An individual’s immune system is capable of distinguishing
between native and foreign antigens and of mounting a response only
against the latter.
Suppressor cells are critical in the regulation of the normal immune
response. A major role has been established for suppressor
T lymphocytes in this phenomenon. Suppressor cells also play a role in
regulating the magnitude and duration of the specific antibody
response to an antigenic challenge. Suppression of the immune
response either by drugs or by radiation, to prevent the rejection of
grafts or transplants or to control autoimmune diseases, is called
immunosuppression.
A number of microbial compounds capable of suppressing the
immune response have been discovered. Cyclosporin A was originally
introduced as a narrow-spectrum antifungal peptide produced by the
mold, Tolypocladium nivenum (originally classified as Trichoderma
polysporum and later as Tolypocladium inflatum), by aerobic fermentation.
Cyclosporins are a family of neutral, highly lipophilic, cyclic
undecapeptides containing some unusual amino acids, synthesized by
a non-ribosomal peptide synthetase, cyclosporin synthetase. Discovery
of the immunosuppressive activity led to its use in heart, liver and
kidney transplants and to the overwhelming success of the organ
transplant field. Cyclosporin was approved for use in 1983. It is
thought to bind to the cytosolic protein cyclophilin (immunophilin)
of immunocompetent lymphocytes, especially T lymphocytes.
This complex of cyclosporin and cyclophilin inhibits calcineurin,
which under normal circumstances is responsible for activating
the transcription of interleukin-2. It also inhibits lymphokine production
and interleukin release and therefore leads to a reduced function
of effector T cells. Sales of cyclosporin A have reached US$1.5 billion
per year.
Other important transplant agents include sirolimus (rapamycin)
and tacrolimus (FK506), which are produced by actinomycetes.
Rapamycin is especially useful in kidney transplants as it lacks
the nephrotoxicity seen with cyclosporin A and tacrolimus. It is
a macrolide, first discovered in 1975 as a product of S. hygroscopicus,
and was initially proposed as an antifungal agent. However, this
was abandoned when it was discovered that it had potent immunosuppressive
and antiproliferative properties. This compound binds
to the immunophilin FK506-binding protein (FKBP12), and this
binary complex interacts with the rapamycin-binding domain
and inactivates a serine-threonine kinase termed the mammalian
target of rapamycin. The latter is known to control proteins
that regulate mRNA translation initiation and G1 progression.81
The antiproliferative effect of rapamycin has also been used
in conjunction with coronary stents to prevent restenosis,
which usually occurs after the treatment of coronary artery
disease by balloon angioplasty. Rapamycin also shows promise in
treating tuberous sclerosis complex (TSC), a congenital disorder that
leaves sufferers prone to benign tumor growth in the brain, heart,
kidneys, skin and other organs. In a study of rapamycin as a treatment
for TSC, University of California, Los Angeles (UCLA) researchers
observed a major improvement in mice regarding retardation related
to autism.
As rapamycin has poor aqueous solubility, some of its analogs,
RAD001 (everolimus), CCI-799 (tensirolimus) and AP23573
(ARIAD), have been developed with improved pharmaceutical properties.
Everolimus is currently used as an immunosuppressant to
prevent the rejection of organ transplants. Although it does not
have FDA approval in the USA, it is approved for use in Europe
and Australia, and phase III trials are being conducted in the US.
Everolimus may have a role in heart transplantation as it has been
shown to reduce chronic allograft vasculopathy in such transplants.83
Everolimus is also used in drug-eluting coronary stents as an immunosuppressant
to prevent rejection. CCI-779 is a rapamycin ester that
can be converted to rapamycin in vivo. RAD001 is a rapamycin analog
currently being investigated in phase II trials for recurrent endometrial
cancer as a single agent, and in phase I/II trials for the treatment of
glioblastoma in combination with the inhibitor of certain epidermal
growth factor receptor and vascular endothelial growth factor receptor
family members. AP23573 is a novel non-prodrug rapamycin analog
with a nonlinear pharmacokinetic behavior that has demonstrated
antiproliferative activity against several human tumor cell lines in vitro
and against experimental tumors in vivo. This agent is currently
under evaluation in phase I–II trials, including patients with different
tumors. Two additional small-molecule rapamycin analogs, AP23841
and AP23675, are currently in preclinical development for the treatment
of bone metastases and primary bone cancer.
Tacrolimus (FK506) was discovered in 1987 in Japan. It is
produced by Streptomyces tsukubaensis. However, its use was almost
abandoned because of dose-associated toxicity. Dr Thomas Starzl
(University of Pittsburgh) rescued it by using lower doses, realizing
that it was approximately 100 times more active as an immunosuppressive
than cyclosporin A. It was introduced in Japan in 1993, and
in 1994 it was approved by the FDA for use as an immunosuppressant
in liver transplantation. Furthermore, its use has been extended
to include bone marrow, cornea, heart, intestines, kidney, lung,
pancreas, trachea, small bowel, skin and limb transplants, and for
the prevention of graft-vs-host disease. Topically, it is also used against
atopic dermatitis, a widespread skin disease. In the laboratory,
tacrolimus inhibits the mixed lymphocyte reaction, the formation of
interleukin-2 by T lymphocytes, and the formation of other soluble
mediators, including interleukin-3 and interferon g. Recently, it has
been reported that tacrolimus inhibits tumor growth factor-b-induced
signaling and collagen synthesis in human lung fibroblastic cells. This
factor plays a pivotal role in tissue fibrosis, including pulmonary
fibrosis. Therefore, tacrolimus may be useful for the treatment of
pulmonary fibrosis, although its use in the acute inflammatory phase
may exacerbate lung injury.
between native and foreign antigens and of mounting a response only
against the latter.
Suppressor cells are critical in the regulation of the normal immune
response. A major role has been established for suppressor
T lymphocytes in this phenomenon. Suppressor cells also play a role in
regulating the magnitude and duration of the specific antibody
response to an antigenic challenge. Suppression of the immune
response either by drugs or by radiation, to prevent the rejection of
grafts or transplants or to control autoimmune diseases, is called
immunosuppression.
A number of microbial compounds capable of suppressing the
immune response have been discovered. Cyclosporin A was originally
introduced as a narrow-spectrum antifungal peptide produced by the
mold, Tolypocladium nivenum (originally classified as Trichoderma
polysporum and later as Tolypocladium inflatum), by aerobic fermentation.
Cyclosporins are a family of neutral, highly lipophilic, cyclic
undecapeptides containing some unusual amino acids, synthesized by
a non-ribosomal peptide synthetase, cyclosporin synthetase. Discovery
of the immunosuppressive activity led to its use in heart, liver and
kidney transplants and to the overwhelming success of the organ
transplant field. Cyclosporin was approved for use in 1983. It is
thought to bind to the cytosolic protein cyclophilin (immunophilin)
of immunocompetent lymphocytes, especially T lymphocytes.
This complex of cyclosporin and cyclophilin inhibits calcineurin,
which under normal circumstances is responsible for activating
the transcription of interleukin-2. It also inhibits lymphokine production
and interleukin release and therefore leads to a reduced function
of effector T cells. Sales of cyclosporin A have reached US$1.5 billion
per year.
Other important transplant agents include sirolimus (rapamycin)
and tacrolimus (FK506), which are produced by actinomycetes.
Rapamycin is especially useful in kidney transplants as it lacks
the nephrotoxicity seen with cyclosporin A and tacrolimus. It is
a macrolide, first discovered in 1975 as a product of S. hygroscopicus,
and was initially proposed as an antifungal agent. However, this
was abandoned when it was discovered that it had potent immunosuppressive
and antiproliferative properties. This compound binds
to the immunophilin FK506-binding protein (FKBP12), and this
binary complex interacts with the rapamycin-binding domain
and inactivates a serine-threonine kinase termed the mammalian
target of rapamycin. The latter is known to control proteins
that regulate mRNA translation initiation and G1 progression.81
The antiproliferative effect of rapamycin has also been used
in conjunction with coronary stents to prevent restenosis,
which usually occurs after the treatment of coronary artery
disease by balloon angioplasty. Rapamycin also shows promise in
treating tuberous sclerosis complex (TSC), a congenital disorder that
leaves sufferers prone to benign tumor growth in the brain, heart,
kidneys, skin and other organs. In a study of rapamycin as a treatment
for TSC, University of California, Los Angeles (UCLA) researchers
observed a major improvement in mice regarding retardation related
to autism.
As rapamycin has poor aqueous solubility, some of its analogs,
RAD001 (everolimus), CCI-799 (tensirolimus) and AP23573
(ARIAD), have been developed with improved pharmaceutical properties.
Everolimus is currently used as an immunosuppressant to
prevent the rejection of organ transplants. Although it does not
have FDA approval in the USA, it is approved for use in Europe
and Australia, and phase III trials are being conducted in the US.
Everolimus may have a role in heart transplantation as it has been
shown to reduce chronic allograft vasculopathy in such transplants.83
Everolimus is also used in drug-eluting coronary stents as an immunosuppressant
to prevent rejection. CCI-779 is a rapamycin ester that
can be converted to rapamycin in vivo. RAD001 is a rapamycin analog
currently being investigated in phase II trials for recurrent endometrial
cancer as a single agent, and in phase I/II trials for the treatment of
glioblastoma in combination with the inhibitor of certain epidermal
growth factor receptor and vascular endothelial growth factor receptor
family members. AP23573 is a novel non-prodrug rapamycin analog
with a nonlinear pharmacokinetic behavior that has demonstrated
antiproliferative activity against several human tumor cell lines in vitro
and against experimental tumors in vivo. This agent is currently
under evaluation in phase I–II trials, including patients with different
tumors. Two additional small-molecule rapamycin analogs, AP23841
and AP23675, are currently in preclinical development for the treatment
of bone metastases and primary bone cancer.
Tacrolimus (FK506) was discovered in 1987 in Japan. It is
produced by Streptomyces tsukubaensis. However, its use was almost
abandoned because of dose-associated toxicity. Dr Thomas Starzl
(University of Pittsburgh) rescued it by using lower doses, realizing
that it was approximately 100 times more active as an immunosuppressive
than cyclosporin A. It was introduced in Japan in 1993, and
in 1994 it was approved by the FDA for use as an immunosuppressant
in liver transplantation. Furthermore, its use has been extended
to include bone marrow, cornea, heart, intestines, kidney, lung,
pancreas, trachea, small bowel, skin and limb transplants, and for
the prevention of graft-vs-host disease. Topically, it is also used against
atopic dermatitis, a widespread skin disease. In the laboratory,
tacrolimus inhibits the mixed lymphocyte reaction, the formation of
interleukin-2 by T lymphocytes, and the formation of other soluble
mediators, including interleukin-3 and interferon g. Recently, it has
been reported that tacrolimus inhibits tumor growth factor-b-induced
signaling and collagen synthesis in human lung fibroblastic cells. This
factor plays a pivotal role in tissue fibrosis, including pulmonary
fibrosis. Therefore, tacrolimus may be useful for the treatment of
pulmonary fibrosis, although its use in the acute inflammatory phase
may exacerbate lung injury.
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