Download Immunosuppression

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Prof. Ileana Constantinescu
Immunosuppressive protocols in
transplantation include the targeting of IL2/IL-2R axis that are considered to be the
most important pathway for T–cell
proliferation.
Immunosuppressants classification
•Calcineurin inhibitors:
Cyclosporine, Tacrolimus
•Antimetabolites:
Mycophenolat mofetil,
Azathioprine
•Corticosteroids
•Proliferation inhibitors (mTOR inhibitors/
mammalian target of rapamycin):
Sirolimus, Everolimus
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The consideration of the various factors affecting transplant
outcome now turns to a discussion of a subject of tremendous
importance not only to recipient selection but also to longterm
transplant recipient care and management, namely the issue of
often associated immunosuppression.
Since graft rejection is provoked by an undesirable but healthy
immune response on the part of the host, it is imperative for
favorable transplant outcome that the transplant recipient be in
some way immunosuppressed.
Immunosuppression of the transplant recipient falls into one of
two categories, either suppression targeted specifically toward
donor antigen or targeted nonspecifically, resulting in broader
immunocompromise of the transplant recipient. Means of
achieving
both
antigen-nonspecific
and
specific
immunosuppression.
Total lymphoid irradiation, while infrequently used today,
effectively eliminates the host immune response, resulting in
graft survival, albeit profound immunosuppression.
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More frequent approaches to cripple the transplant recipient's
immune system have included the use of anti-lymphocyte
globulins, such as OKT-3, directed against the which serves to
inhibit T cell-mediated responses. CD3 component of the human T
cell receptor, antimetabolite drugs, such as azathioprine, inhibit
nucleotide synthesis and result in suppressing the proliferative
capacity of rapidly dividing cells, such as lymphocytes recently
recruited to participate in an immune response.
Such drugs are frequently used in combination with steroids, such
as prednisone, which is broadly immunosuppressive by inhibiting
lymphocyte function, as well as a drugs called Cyclosporine A or
Tacrolimus (FK506) which more specifically inhibits T cell
expression of cytokine effector molecules. A triple regimen
consisting of azathioprine, prednisone, and cyclosporine A is
commonly used post-transplant to manage heart and kidney
transplant recipients.
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Such effective immunosuppressive measures, due to their
broad impact on the host's immune system, as well as
frequent adverse side effects, have raised the issue of
identifying means of suppressing the transplant rejection
response in a more antigen-specific way. It is hoped that
such antigen-specific means of immunosuppression, though
still in their infancy, will impact less on the host's immune
system and result in fewer side effects associated with
multiple drug use.
One strategy considered in antigen-specific
immunosuppression is to employ antibodies directed against
graft antigens, such as MHC alloantigens, which results in a
prolongation of graft survival known as enhancement.
The mechanism by which anti-graft antibodies promote
transplant survival is currently under investigation. Another
donor antigen-specific approach to immunsuppression, still
in an experimental phase of study, is the use of anti-T cell
receptor (TCR) antibodies to block host T cells specific for
allogeneic MHC.
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This kind of therapy implies a detailed knowledge not
only of which MHC alloantigens are expressed on each
graft, but also which antigen epitopes are critical for
generating host T cell help during the alloimmune
response.
Antibody therapy, whether donor antigen-specific or
nonspecific, due to its passive nature, usually requires
chronic administration. Associated with long-term
antibody therapy is the adverse sensitization of the
individual receiving these antibodies, which are usually
raised in nonhuman species.
These antibodies, therefore, act as alloantigens due to
foreign isotope sequences and as such have the
potential to provoke anti-antibody responses in the
recipient. Clearly, such a situation renders antibody
therapy of limited longterm value.
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In the face of these therapeutic difficulties, an appealing strategy aimed at
inducing donor antigen specific immunosuppression is the concept of
tolerance, defined here as specific, acquired, long lasting immunological
unresponsiveness. Tolerance to self antigens occurs very early in life, during
fetal and neonatal development. Self-tolerance or central tolerance is principally
acquired by negative selection or elimination of potentially self-reactive T cell
clones during thymic development. Negative selection in the thymus is
characterized by programmed cell death in a process referred to as clonal
deletion.
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Tolerance to prospective donor alloantigens, however, raises the issue of how
to achieve tolerance in the adult transplant recipient long after central or selftolerance has been achieved. Issues surrounding how to establish peripheral
(nonthymic) tolerance form the basis of many experimental studies in the fields
of transplantation and autoimmunity today. While still at their inception, these
studies aim to elucidate how prior oral or intravenous administration of donor
allo MHC antigens, in the case of transplantation, sometimes achieves a tolerant
state in the transplant recipient.
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Also under investigation are the doses of antigen required to
induce tolerance, described as either low zone or high zone,
depending upon the relative doses of antigen needed to
achieve it. Route of administration and antigen dose aside,
experimental observations published to date have indicated
that tolerance to donor allo MHC antigens may be established
by a combination of active suppression of the recipient
immune response and/or failure to respond to foreign
antigen mediated by either T cell clonal deletion or anergy.
Anergy may be defined as the absence of an immune
response due to loss of cell function or "immune paralysis"
and may be reversible. Future transplant therapy awaits
clarification of these issues.
Immunosupression
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Cyclosporin A: MEIA Axsym/TDx, HPLC
Tacrolimus: MEIA IMx, HPLC
Sirolimus: MEIA IMx, HPLC
Methotrexat: MEIA TDx
Sadimmun. Concentrate for I.v. infusion
Immunosuppressive agent
Composition
Active component
Sandimmun Neoral
1 soft gelatin capsule
Sandimmun Neoral
oral solution
Sandimmun
concentrate
for I.v.infusion
Ciclosporin
10 mg; 25 mg
100 mg/mL
50 mg/mL
50 mg; 100 mg
Sandimmun Neoral is a new pharmaceutical form of the active ingredient ciclosporin based on the microemulsion principle,
which reduces the variability of pharmacokinetic parameters, and provides dose linearity of ciclosporin exposure with a more
consistent absorption profile and less influence from concomitant food intake. The formulation is a microemulsion
preconcentrate which in pharmacokinetic and clinical studies has demonstrated that the correlation between trough
concentration and exposure to ciclosporin is much stronger when ciclosporin is given as Sandimmun Neoral than when it is
given as Sandimmun. The formation of the microemulsion itself takes place in the presence of water, either in the form of a
beverage or in the form of the gastric fluid.
Therapeutic indications
Transplantation indications
Solid organ transplantation
• Prevention of graft rejection following kidney, liver, heart, combined heart-lung, lung, or pancreas allogeneic transplantations.
• Treatment of transplant rejection in patients previously receiving other immunosuppressive agents.
Bone marrow transplantatiom
• Prevention of graft rejection following bone marrow transplantation.
• Prevention or treatment of graft-versus-host disease (GVHD)
Challenges in Immunosuppression
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Cyclosporin complex pharmacokinetics impact clinical outcomes1
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Neoral® Absorption Profiling demonstrates CsA absorption monitoring can result in more effective
immunosuppression2
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Optimising immunosuppression requires individualisation of Neoral® doses4
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C-2 monitoring is validated as the most effective and practical single sampling point for Neoral®
monitoring3
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Cyclosporin blood level monitoring is standard practice for Neoral® management of the transplant
recipient4
1. Lindholm A, Kahan BD. Clin Pharmacol Ther. 1993;55:205-218. 2. Mahalati K et al. Transplantation.1999;68:55-62.
3. Johnston A et al. Transplant Proc. 2000;32(suppl 3A):53S-56S. 4. Kahan BD. N Engl J Med. 1989;321:1725-1738.
Improving Patient Outcomes in Transplantation
 The importance of the absorption phase in Neoral ® pharmacokinetics1
 AUC0-4 monitoring in renal transplantation 2
 C-2 monitoring in liver transplantation3
 Application of C-2 monitoring to all transplant recipients 4
1. Johnston A et al. Transplant Proc. 2000;32(suppl 3A):53S-56S. 2. Mahalati K et al. Transplantation. 1999;68:55-62. 3. Levy G
et al. Transplantation. 2000;69:S387. 4. Belitsky P et al. Transplant Proc. 2000;32(suppl 3A):45S-52S.
Neoral® C-2 Monitoring—Why the Need?
 Issue
– C-0 (trough) monitoring was introduced to minimise toxicity1
– C-0 monitoring does not optimise the clinical benefits of Neoral®2-4
– AUC monitoring is cumbersome and expensive as a routine
management tool5
1. Uchida K et al. Dev Toxicol Environ Sci. 1986;14:163-166. 2. Mahalati R et al. Transplantation.
1999;68:55-62. 3. Johnston A et al. Transplant Proc. 2000;32(suppl 3A) 53S-56S. 4. Mahalti K et al.
Transplantation. 2000;69:S114. 5. Amante AJ et al. Clin Chem. 1996;42:1294-1295.
Intrasubject % CV
Greatest Degree of Intra-subject Variability
Occurs 1 to 2 Hours Post-Dose
50
45
40
35
30
25
20
15
10
5
0
0
0.33 0.66
1
1.5
2
2.5
3
4
6
9
12
Hours Post-Dose
Stable Cardiac Transplant Recipients: 1, 12, 52 Weeks Intrasubject Variability
in CsA Mean Concentration Values
Johnston A et al. Transplant Proc. 2000;32(suppl 3A):53S-56S.
1400
AUC0-4
1200
AUC0-4
1000
800
600
400
200
0
0
C-0
2
C-2
4
6
8
10
12
Hours Post-Dose
Extent and rate of absorption are highly variable.
Patient differences are highlighted in the absorption phase.
Adapted from Johnston A et al. Transplant Proc. 2000;32:53S-56S.
Low Bioavailability and High Clearance are CsA
Pharmacokinetic Risk Factors for Acute Rejection
P<.002
40
20
0
500
Clearance (mL/min)
Oral Bioavailability (%)
60
Rejector
Non-Rejector
P<.02
400
300
200
100
0
Rejector
Lindholm A, Kahan BD. Clin Pharmacol Ther. 54:205-218, 1993.
Non-Rejector
Impact of Variability on Health Care
Costs Is Significant
$60.000
Physician cost
Facility cost
Cost (US $)
$50.000
$40.000
$30.000
Inpatient
$56,738
Inpatient
$45,376
$20.000
$10.000
Outpatient
$4,260
Outpatient
$3,413
$0
Less Variable
More Variable
Cyclosporin AUC
Cyclosporin AUC
Lower variability = Improved outcomes = More efficient patient care
Kahan BD et al. J Am Soc Nephrol. 2000;11:1122-1131.
Incidence of Rejection (%)
Incidence of Rejection (%)
C-0 Does Not Predict Acute Rejection: Cmax Does
60
54.5%
45.5%
40
34%
38%
20
0
<250
80
250-300
301-400
C-0 (ng/mL)
>400
71%
60
44%
36%
40
34%
20
0
<600
601-850
851-1200
Cmax (ng/mL)
Grant D et al. Transplantation. 1999;67:1133-1137.
>1200
C-2 Is a Surrogate Marker of Cmax
 Cmax requires multiple blood samples and subsequent
extrapolation of cyclosporin concentration-time curve
 A single sampling point is the ideal monitoring tool
 C-2 has the best correlation with Cmax in liver
transplant patients
Grant D et al. Transplantation. 1999;67:1133-1137.
Choice of C-2 for Neoral® Monitoring
 Pharmacokinetic evidence for C-2
– The region of highest pharmacokinetic variability1
– The single sampling point that defines CsA absorption2
 Pharmacodynamic evidence for C-2
– Correlates with the period of maximum calcineurin inhibition3
– More extensive and consistent IL-2 suppression compared with C-04
1. Johnston A et al. Transplant Proc. 2000;32(suppl 3A):53S-56S. 2. Belitsky P et al. Transplant Proc.
2000;32(suppl 3A):45S-52S. 3. Halloran PF et al. Transplantation. 1999;68:1356-1361. 4. Sindhi R et al.
Transplantation. 2000;69:432-436.
Calcineurin Inhibition Maximal and IL-2 Suppression Most
Consistent at 2 Hours Post-Dose
100
50
80
40
60
30
40
20
20
0
0
1
2
C-0
C-2
Hours Post-Dose
Adapted from Halloran P et al.
Transplantation.1999;68:1356-1361.
10
4
0
C-0
C-2
Sampling Point
Sindhi R et al. Transplantation.
2000;69:432-436.
C-2: A Sensitive Indicator of Risk for Subclinical
Rejection
P=.04
C-2 Level (µg/mL)
1.25
± 0.04
1.20
1.15
1.10
1.05
± 0.03
1.00
0.95
1.2
1.0
0.90
Mean C-2 in Patients Mean C-2 in Patients
With No ScRj
With ScRj
Mean C-2 in Patients Without Subclinical Rejection (No ScRj) or With Subclinical
Rejection (ScRj) at Biopsy 6 to 9 Months Post-Transplant
Barama A et al. Transplantation. 2000;69:S225.
Kidney Transplant
Cyclosporinemia (ng/ml)
C0
Determination at 12 hours after administration:
Month 1
Month 2 – Month 3
Month 4 – Month 12
After 1 year
C2
250-350 ng/ml (preferably min 300 ng/ml)
250-300 ng/ml
250 ng/ml
200-250 ng/ml
Determination at 2 hours after administration:
Month 1
Month 2
Month 3
After 1 year
1600-1800 ng/ml
1400-1600 ng/ml
1200-1400 ng/ml
700-800 ng/ml
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Day 1 - Day 7
Day 8 – Day 30
Day 31 – Day 60
Day 61 – Day 90
After 90 Days
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SIROLIMUS: 6 – 7 ng/ml
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15 - 20 ng/ml
10 – 20 ng/ml
5 – 10 ng/ml
5 - 10 ng/ml
5 ng/ml
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When immunosuppressant drugs weaken the immune system, the body
becomes less resistant to infection. Any infections that develop will be more
difficult to treat because of this. These drugs also increase the likelihood of
uncontrolled bleeding due to injury or infection.
People taking immunosuppressant drugs should be careful to avoid catching an
infection. Precautions include:
frequent hand washing
avoiding sports in which injuries occur
extra care when using sharp objects such as knives or razors
avoiding close contact with people who have infections or colds
A physician should be notified immediately when the following symptoms occur:
 fever or chills
 pain in the lower back, on the sides
 pain or difficulty urinating
 unusual bruising or bleeding
 blood in your urine
 stools that are bloody or black
Immunosuppressant drugs can cause adverse reactions and birth defects.
Physicians should be made aware of the following conditions before immunosuppressant
drugs are prescribed:
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allergies
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pregnancy
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lactation
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shingles or chickenpox
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kidney or liver disease
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intestinal problems
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The most significant side effect of immunosuppressant drugs is an increased risk of
infection. The drugs can also put you at a higher risk for cancer because the immune
system also protects you from this disease.
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Other, less serious side effects can include loss of appetite, nausea, vomiting, increased
hair growth, and hand trembling. These effects typically subside as the body adjusts to
the immunosuppressant drugs.
The following side effects indicate the need for immediate attention:
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a feeling of being unusually tired or weak
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fever or chills
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frequent urination
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Immunosuppressant drugs can interact with many other medications. This can cause
dangerous effects in which the immunosuppressants may lose or even increase their
effect. The primary caregiver should be made aware of any prescription or over-thecounter medications their patients are taking while on immunosuppressant therapy.
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Transplantation immunology is complex.
Our Immunogenetic Centre provide expanded
immunological monitoring together with virological
and drug monitoring of the transplanted patients.
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Our goal is to offer complete integrated monitoring
data and to fulfil EFI Standards.
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We are open for collaborative work and research
projects within EFI.
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Clinical and laboratory scientists should work
together as a team in order to have a complete
overview of the transplanted patients.