Immunosuppressants are drugs or medicines that lower the body's ability to reject a transplanted organ. Another term for these drugs is anti-rejection drugs. There are 2 types of immunosuppressants: Induction drugs: Powerful ntirejection medicine used at the time of transplant Maintenance drugs: Antirejection medications used for the long term.
6. Immunosuppressants are drugs or medicines
that lower
the body's ability to reject a transplanted organ.
Another
term for these drugs is anti-rejection drugs.
There are 2 types of immunosuppressants:
• Induction drugs: Powerful antirejection
medicine used
at the time of transplant
• Maintenance drugs: Antirejection
medications used for
the long term.
7.
8. The ability to prolong life by transplanting organs
had
long been a dream of medical practitioners.
• Early efforts at transplantation were unsuccessful
because of inadequacies in surgical technique and
lack of
fundamental knowledge of the immune system.
• The kidney was the first such organ to be
successfully
transplanted.
• Initial attempts at immunosuppression were with
total
body radiation, but all the patients died.
• Steroids alone were then used, also without
success. 4
9. 1950’s
• First successful kidney transplant
• Total body irradiation for immunosuppression
• Steroids
1960’s
• Azathioprine
1970’s
• Polyclonal anitbodies – anti-lymphocyte globulin
(now Atgam ,
Thymoglobulin )
1980’s
• Cyclosporine (Sandimmune ), “triple drug therapy”
• Monoclonal antibody, OKT3 (Orthoclone ) in 1985
5
13. • Preparation made by immunization of animals
with
human lymphoid tissue
Rabbits ➠
• Thymoglobulin (Genzyme)
• Anti-T-lymphocyte immune globulin (ATG-
Fresinius)
Horses ➠ ATGAM
• Several studies found that rATG was more
effective in
preventing rejection and was associated with
better graft
survival than ATGAM.
14.
15. • Rapid T-cell depleting agent through
complementdependent
cell lysis in the blood compartment and
apoptotic cell death in the lymphoid tissues.
• Also modulates cell surface molecules that regulate T
cell
activation as well as adhesion molecules and chemokine
receptors involved in leukocyte-endothelial interactions.
• Repopulation leads to expansion of specific T-cell subsets
that have been shown to exhibit regulatory suppressor
functions, such as CD8+CD57+CD28- T cells.
11
16. • rATG are antibodies derived from rabbit sources
which
are commonly used induction agents although they
are
approved for corticosteroid resistant rejection.
• These antibodies are FDA approved for treatment of
acute rejection at dose of 1.5 mg/kg for 7-14 days,
• Reported induction doses range from 1-6 mg/kg per
dose over 1-10 days with a more typical regimen of
1.5
mg/kg for 3-5 days
Kalluri HV, Hardinger KL. Current state of renal
transplant immunosuppression: 12
Present and future. World J Transplant 2012; 2(4):
51-68
17. • Common adverse events include cytokine release
• Side effect
– Leukopenia
– serum sickness (cross-reactivity with other tissue
antigens)
– adversely affects the ability of the patient to make
antibodies against foreign protein
– thrombocytopenia
– pruritis
– fever
– arthralgias
– opportunistic infections
– malignancies
18.
19.
20.
21.
22.
23.
24. • BASILIXIMAB has high specificity to the alfa-chain of IL-2
receptor on the surface of T cells which act by blocking
activated lymphocytes.
• Basiliximab has the FDA’s approval for the prophylaxis of
acute organ rejection in patients with renal
transplantation when used as part of a triple
immunosuppressive regimen that includes CsA, MMF and
corticosteroids.
• Its use is recommended for other solid organ transplant
recipients, as well. 20
Maravic-Stojkovic V, Stojkovic B, Peric M. Modern
immunosuppressive agents
after heart transplantation. Curr Trend Cardiol.
2017;1(2):41-48.
25. • Basiliximab is registered for intravenous administration
only, as a bolus or as infusion over 30 minutes.
• It should be administrated only two times: first dose 20
mg within 2 hours after starting surgery, and second dose
4 days after transplantation.
• These saturate receptors and prevent T lymphocytes
from
replication, and also from activating the B cells, which are
responsible for the production of antibodies, which would
bind to the transplanted organ and stimulate an immune
response against the graft
26. • Zenapax
• Description
– Humanized monoclonal antibody against CD25
(interleukin-2– receptor α chain)
• Mechanism
– Binds to and blocks the interleukin-2– receptor α
chain (CD25 antigen) binds with high-affinity to the
Tac subunit of the high-affinity IL-2 receptor complex
and inhibits IL-2 binding
– on activated T cells, depleting them and inhibiting
interleukin-2–induced T-cell activation
27.
28.
29.
30.
31.
32.
33.
34. Daclizumab: IL-2 antagonist: Humanized, 90%
human
10% murine origin
• 1 mg/kg within 24 hours of KT plus additional 4
doses
of 1 mg/kg at a schedule of every 2 weeks after
KT.
• Causes receptor saturation that lasts up to 120
days
• Daclizumab was “retired” from market by the
manufacturer at the end of 2009
• Basiliximab will remain the only IL-2RA in the
market
35.
36.
37. • Orthoclone OKT3
• Description
– Murine monoclonal antibody against CD3 component of T-cell–
receptor signal-transduction complex
• Mechanism
– monoclonal IgG2a antibody
– binds to the T cell receptor-CD3-complex (specifically the CD3
epsilon chain) on the surface of circulating T cells, interfering
with the receptor-antigen-interaction
– resulting in a transient activation of T cells, release of
cytokines,
and blocking of T-cell proliferation and differentiation
– T-cell function usually returns to normal within approximately
48 hours of discontinuation of therapy
38. • OKT3 is a murine monoclonal antibody directed
against
the CD3 receptor.
• Inert T-cell , removed via
opsonization/phagocytosis.
• A substantial T-cell loss could occur within the
first few
hours after an initial dose.
• As T-cell fall, several T-cell derived cytokines
(eg,TNF,
IL-2, and IFN-γ) are released into circulation.
• Dosage: 5mg iv bolus, daily for 10 days
ITS AN OLD MOLECULE NOT USED NOWADAYS
39. • Recombinant DNA-derived humanized
monoclonal
antibody directed against CD52
• CD52 is present on all B- and T-cells
macrophages, NK
cells
• Trigger antibody-dependent lysis of T cell
• FDA approved in refractory B cell chronic
lymphocytic
leukemia treatment
• DOSING: 20-30 mg on the day of
transplantation infused
4-8 hr (over peripheral line)