Immunologic effects of chronic administration of tofacitinib, a Janus kinase inhibitor, in cynomolgus monkeys and rats – Comparison of juvenile and adult responses
Autor: | W. Mark Vogel, Douglas J. Ball, Mark Collinge, Zaher A. Radi, Andrea L. Nilson, Christopher J. Bowman |
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Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Aging medicine.medical_specialty Lymphoma B-Cell Lymphocyte T cell Administration Oral Thymus Gland Toxicology Rats Sprague-Dawley Hemoglobins Leukocyte Count 03 medical and health sciences Immune system Piperidines Internal medicine Leukocytes medicine Animals Janus Kinase Inhibitors Pyrroles Antigens Toxicity Tests Chronic B cell Janus kinase inhibitor Tofacitinib business.industry Organ Size General Medicine Macaca fascicularis Pyrimidines 030104 developmental biology medicine.anatomical_structure Endocrinology Hematocrit Tyrosine kinase 2 Hemocyanins Erythrocyte Count Female business Janus kinase Spleen |
Zdroj: | Regulatory Toxicology and Pharmacology. 94:306-322 |
ISSN: | 0273-2300 |
DOI: | 10.1016/j.yrtph.2018.02.006 |
Popis: | Tofacitinib, an oral Janus kinase (JAK) inhibitor for treatment of rheumatoid arthritis, targets JAK1, JAK3, and to a lesser extent JAK2 and TYK2. JAK1/3 inhibition impairs gamma common chain cytokine receptor signaling, important in lymphocyte development, homeostasis and function. Adult and juvenile cynomolgus monkey and rat studies were conducted and the impact of tofacitinib on immune parameters (lymphoid tissues and lymphocyte subsets) and function (T-dependent antibody response (TDAR), mitogen-induced T cell proliferation) assessed. Tofacitinib administration decreased circulating T cells and NK cells in juvenile and adult animals of both species. B cell decreases were observed only in rats. These changes and decreased lymphoid tissue cellularity are consistent with the expected pharmacology of tofacitinib. No differences were observed between juvenile and adult animals, either in terms of doses at which effects were observed or differential effects on immune endpoints. Lymphomas were observed in three adult monkeys. Tofacitinib impaired the primary TDAR in juvenile monkeys, although a recall response was generated. Complete or partial reversal of the effects on the immune system was observed. |
Databáze: | OpenAIRE |
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