Parasite dose determines the Th1/Th2 nature of the response toLeishmania major independently of infection route and strain of host or parasite

Abstract

Leishmania major causes cutaneous leishmaniasis in mice and man. Infection of mice with relatively low or high numbers of parasites leads respectively to parasite containment, associated with a Th1, cell-mediated response, or progressive disease, associated with a Th2, antibody response in all circumstances studied. These include different parasite strains, different routes of infection, and different hosts previously classified as susceptible, resistant or of intermediate susceptibility. This dose dependency appears to reflect a general rule. We argue that this rule may allow the design of a vaccination strategy that is effective among a genetically diverse population, and that it imposes severe constraints upon proposals for the nature of the "decision criterion" determining whether antigen induces a Th1 or Th2 response.

Site-Dependent Recruitment of Inflammatory Cells Determines the Effective Dose of Leishmania major

“…Here we demonstrate that even before different antigen-presenting cells begin to prime adaptive immunity, the site of inoculation immediately influences the effective dose of L. major parasites that establishes infection. The parasite dose has far-reaching implications for Leishmania infections, including the nature of the adaptive immune response, and is likely one of the most important variables in determining the kinetics and outcome of infection (6,36,(44)(45)(46)(47)(48)). Our observations demonstrate that the number of parasites that establishes infection must be considered in interpreting the influence of the site of infection, as suggested previously (6).…”

“…The parasite dose has far-reaching implications for Leishmania infections, including the nature of the adaptive immune response, and is likely one of the most important variables in determining the kinetics and outcome of infection (6,36,(44)(45)(46)(47)(48)). Our observations demonstrate that the number of parasites that establishes infection must be considered in interpreting the influence of the site of infection, as suggested previously (6). We and others have demonstrated that the relative differences in parasite load or lesion size following inoculation at different sites or with different doses of parasites can change depending on the time of analysis (1,3,7,36,48).…”

Preliminary study towards a novel experimental model to study localized cutaneous leishmaniasis caused bY Leishmania (Leishmania) mexicana

“…The paradigm for the CD4 + T-helper 1 (Th1)/Th2 dichotomy is largely based, 2 . Conflicting data may arise in part because different parasite strains or species are being examined, different tissue target (the mice's footpad, the ear, or base of the tail) are being infected, and different doses ("low" 1x10 2 and "high" 1x10 6 ) of metacyclic promastigotes have been inoculated 20,27,28 . In addition immunological studies carried out in humans did not reproduce the Th1/Th2 dichotomy described in the L. major, C57BL/6 and the BALB/c mouse model of CL 18,23,24 .…”

The Number of Responding CD4 T Cells and the Dose of Antigen Conjointly Determine the Th1/Th2 Phenotype by Modulating B7/CD28 Interactions

“…Ag dose is also known to affect the Th1/Th2 phenotype of the ensuing response. Most in vivo observations show that lower and higher doses, respectively, favor the generation of Th1 and Th2 cells (5,(25)(26)(27)(28)(29)(30), although some in vitro observations are inconsistent with this conclusion (31).…”