JAK3
Tyrosine-protein kinase JAK3 (EC 2.7.10.2) (Janus kinase 3) (JAK-3) (Leukocyte janus kinase) (L-JAK)
Publications[править]
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.
MeSH Terms
- Administration, Oral
- Aging
- Animals
- Antigens
- Erythrocyte Count
- Female
- Hematocrit
- Hemocyanins
- Hemoglobins
- Janus Kinase Inhibitors
- Leukocyte Count
- Leukocytes
- Lymphoma, B-Cell
- Macaca fascicularis
- Male
- Organ Size
- Piperidines
- Pyrimidines
- Pyrroles
- Rats, Sprague-Dawley
- Spleen
- Thymus Gland
- Toxicity Tests, Chronic
Keywords
- Immune function
- Immunology
- Immunomodulation
- Lymphoma
- Tofacitinib
- Toxicology
Optimal expansion protocols for adoptive human T-cell therapy often include interleukin (IL)-15; however, the mechanism by which IL-15 improves the [i]in vivo[/i] antitumor effect of T cells remains to be elucidated. Using human T cells generated from HLA-A2 donors against novel T-cell epitopes derived from the human U266 myeloma cell line Ig light chain V-region (idiotype) as a model, we found that T cells cultured with IL-15 provided superior resistance to tumor growth [i]in vivo[/i], compared with IL-2, after adoptive transfer into immunodeficient hosts. This effect of IL-15 was associated with delayed/reversed senescence in tumor antigen-specific memory CD8 T cells mediated through downregulation of P21 , P16 , and P53 expression. Compared to IL-2, IL-15 stimulation dramatically activated JAK3-STAT5 signaling and inhibited the expression of DNA damage genes. Thus, our study elucidates a new mechanism for IL-15 in the regulation of STAT signaling pathways and CD8 T-cell senescence.
Keywords
- IL-15
- Idiotype
- T cells
- immunotherapy
- myeloma
- senescence