fast
(low threshold)
Response
*Memory cells do not require secondary lymphatic structures to react
T cell responses
Delete (die – apoptosis)
T cell
Suppress ( T regulatory)
Deviate
Anergy
Ignore -- tolerance
(Th2)
Memory
expand
clone
die off
memory
tolerance
exposure to
foreign antigen
time
IL-2 receptor antibodies
Rather than inhibit the secondary
messages which lead to IL-2 production
or the response to IL-2, directly attack
the major element -- IL-2
IL-2 blockers are clinically available
IL-2 R antibodies
Daclimuzab (Zenapax) is a “humanized” antiT cell a chain IL-2 receptor antibody
Basilixamb (Simulect) is a chimeric mouse
anti-CD 25 monoclonal antibody with
affinity for the alpha chain of the IL-2 R
IL-2 receptor antibodies
Vicente et al (NEJM 98): Induction
protocol which included CyA and
daclimizab (IL-2 receptor antibodies)
Results of the study indicated there was
an increase in transplant survival (95 vs
90%), and decreased rejection episodes
in cadaver kidney recipients
IL-2 receptor antibody
Nashan et al used basiliximab as induction
protocol (Lancet 350:1193-1198, 1999)
They reported a reduction in biopsy proven
rejection (30% vs 44%) European trial