BASIC
SCIENCE REVIEW FOR THE PEDIATRIC RHEUMATOLOGIST
Up and
coming therapeutics: FTY720
Theresa T. Lu
MD, PhD
Hospital for Special Surgery
Department of Immunology,
Address correspondence to:
Theresa Lu MD, PhD
Hospital for Special Surgery
Caspary Research Building Rm 200
Tel:
212-774-2532
Fax:
212-774-2337
Email: lut@hss.edu
Running title:
FTY720
Keywords: FTY720,
lymphocyte, recirculation
Adaptive immune responses take place in the secondary lymphoid organs of
the body. The secondary lymphoid organs
include the spleen, lymph nodes, tonsils, and Peyer’s patches. T and B lymphocytes gather in these organs
and survey for incoming antigens that they recognize. Unlike cells of most organs, however, the
majority of the lymphocytes are not permanent residents of the lymphoid
tissues. Instead, to maximize the chance
of encountering the right antigen, T and B cells constantly recirculate through
the body. In the case of peripheral
lymph nodes, B and T cells enter from the bloodstream into the parenchyma of
the lymph node via high endothelial venules and, within the lymph node, home
into their respective zones by following chemotactic cues. In the absence of activation by antigen
encounter, the T and B cells will pause in a particular lymph node for only
about a day. They will then exit the
lymph node via efferent lymphatics and are eventually returned to the blood
circulation via the thoracic duct. Once
in the circulation, they are able to enter a different lymphoid tissue to
further survey for antigens.
If T cells are activated in the lymph node, however,
they differentiate into effector cells that leave the lymph node and home to
the peripheral tissues [reviewed in 1, 2]. The ability to
mount efficient immune responses, then, is dependent on the ability of
lymphocytes to recirculate through the body to find their cognate antigens and
for the effector cells to leave the lymph node to home to peripheral tissues. Sequestration of lymphocytes within the lymph
node, then, could be a potential method of immune suppression.
In 1994, a compound, ISP-1, was isolated from a
fungus used in Chinese herbal medicine.
This compound had immunosuppressive activities that were 10 to 100-fold
more potent than cyclosporine, which had also been isolated from the same
fungus. ISP-1 inhibited serine
palmitoyltransferase and demonstrated anti-proliferative properties. In search of a more potent derivative with
fewer side effects, FTY720 was synthesized in 2000 [3]. FTY720
demonstrated potent immune suppression.
In vivo, it effectively prolonged graft survival in preclinical models
of organ graft rejection and graft versus host disease [4, 5]. In adjuvant
and collagen-induced models of arthritis, FTY720 was able to ameliorate paw
swelling and bone destruction [6].
Unlike ISP-1, FTY720 did not inhibit serine
palmitoyltransferase. Instead,
investigators noticed that it reduced the number of circulating T and B cells
in the bloodstream. Although cytotoxic
in micromolar concentrations in vitro, the effect on blood lymphocyte counts
occurred at nanomolar concentrations in the bloodstream. Since cytotoxicity was unlikely, Chiba et al
looked at lymphoid tissue counts of lymphocytes and found that FTY720 treatment
lead to a rapid increase of lymphocytes within lymphoid tissues that
corresponded to the decline in blood counts and thoracic duct lymphocyte
counts. FTY720, then, caused a
sequestration of lymphocytes within lymphoid tissues, and they hypothesized
that the immunosuppressive activity of FTY720 was related to the defective
lymphocyte circulation [7].
The mechanism for the FTY720-mediated sequestration
was partially elucidated in 2002 by Mandala et al. [8]. They found
that FTY resembled the lysophospholipid sphingosine and that the drug was
metabolized into a compound that resembled sphingosine-1-phosphate (S1P). Competitive binding assays showed that the
metabolized FTY720 could bind four of five S1P receptors and in in-vitro assays
showed that FTY720 could act as an S1P receptor agonist. In vivo, FTY720 treatment or S1P infusion
resulted in the rapid induction of lymphopenia in blood. The investigators also examined thoracic duct
cell counts as a measure of lymphocyte retention in lymphoid tissues, and found
a relative lymphopenia there as well.
These results showed that FTY720 could act as an S1P agonist in vivo,
and also revealed S1P to be a mechanism for mediating lymphocyte sequestration
within lymphoid tissues. Further
analysis revealed that S1P seemed to act at the point of lymphocyte egress from
lymphoid tissue into lymphatic sinuses, although the relative contributions of
the lymphocytes versus the sinus endothelium were unclear.
More recently, analysis of S1P receptor knockout mice
revealed that mice missing a single S1P receptor, S1P1, mimicked the phenotype
associate with FTY720 treatment.
Moreover, the absence of S1P1 on the lymphocytes alone in the presence
of normal S1P1 on the sinus endothelium, could mediate the effect, suggesting
that the control of lymphocyte egress was mediated by lymphocyte, rather than
endothelial, factors. Because the
S1P1-deficient mice resembled FTY-treated mice and because FTY treatment led to
a down-regulation of lymphocyte S1P1, the authors hypothesized that FTY may act
as a partial antagonist to S1P1 [9].
How the blockade of lymphocyte exit from the lymph
node results in clinically useful immunosuppression is not yet well understood,
but studies have been suggestive of several mechanisms. Both naïve and activated/effector T cells
are sequestered from the bloodstream [10, 11]. Using a
delayed hypersensitivity response and an autoimmune diabetes model to test for
effector CD8 activity, Pinschewer et al showed that the sequestration of these
cells by FTY720 was associated with attenuated end organ damage [12]. The
inability of effector cells to leave the lymph nodes and home to end organs,
then, may be one of the reasons why FTY720 has been effective in models of
solid organ transplant. The
sequestration of naïve T lymphocytes was also associated with decreased local
(i.e. draining lymph node) primary immune responses, which may also contribute
to useful clinical immune suppression [11]. Interestingly,
immune responses to models of systemic infection are preserved [12].
Potentially, this attribute may
be very useful clinically. This type of immune response is mediated primarily
by the spleen, which has a circulation pattern distinct from that of lymph
nodes [1]. Further
investigations are needed to understand how FTY differentially affects
different types of immune responses.
Recently, FTY was tested in a multiple-dose,
randomized, placebo-controlled phase I study of renal transplant patients. As expected, FTY720 administration to stable
renal transplant patients maintained on cyclosporine and prednisone resulted in
a dose-dependent transient drop in peripheral lymphocyte counts. The drug was well tolerated for up to 28 days
except for asymptomatic bradycardic episodes and did not affect blood
concentrations of cyclosporine.
Importantly, the incidence of infections was similar between placebo and
treatment groups [13]. Novartis,
the manufacturer of FTY, is also conducting a small pilot study on multiple
sclerosis patients (Shreeram Aradhye, Novartis, personal communication). The question for us is whether FTY will be
useful for the treatment of our autoimmune diseases. The utility of FTY720 for complex systemic
diseases such as SLE will need to await further investigation of FTY720 as well
as of the anatomical origin of these diseases.
If the drug truly does work by preventing naïve cells from recirculating
or effector cells from reaching their target, FTY720 could be potentially
useful in antigen-driven T cell-mediated diseases such as juvenile arthritis [14]. This is a
drug we should watch for in the near future.
Note:
This work was supported by an Arthritis Foundation Arthritis Investigator
Award, the William T. Morris Foundation, and the Norman and Rosita Winston
Foundation.
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