Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice

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

Research output: Contribution to journalArticlepeer-review


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-gamma+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-gamma+ and IFN-gamma+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.
Original languageEnglish
Pages (from-to)1204-1216
Number of pages13
JournalJournal of Clinical Investigation
Issue number4
Publication statusPublished - 1 Apr 2010


  • Actins
  • Animals
  • Antigens, CD31
  • CD4-Positive T-Lymphocytes
  • Immunocompetence
  • Indoles
  • Interferon-gamma
  • Leishmania donovani
  • Leishmaniasis, Visceral
  • Mice
  • Mice, Inbred C57BL
  • Nitric Oxide
  • Protein Kinase Inhibitors
  • Pyrroles
  • Receptor Protein-Tyrosine Kinases
  • Splenomegaly

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