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Blood, 15 January 2002, Vol. 99, No. 2, pp. 680-689
TRANSPLANTATION
Selective inhibitor of Janus tyrosine kinase 3, PNU156804,
prolongs allograft survival and acts synergistically with cyclosporine
but additively with rapamycin
Stanislaw M. Stepkowski,
Rebecca A. Erwin-Cohen,
Fariba Behbod,
Mou-Er Wang,
Xienui Qu,
Neelam Tejpal,
Zsuzsanna S. Nagy,
Barry D. Kahan, and
Robert A. Kirken
From the Department of Surgery/Division of Immunology
and Organ Transplantation and the Department of Integrative Biology and
Pharmacology, University of Texas Medical School at Houston, and the
Department of Biochemistry and Molecular Biology, Medical Health
Science Center, University of Debrecen, Hungary.
Janus kinase 3 (Jak3) is a cytoplasmic tyrosine (Tyr) kinase
associated with the interleukin-2 (IL-2) receptor common gamma chain
( c) that is activated by multiple T-cell growth factors (TCGFs) such as IL-2, -4, and -7. Using human T cells, it was found
that a recently discovered variant of the undecylprodigiosin family of
antibiotics, PNU156804, previously shown to inhibit IL-2-induced cell
proliferation, also blocks IL-2-mediated Jak3 auto-tyrosine
phosphorylation, activation of Jak3 substrates signal transducers and
activators of transcription (Stat) 5a and Stat5b, and extracellular
regulated kinase 1 (Erk1) and Erk2 (p44/p42). Although PNU156804
displayed similar efficacy in blocking Jak3-dependent T-cell
proliferation by IL-2, -4, -7, or -15, it was more than 2-fold less
effective in blocking Jak2-mediated cell growth, its most homologous
Jak family member. A 14-day alternate-day oral gavage with 40 to 120 mg/kg PNU156804 extended the survival of heart allografts in a
dose-dependent fashion. In vivo, PNU156804 acted synergistically with
the signal 1 inhibitor cyclosporine A (CsA) and additively with the
signal 3 inhibitor rapamycin to block allograft rejection. It is
concluded that inhibition of signal 3 alone by targeting Jak3 in
combination with a signal 1 inhibitor provides a unique strategy to
achieve potent immunosuppression.
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