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ORIGINAL ARTICLE
Janus Kinase Inhibitor Tofacitinib Shows Potent Efficacy
in a Mouse Model of Autoimmune Lymphoproliferative
Syndrome (ALPS)
Seiji Yokoyama
1
&Pin-Yu Perera
2
&Seigo Terawaki
1
&Nobumasa Watanabe
1
&
Osamu Kaminuma
1
&Thomas A. Waldmann
3
&Takachika Hiroi
1
&Liyanage P. Perera
3
Received: 4 August 2015 /Accepted: 24 September 2015 /Published online: 9 October 2015
#Springer Science+Business Media New York (outside the USA) 2015
Abstract
Purpose Autoimmune lymphoproliferative syndrome
(ALPS) is a non-malignant genetic disorder of lymphocyte
homeostasis with defective Fas-mediated apoptosis. Current
therapies for ALPS primarily target autoimmune manifesta-
tions with non-specific immune suppressants with variable
success thus highlighting the need for better therapeutics for
this disorder.
Methods The spectrum of clinical manifestations of ALPS is
mirrored by MRL/lpr mice that carry a loss of function muta-
tion in the Fas gene and have proven to be a valuable model in
predicting the efficacy of several therapeutics that are front-
line modalities for the treatment of ALPS. We evaluated the
potential efficacy of tofacitinib, an orally active, pan-JAK in-
hibitor currently approved for rheumatoid arthritis as a single
agent modality against ALPS using MRL/lpr mice.
Results We demonstrate that a 42-day course of tofacitinib
therapy leads to a lasting reversal of lymphadenopathy and
autoimmune manifestations in the treated MRL/lpr mice,
Specifically, in treated mice the peripheral blood white blood
cell counts were reversed to near normal levels with almost a
50 % reduction in the TCRαβ
+
CD4
−
CD8
−
T lymphocyte
numbers that coincided with a parallel increase in CD8
+
T
cells without a demonstrable effect on CD4
+
lymphocytes
including FoxP3
+
regulatory T cells. The elevated plasma
IgG and IgA levels were also drastically lowered along with
a significant reduction in plasmablasts and plasmacytes in the
spleen.
Conclusion On the basis of these results, it is likely that
tofacitinib would prove to be a potent single agent therapeutic
modality capable of ameliorating both offending lymphade-
nopathy as well as autoimmunity in ALPS patients.
Keywords Autoimmunity .lymphoproliferation .ALPS .
tofacitinib .SLE
Abbreviations
ALPS Autoimmune lymphoproliferative syndrome
DN Double negative
SLE Systemic lupus erythematosus
Introduction
Autoimmune lymphoproliferative syndrome (ALPS) is a non-
malignant disorder of defective lymphocyte homeostasis and
is characterized by massive accumulation of lymphocytes
resulting in splenomegaly, and lymphoadenopathy [1,2].
The majority of ALPS patients harbor heterozygous germline
mutations in the death-receptor encoding TNF receptor super-
family, member 6 gene (TNFRSF6 also known as Fas or
CD95) that are inherited in an autosomal dominant manner
[3,4]. The presence of a large number of TCRαβ
+
CD4
−
CD8
−
Electronic supplementary material The online version of this article
(doi:10.1007/s10875-015-0203-z) contains supplementary material,
which is available to authorized users.
*Takachika Hiroi
hiroi-tk@igakuken.or.jp
*Liyanage P. Perera
pereral@mail.nih.gov
1
Department of Genome Medicine, The Tokyo Metropolitan
Institute of Medical Science, 2-1-6, kamikitazawa,
Setagaya-ku, Tokyo 156-8506, Japan
2
Veterans Affairs Medical Center, Washington, DC 20422, USA
3
Lymphoid Malignancies Branch, National Cancer Institute,
Bldg 10 4N114, Bethesda, MD 20892-1374, USA
J Clin Immunol (2015) 35:661–667
DOI 10.1007/s10875-015-0203-z
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