Senescent BALB/c mice are able to develop resistance to Leishmania major infection.

Aging has been associated with a decline in immunocompetence and resistance to infections, partially due to dysregulated NO production by macrophages and deficits in mounting Th2 cell responses. We wondered if these alterations would reverse the immune response in experimental leishmaniasis. Bone-marrow-derived macrophages from 2- and 18-month-old (senescent) C57BL/6 or BALB/c mice showed no marked difference in leishmanicidal functions. In vivo infections of resistant C57BL/6 mice with Leishmania major revealed no difference between senescent and young mice. However, among susceptible BALB/c mice, senescent animals showed less foot-pad swelling than young mice, and 40 to 60% of them even showed healing of ulcers, reduced parasite dissemination, and a Th1 cell response. These changes were associated with a spontaneous release of interleukin-12 (IL-12) by macrophages from aged but not from young mice. Since exogenous microbial stimulation can influence immune responses during aging, we also infected senescent mice who were raised under specific-pathogen-free (SPF) conditions. They showed neither resistance nor a Th1 response, but their macrophages still spontaneously released IL-12. A microbiological analysis showed that conventionally kept mice, but not SPF mice, had experienced infection with murine hepatitis virus (MHV), an infection associated with a Th1-like response. We conclude that for the reversal of the immune response, senescence is the premier requirement but needs to be completed by another mandatory event such as microbial stimulation. One of the age-related, but not environment-related, factors is the spontaneous release of IL-12 by macrophages, while confrontation with MHV presents an environment-related difference, with both having the potential to support a Th1 response.