Designing therapies against experimental visceral leishmaniasis by modulating the membrane fluidity of antigen-presenting cells.
The membrane fluidity of antigen-presenting cells (APCs) has a significant bearing on T-cell-stimulating ability and is dependent on the cholesterol content of the membrane. The relationship, if any, between membrane fluidity and defective cell-mediated immunity in visceral leishmaniasis has been investigated. Systemic administration of cholesterol by liposome delivery (cholesterol liposomes) in Leishmania donovani-infected hamsters was found to cure the infection. Splenic macrophages as a prototype of APCs in infected hamsters had decreased membrane cholesterol and an inability to drive T cells, which was corrected by cholesterol liposome treatment. The effect was cholesterol specific because liposomes made up of the analogue 4-cholesten-3-one provided almost no protection. Infection led to increases in interleukin-10 (IL-10), transforming growth factor beta, and IL-4 signals and concomitant decreases in gamma interferon (IFN-gamma), tumor necrosis factor alpha, and inducible NO synthase signals, which reverted upon cholesterol liposome treatment. The antileishmanial T-cell repertoire, whose expansion appeared to be associated with protection, was presumably type Th1, as shown by enhanced IFN-gamma signals and the predominance of the immunoglobulin G2 isotype. The protected group produced significantly more reactive oxygen species and NO than the infected groups, which culminated in killing of L. donovani parasites. Therefore, cholesterol liposome treatment may be yet another simple strategy to enhance the cell-mediated immune response to L. donovani infection. To our knowledge, this is the first report on the therapeutic effect of cholesterol liposomes in any form of the disease.
Banerjee
Subha
S
Indian Institute of Chemical Biology, Council of Scientific & Industrial Research, Kolkata 700032, India.
Ghosh
June
J
Sen
Subha
S
Guha
Rajan
R
Dhar
Ranjan
R
Ghosh
Moumita
M
Datta
Sanchita
S
Raychaudhury
Bikramjit
B
Naskar
Kshudiram
K
Haldar
Arun Kumar
AK
Lal
C S
CS
Pandey
K
K
Das
V N R
VN
Das
Pradeep
P
Roy
Syamal
S
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D002462:Cell Membrane / Q000737:chemistry; D002784:Cholesterol / Q000032:analysis / Q000627:therapeutic use; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D007891:Leishmania / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000276:immunology*; D008081:Liposomes / Q000627:therapeutic use; D008264:Macrophages / Q000737:chemistry / Q000276:immunology; D008560:Membrane Fluidity / Q000187:drug effects*; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D008081:Liposomes; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D002784:Cholesterol