title: Distinct immunological states in murine cutaneous leishmaniasis by immunising with different amounts of antigen: the generation of beneficial, potentially harmful, harmful and potentially extremely harmful states.
abstract: Infection of BALB/c mice with a standard and substantial number of Leishmania major parasites results in progressive disease, following the induction of a parasite-specific Th2 response. These mice have been designated as "susceptible" on this basis. We show that distinct types of immune response can be generated in "susceptible" BALB/c mice depending upon the number of parasites employed for infection, and that the pathophysiological consequences of such distinct responses are dramatically different. Infection with very low numbers of parasites results in the exclusive induction of a cell-mediated, Th1 response, and the generation of resistance to the standard and substantial challenge. Spleen cells from such resistant mice can confer resistance upon normal mice when transferred to them, but these spleen cells do not contain T cells expressing DTH or Th1 effector cells that produce IFN gamma on short term culture (48 hrs) with parasite antigen. The immune response in this case appears to result in the virtual elimination of parasites from the lymph node draining the site of infection and, by implication, from the infected mouse. We suggest that such elimination results in the absence of antigen stimulation and hence of effector T cells, and that "memory Th1 cells" are responsible for the capacity of spleen cells to confer resistance on normal mice. We predict such mice will not suffer parasitemia upon immune suppression, i.e. are not susceptible to reactivation disease. This is the "beneficial state". In contrast to this infection with a very low number of parasites infection with a low number usually results in one of two states: (i) The generation of a response with a very small Th2 component, production of a small amount of antibody, chronic parasitemia and hence chronic generation of parasite-specific effector Th1/Th2 cells, or (ii) The generation of a response with a greater Th2 component, the production of more antibody, the formation of a frank lesion, and the long term generation of a stable, mixed Th1/Th2 response. We refer to the latter state as borderline leishmaniasis in analogy with borderline leprosy. Parasites can be recovered from the draining lymph node in both these cases many months after infection. We therefore believe that mice infected with a low number of parasites, that harbour a chronic subclinical infection, will suffer reactivation disease upon immune suppression, and we consequently designate the state generated as potentially harmful. We consider mice with borderline disease to be in a harmful state. Mice immunised with high doses of parasite antigen produce in the long term Th2 responses, whereas those immunised with lower doses produce Th1 responses. Mice immunised to produce a Th2 response were subsequently infected with a very low number of parasites that is normally contained. The generation of a Th2 response results in the generation of a Th2 imprint, such that the response to the low dose infection is modulated from a Th1 to a Th2 mode, resulting in progressive disease. We argue that immunisation/vaccination, resulting in a state that deviates the protective response to a non-protective mode, may result in epidemics. Such a state has the potential for being extremely harmful.
authors.affiliation: Department of Microbiology, University of Saskatchewan, Saskatoon, Canada.
authors.forename: P A
authors.initials: PA
authors.lastname: Bretscher
authors.forename: O
authors.initials: O
authors.lastname: Ogunremi
authors.forename: J N
authors.initials: JN
authors.lastname: Menon
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology*; D006968:Hypersensitivity, Delayed; D007371:Interferon-gamma / Q000096:biosynthesis; D018320:Leishmania major / Q000276:immunology* / Q000302:isolation & purification; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000503:physiopathology; D008198:Lymph Nodes / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D016052:Protozoan Vaccines / Q000009:adverse effects; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D016052:Protozoan Vaccines; D007371:Interferon-gamma