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The Potent ITK/BTK Inhibitor Ibrutinib Is Effective for the Treatment of Experimental Visceral Leishmaniasis Caused by Leishmania donovani.
- Source :
-
The Journal of infectious diseases [J Infect Dis] 2019 Jan 29; Vol. 219 (4), pp. 599-608. - Publication Year :
- 2019
-
Abstract
- Background: New drugs are needed for leishmaniasis because current treatments such as pentavalent antimonials are toxic and require prolonged administration, leading to poor patient compliance. Ibrutinib is an anticancer drug known to modulate T-helper type 1 (Th1)/Th2 responses and has the potential to regulate immunity against infectious disease.<br />Methods: In this study, we evaluated the efficacy of oral ibrutinib as a host-targeted treatment for visceral leishmaniasis (VL) caused by Leishmania donovani using an experimental mouse model.<br />Results: We found that oral ibrutinib was significantly more effective than the pentavalent antimonial sodium stibogluconate (70 mg/kg) for the treatment of VL caused by L. donovani. Ibrutinib treatment increased the number of interleukin 4- and interferon γ-producing natural killer T cells in the liver and spleen and enhanced granuloma formation in the liver. Further, ibrutinib treatment reduced the influx of Ly6Chi inflammatory monocytes, which mediate susceptibility to L. donovani. Finally, ibrutinib treatment was associated with the increased production of the cytokines interferon γ, tumor necrosis factor α, interleukin 4, and interleukin 13 in the liver and spleen, which are associated with protection against L. donovani.<br />Conclusions: Our findings show that oral ibrutinib is highly effective for the treatment of VL caused by L. donovani and mediates its antileishmanial activity by promoting host immunity. Therefore, ibrutinib could be a novel host-targeted drug for the treatment of VL.
- Subjects :
- Adenine analogs & derivatives
Administration, Oral
Animals
Cytokines metabolism
Disease Models, Animal
Female
Immunity, Cellular
Mice
Mice, Inbred BALB C
Piperidines
Treatment Outcome
Immunologic Factors administration & dosage
Leishmania donovani growth & development
Leishmaniasis, Visceral drug therapy
Protein Kinase Inhibitors administration & dosage
Pyrazoles administration & dosage
Pyrimidines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1537-6613
- Volume :
- 219
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of infectious diseases
- Publication Type :
- Academic Journal
- Accession number :
- 30239895
- Full Text :
- https://doi.org/10.1093/infdis/jiy552