Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice
Jane E. Dalton, … , Mark Coles, Paul M. Kaye
Jane E. Dalton, … , Mark Coles, Paul M. Kaye
Published March 15, 2010
Citation Information: J Clin Invest. 2010;120(4):1204-1216. https://doi.org/10.1172/JCI41281.
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Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

Abstract

Receptor tyrosine kinases are involved in multiple cellular processes, and drugs that inhibit their action are used in the clinic to treat several types of cancer. However, the value of receptor tyrosine kinase inhibitors (RTKIs) for treating infectious disease has yet to be explored. Here, we have shown in mice that administration of the broad-spectrum RTKI sunitinib maleate (Sm) blocked the vascular remodeling and progressive splenomegaly associated with experimental visceral leishmaniasis. Furthermore, Sm treatment restored the integrity of the splenic microarchitecture. Although restoration of splenic architecture was accompanied by an increase in the frequency of IFN-γ+CD4+ T cells, Sm treatment alone was insufficient to cause a reduction in tissue parasite burden. However, preconditioning by short-term Sm treatment proved to be successful as an adjunct therapy, increasing the frequency of IFN-γ+ and IFN-γ+TNF+CD4+ T cells, enhancing NO production by splenic macrophages, and providing dose-sparing effects when combined with a first-line immune-dependent anti-leishmanial drug. We propose, therefore, that RTKIs may prove clinically useful as agents to restore immune competence before the administration of chemo- or immunotherapeutic drugs in the treatment of visceral leishmaniasis or other diseases involving lymphoid tissue remodeling, including cancer.

Authors

Jane E. Dalton, Asher Maroof, Benjamin M.J. Owens, Priyanka Narang, Katherine Johnson, Najmeeyah Brown, Lovisa Rosenquist, Lynette Beattie, Mark Coles, Paul M. Kaye

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Figure 4

RTKI treatment inhibits pathogen-induced splenic vascular remodeling.

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RTKI treatment inhibits pathogen-induced splenic vascular remodeling. (A...
(A) Spleen/body weight ratios in 21- and 28-dpi L. donovani–infected mice, measured before and after Sm treatment compared with vehicle control (VC) or no treatment. The significant increase in spleen weights and spleen/body weight ratios observed at 28 dpi compared with 21 dpi was inhibited by Sm treatment compared with vehicle control treatment. *P = 0.03, **P = 0.008. (B) Splenic parasite burdens were not altered by Sm treatment. ***P = 0.006. (C) Changes in splenic vasculature after Sm treatment, assessed by FITC-dextran angiography. Boxed regions are shown at higher magnification below, showing details of vascular branching. Original magnification, ×24 (naive, top); ×120 (naive, bottom); ×12 (infected, top); ×60 (infected, bottom). (D) Effect of Sm treatment on expression of CD31 (red) in L. donovani–infected spleens. Sections were counterstained with DAPI (blue). Scale bars: 100 μm. (E) Effect of Sm and vehicle control treatment on the expression of Meca32 (green) in L. donovani–infected compared with naive mouse spleens. Scale bars: 100 μm. (F and G) Area covered by CD31+ (F) and Meca32+ (G) endothelial cells in whole spleen following Sm treatment, determined using computer-assisted morphometric analysis. A significant decrease in the CD31+ (**P = 0.005) and Meca32+ (**P = 0.004) vascular areas was observed in tissues from Sm-treated mice compared with vehicle control–treated mice. Data are mean ± SEM of at least 3 independent experiments (n = 5 per time point).