Inhibition of receptor tyrosine kinases restores immunocompetence and improves immune-dependent chemotherapy against experimental leishmaniasis in mice.
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.
Dalton
Jane E
JE
Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, United Kingdom.
Maroof
Asher
A
Owens
Benjamin M J
BM
Narang
Priyanka
P
Johnson
Katherine
K
Brown
Najmeeyah
N
Rosenquist
Lovisa
L
Beattie
Lynette
L
Coles
Mark
M
Kaye
Paul M
PM
D000199:Actins / Q000032:analysis; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D007121:Immunocompetence / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013163:Splenomegaly / Q000473:pathology; D000077210:Sunitinib
C541116:ACTA2 protein, human; D000199:Actins; D007211:Indoles; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D009569:Nitric Oxide; D007371:Interferon-gamma; D020794:Receptor Protein-Tyrosine Kinases; D000077210:Sunitinib