The impaired Th1 immune response of C3HeB/FeJ mice infected with Leishmania amazonensis: lessons learned from immunotherapy and vaccines

Leishmaniasis is a zoonotic disease caused by intracellular protozoan parasites of the genus Leishmania. Leishmania major and Leishmania amazonensis are both causative agents of cutaneous leishmaniasis in the Old and New World, respectively. While C3H mice are resistant to a L. major infection, they are susceptible to a L. amazonensis challenge and this is characterized by the development of chronic cutaneous lesions. Resistance to L. major is mediated by a T helper 1 (Th1) immune response characterized by CD4+ T cells producing IFN-gamma. In contrast, the susceptibility to L. amazonensis is associated with an impaired Th1 response and CD4 + T cell defects. Dendritic cells (DC) are the most potent antigen-presenting cells in vitro and in vivo and they have been used successfully as vaccine adjuvants to promote Th1 response in mouse studies of Leishmania spp. infection. Our hypothesis was that the induction of a Th1 response in C3H mice would promote resistance to a subsequent L. amazonensis challenge. Using a DC-based immunotherapy, we were able to induce a Th1 response in mice chronically infected with L. amazonensis. However, this did not mediate healing of the infection. When given before infection, a DC-based vaccine also promoted a Th1 response but it was not protective against a subsequent L. amazonensis promastigote challenge. Taken together, this data suggested that a Th1 response may not mediate resistance to L. amazonensis infection. However, we also show that the Th1 response elicited in C3H mice that had healed a previous L. major infection could promote resistance to a subsequent L. amazonensis infection. Therefore, future studies using the immune response of mice that have healed a L. major infection as a model will be needed to determine which immune factors are necessary and/or sufficient to induce protection to a L. amazonensis infection. This will be helpful for the design of future therapeutic and/or vaccine strategies against L. amazonensis