Immunoregulation of genetically controlled acquired responses to Leishmania donovani infection in mice: the effects of parasite dose, cyclophosphamide and sublethal irradiation

Abstract

Summary On a B10 (Lsh^s) genetic background, the development of acquired T cell mediated immunity to Leishmania donovani infection in mice is under H-2 linked genetic control. Following intravenous inoculation of 10⁷ amastigotes three phenotypic patterns of recovery have been described: ‘early cure’ (H-2^r,s), ‘cure’ (H-2^b) and ‘non-cure’ (H-2^d,q,f). In an attempt to determine the immunological basis for this H-2 linked genetic control the effects of varying parasite dose (5 × 10³ to 5 × 10⁷ amastigotes) and of pre-treatments with cyclophosphamide (50 or 200 mg/kgbody weight CY) or sublethal irradiation (100 or 550 rad) on the course of infection, and on circulating anti-leishmanial IgG levels, were examined in strains representative of the three phenotypes: B10.D2/n (H-2^d), C57BL/10ScSn (H-2^b) and B10.RIII (H-2^r). It was found that with low parasite doses (5 × 10³ or 5 × 10⁴) ‘non-cure’ mice presented a ‘cure’ profile whilst raising the dose (5 × 10⁷) caused some perturbation of the normal self-curing response in ‘cure’ (but not ‘early cure’) mice. The highest dose did not, however, lead to progressive disease in the genetically non-cure strain. For the parasite dose experiments circulating anti-leishmanial IgG levels were higher in the early cure and cure strains than in the H-2^d non-cure strain. The higher doses of CY and sublethal irradiation administered prior to infection had a clear prophylactic effect on the non-cure strain with some effect also observed in cure and early cure strains. This was thought to be due to deletion of the precursors of T suppressor (Ts) cells suppressing cell-mediated immunity. Resolution of the liver parasite load in pre-treated mice took place despite minimal or undetectable levels of circulating anti-leishmanial IgG. Similarly, the earlier resolution of parasite load in pre-treated cure and early cure mice occurred even though the antibody response was severely reduced. This suggests that the high antibody responses observed in early cure and cure strains do not normally mediate cure and may simply reflect the independent effect of H-2 on T helper function for the humoral response.