science pharmaceutical expo biotech jobs
Originally published online as doi:10.1189/jlb.0504282 on September 15, 2004

Published online before print September 15, 2004
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0504282v1
76/6/1248    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Conklyn, M.
Right arrow Articles by Kudlacz, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Conklyn, M.
Right arrow Articles by Kudlacz, E.
(Journal of Leukocyte Biology. 2004;76:1248-1255.)
© 2004 by Society for Leukocyte Biology

The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing

Maryrose Conklyn1, Catharine Andresen, Paul Changelian and Elizabeth Kudlacz

Pfizer Global Research and Development, Department of Antibacterials, Immunology and Cancer, Groton, Connecticut

1 Correspondence: MS8220-2326, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340. E-mail: maryrose_j_conklyn{at}groton.pfizer.com

Janus kinase 3 (JAK3) is a cytoplasmic tyrosine kinase associated with the common {gamma} chain, an integral component of cytokine receptors of the interleukin (IL)-2 family, including IL-4, -7, -9, -15, and -21. CP-690550 is a JAK3 inhibitor with immunosuppressive properties under development for transplantation. We evaluated alterations in circulating lymphocyte subsets in cynomolgus monkey blood following chronic (3-week), oral CP-690550 administration. Natural killer (NK) and CD8+ T cell numbers were reduced in a dose- and time-dependent manner; the latter was a primary effect on memory subsets. CD4+ T and B cell numbers were unaffected or slightly increased, respectively. NK cell numbers were reduced ~80% (vs. 35% in vehicle-treated animals) and returned to baseline levels within 3 weeks following treatment cessation. CD8+ T cells declined by a maximum 43% (vs. 25% for vehicle-treated animals) but rebounded significantly (300%) within 2 weeks after the last dose. Although CP-690550 did not result in reduction of CD4+ T cell number, these cells also increased (225%) within 2 weeks of treatment cessation. IL-15 is important for maintaining homeostasis of these cell types, and CP-690550 inhibited IL-15-induced CD69 expression in NK cells [inhibitory concentration 50% (IC50)=48.0±8.4 nM] and CD8+ T cells (IC50=16.2±1.5 nM).

Key Words: memory T cells • IL-15 • CD69 • transplantation