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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Research Article Infectious disease

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 1

Vascular remodeling in L. donovani–infected spleens.

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Vascular remodeling in L. donovani–infected spleens. (A and B) Splee...
(A and B) Spleen weights (A) and parasite burdens (B) measured during the course of infection. Data are mean ± SEM from 3 independent experiments (n = 8–10 per time point). (C) Splenic vasculature, visualized by FITC-dextran angiography, of naive versus infected (28 dpi) mice. Original magnification, ×12. (D) Whole mount staining of α-SMA+ vasculature (red) in spleens from naive and 28-dpi mice. Images from Supplemental Videos 1 and 2 are shown. Original magnification, ×200. (E) Proliferation of vascular endothelial cells in infected mice, but not naive mice, analyzed by immunostaining of frozen spleen sections with CD31 (blue/purple), α-SMA (red), and the proliferation marker Ki67 (green). Scale bar: 100 μm. (F) Quantification of large-caliber vessels counted for CD31+Ki67+ cells. At least 4 vessels were counted per spleen section. Data are mean ± SEM of at least 2 independent experiments (n = 3 per time point). ***P = 0.0003.