The immune modulator FYT720 prevents autoimmune diabetes
in nonobese diabetic mice૾
Zandong Yang,
a,
* Meng Chen,
a
Lawrence B. Fialkow,
a
Justin D. Ellett,
a
Runpei Wu,
a
Volker Brinkmann,
b
Jerry L. Nadler,
a
and Kevin R. Lynch
c,
*
a
Department of Internal Medicine, P.O. Box 801413, University of Virginia, Charlottesville, VA 22908, USA
b
Novartis Pharma AG Transplantation Research, WSJ-386.101, CH-4002 Basel, Switzerland
c
Department of Pharmacology, P.O. Box 800735, University of Virginia, Charlottesville, VA 22908, USA
Received 30 October 2002; accepted with revision 19 December 2002
Abstract
FTY720 is a novel immune regulatory drug derived from the fungal sphingosine analog ISP-1 (myriocin). FTY720 causes a
redistribution of lymphocytes from circulation to secondary lymphoid tissues. Type 1 diabetes is an autoimmune disorder caused by
cellular-mediated destruction of insulin-producing pancreatic

cells in the islets of Langerhans. Indeed, local infiltration of islets by
mononuclear cells is the hallmark of Type 1 diabetes. Based on both FTY720’s action and the involvement of cellular infiltration in the
disease progression, we tested FTY720 for its ability to prevent autoimmune diabetes in diabetes-prone, nonobese diabetic (NOD) mice. We
found that treatment with FTY720 completely prevented NOD mice from developing autoimmune diabetes. The FTY720-treated animals
showed both reduced numbers of circulating lymphocytes and sharply diminished cellular infiltration of pancreatic islets. These results
suggest that FTY720 may be effective in prevention of autoimmune diabetes or in slowing its progression.
© 2003 Elsevier Science (USA). All rights reserved.
Keywords: FTY720; Autoimmune diabetes; NOD mice; Insulitis; Lymphocytes
Introduction
The novel immune-modulating drug FTY720 was de-
rived from ISP-1 (myriocin), which is a sphingosine-like
metabolite of the ascomycete Isaria sinclairii [1–3]. Like
ISP-1, FTY720 prolongs the survival of skin allografts in
rodents, but lacks the gastrointestinal toxicity of the parent
compound. Unlike ISP-1, FTY720 does not inhibit serine
palmitoyl transferase (the initial enzyme in sphingolipid
biosynthesis) [4]; rather, FTY720 is phosphorylated to form
a potent sphingosine 1-phosphate (S1P) analog that interacts
with four (of five) S1P receptors and thus activates multiple
signaling pathways [5,6].
Treatment with a single dose of FTY720 results in a
transient lymphopenia resulting from a reversible reappor-
tionment of T and B lymphocytes between circulatory and
secondary lymphoid tissue compartments [7,8]. The redi-
rection of T lymphocytes away from tissue grafts and sites
of inflammation is thought to underlie the effectiveness of
FTY720 in transplantation and autoimmunity. Indeed,
FTY720, in combination with cyclosporin and corticoste-
roids, has been shown to be safe and effective in human
renal transplant patients [9,10]. FTY720 has been shown to
be highly effective in several animal models of transplan-
tation [11,12], including pancreatic islet transplantation
[13,14]. In addition, FTY720 has been found to be effective
in treating autoimmune disorders in animal models, includ-
ing models for autoimmune myocarditis [15], uveoretinitis
[16], and systemic lupus erythematosus [17]. The mecha-
nisms of action, molecular targets, and efficacy of FTY720
૾ This work was supported by both a pilot study grant (to Z.Y. and
K.R.L.) and by the Islet Core grant (to Z.Y. and J.L.N.) in the University
of Virginia Diabetes Research Center grant from the National Institutes of
Health (P30 DK063609-01).
* Corresponding authors.
E-mail address: zy4g@virginia.edu (Z. Yang) or krl2z@virginia.edu
(K.R. Lynch).
R
Available online at www.sciencedirect.com
Clinical Immunology 107 (2003) 30–35 www.elsevier.com/locate/yclim
1521-6616/03/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved.
doi:10.1016/S1521-6616(02)00054-2