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Infection and Immunity, February 2001, p. 673-680, Vol. 69, No. 2
Department of Dermatology, University
Hospitals of Cleveland,1 Division of
Geographic Medicine, Case Western Reserve
University,2 and VA Medical
Center,3 Cleveland, Ohio 44106
Received 6 July 2000/Returned for modification 9 September
2000/Accepted 6 November 2000
Dendritic cells are potent antigen-presenting cells that also
produce interleukin-12 (IL-12) during innate and adaptive cellular immune responses and that thereby promote the differentiation of gamma
interferon (IFN-
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.2.673-680.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Pretreatment with Recombinant Flt3 Ligand Partially
Protects against Progressive Cutaneous Leishmaniasis in
Susceptible BALB/c Mice
)-producing Th1-type CD4+ T lymphocytes.
We hypothesized that expanded dendritic-cell populations in mice
pretreated with the hematopoietic cytokine Flt3L would protect against
cutaneous Leishmania major infection. Pretreatment of
disease-susceptible BALB/c mice with 10 µg of recombinant Flt3L (rFlt3L) for 9 to 10 days before infection increased lymph node IL-12
p40 productive capacity 20-fold compared to that of saline-injected controls. Furthermore, 9 of 22 (40.9%) rFlt3L-pretreated BALB/c mice
resolved their cutaneous infections, whereas none of the 22 control
BALB/c mice healed. Healed, rFlt3L-pretreated mice did not develop
disease following reinfection. Flt3L pretreatment also reduced parasite
numbers 1,000-fold in the cutaneous lesions at 2 weeks after infection
relative to numbers in lesions of untreated controls. However, Flt3L
pretreatment did not significantly alter L. major-induced
IFN-
and IL-4 production in lymph node culture at 1, 2, and 4 weeks
after infection. Despite the lack of Th immune deviation, Flt3L
ligand-pretreated lymph nodes expressed up to 10-fold higher levels of
IL-12 p40 and inducible (type 2) nitric oxide synthase mRNA at 7 days
after infection. In contrast, treatment with rFlt3L after infection
failed to protect against disease despite comparable expansions of
dendritic cells and IL-12 p40 productive capacity in both infected and
uninfected BALB/c mice treated with rFlt3L. We conclude that rFlt3L
pretreatment before infection with L. major reduces
parasite load and promotes healing of cutaneous lesions without stable
cytokine deviation towards a dominant Th1 cytokine phenotype.
*
Corresponding author. Mailing address: Division of
Geographic Medicine W-137, Case Western Reserve University School of
Medicine, Cleveland, OH 44106-4983. Phone: (216) 368-1859. Fax: (216)
368-4825. E-mail: fxh10{at}po.cwru.edu.
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