Single gene control of resistance to cutaneous leishmaniasis in mice

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Although previous studies demonstrated a requirement for CD40-CD40 ligand (CD40L) interaction in the development of resistance to Leishmania infection, we recently showed that mice lacking the gene for CD40L (CD40L ؊/؊ mice) can control Leishmania major infection when they are infected with reduced numbers of parasites. In this study, we examine the cytokine pattern in healing versus nonhealing CD40L ؊/؊ mice and investigated whether CD40 activation is required for resistance to reinfection. We observed that CD4؉ cells in healed CD40L؊/؊ mice produce high levels of gamma interferon compared to cells from nonhealing, highdose-inoculated mice. In addition, we observed a higher frequency of interleukin-12 (IL-12)-producing cells and a reduced number of IL-4-producing cells in mice infected with reduced numbers of parasites. Importantly, we found that healed CD40L ؊/؊ mice are highly resistant to reinfection with a large parasite inoculum. In addition, by comparing the cytokine patterns at an early and late stage of infection in nonhealing CD40L mice, we demonstrated that nonhealing CD40L؊/؊ mice produce a weak Th1-type response during the early stage of infection, but this response wanes as a Th2-type response emerges during late stages of infection. Anti-IL-4 antibody treatment, starting either at the beginning of infection or at week 4 postinfection enabled CD40L؊/؊ mice to control a high-dose infection. Together, these results show that CD40-CD40L interaction, although important for IL-12 production in high-dose infections, is not required for either the development or maintenance of resistance in mice infected with reduced numbers of parasites.

mentioning

confidence: 99%

CD40-CD40 Ligand Costimulation Is Not Required for Initiation and Maintenance of a Th1-Type Response toLeishmania majorInfection

Padigel

Farrell

2003

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“…By contrast, the experimental model of leishmaniasis that makes use of genetically defined inbred mice, infected under controlled conditions, has proved a powerful tool to study some of the host parameters associated with susceptibility or resistance. The importance of genetic factors in shaping the innate or acquired immunity of the host to L. major parasites has been demonstrated (9,15,22). Thus, factors that determine the development of a TH1 response are associated with resistance, whereas factors that orient the immune response toward a TH2 dominance are associated, as in BALB/c mice, with protracted infection and visceralization (14,27,45).…”

mentioning

confidence: 99%

Heterogeneity of WildLeishmania majorIsolates in Experimental Murine Pathogenicity and Specific Immune Response

Kébaïer¹,

Louzir²,

Chenik³

et al. 2001

Virulence variability was investigated by analyzing the experimental pathogenicity of 19 Leishmania major strains in susceptible BALB/c mice. Twelve strains were isolated from Tunisian patients with zoonotic cutaneous leishmaniasis; seven strains were isolated in Syria (n ‫؍‬ 1), Saudi Arabia (n ‫؍‬ 2), Jordan (n ‫؍‬ 2), or Israel (n ‫؍‬ 2). BALB/c mice were injected in the hind footpad with 2 ؋ 10 6 amastigotes of the various isolates, and lesion progression was recorded weekly for 9 weeks. Interleukin-4 (IL-4) and gamma interferon (IFN-␥) production of lymph node mononuclear cells activated in vitro with parasite antigens were evaluated 5 weeks after infection. We show that disease progression induced by different L. major isolates was largely heterogeneous although reproducible results were obtained when using the same isolate. Interestingly, isolates from the Middle East induced a more severe disease than did the majority of Tunisian isolates. Strains with the highest virulence tend to generate more IL-4 and less IFN-␥ in vitro at week 5 postinfection as well as higher levels of early IL-4 mRNA in the lymph node draining the inoculation site at 16 h postinfection. These results suggest that L. major isolates from the field may differ in virulence, which influences the course of the disease induced in mice and the type of immune response elicited by the infected host.

“…Although a majority of inbred strains of mice develop small, self-healing lesions following infection with the protozoan parasite Leishmania major, a few mouse strains, such as BALB/c, develop large, nonhealing cutaneous lesions and ultimately succumb to disseminated disease (7,16). Mice that spontaneously resolve their infections develop Th1-type responses characterized by heightened production of the macrophage-activating cytokine, IFN-␥, while nonhealing BALB/c mice develop Th2-type responses in which interleukin-4 (IL-4) is the dominant cytokine produced by a CD4 ϩ effector cells (11,22,32).…”

mentioning

confidence: 99%

Combined Treatment with Interleukin-12 and Indomethacin Promotes Increased Resistance in BALB/c Mice with EstablishedLeishmania majorInfections

Padigel

Scott

et al. 2002

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Following infection of susceptible BALB/c mice with Leishmania major, early production of interleukin-4 (IL-4) is associated with the development of a nonprotective Th2 response and the development of progressive disease. Treatment of mice with IL-12 at the time of infection can promote the activation of a protective Th1 response; however, IL-12 treatment of mice with established infections has little effect on the progress of lesion development. This may be due to a down-regulation of the IL-12 receptor β2 chain (IL-12Rβ2) that accompanies the expansion of IL-4-producing Th2 cells. We have examined whether prostaglandins function to regulate in vivo responsiveness to IL-12. Mice treated with indomethacin are responsive to treatment with exogenous IL-12 through at least the first 2 weeks of infection and, unlike control mice treated with IL-12, develop an enhanced Th1-type response associated with increased enhanced resistance to infection. Cells from indomethacin-treated mice also exhibit enhanced production of gamma interferon (IFN-γ) following in vitro stimulation with IL-12. Although in vivo indomethacin treatment did not appear to influence IL-12 production in infected mice, cells from indomethacin-treated mice did express higher levels of IL-12Rβ2, suggesting that prostaglandins may play a role in the loss of IL-12 responsiveness observed during nonhealing L. major infections