We have previously reported on the use of the SCID bg mouse infected with M. PTB as a model to study paratuberculosis. Here, we investigated the influence of immune reconstitution (by adoptive transfer of congenic spleen cells) on clinical disease and pathology in SCID bg mice previously infected with M. PTB. Thirty six SCID bg and 12 BALB/c mice were used in eight groups of six mice each. Test mice were injected intraperitoneally (ip) with 10⁶ cfu of M. PTB. Immune reconstitution was achieved by injecting SCID bg mice with 3.0 X 10⁷ spleen cells obtained from either naive or BALB/c mice previously injected ip with 106 cfu of live M. PTB. The mice were necropsied after being observed for 12 wks (10 wks after immune reconstitution). All mice injected with spleen cells (n=24) were successfully reconstituted as evidenced by the production of plasma Ig's and the presence of CD4+, CD8+ and B220+ lymphocytes in the spleen. While three (3/6) of the infected (but not reconstituted) SCID bg mice developed clinical disease, none of the infected reconstituted mice did (n=12). The mean body weight of the former group did not change during the experimental period: The mean body weights of other 7 groups (n=42) however increased. Reconstitution with either naive spleen cells (n=6) or spleen cells from infected BALB/c mice (n=6) reduced the severity of clinical disease, macroscopic and microscopic lesions, and bacterial load within liver lesions (p=0.05). Spleen indices (spleen wt/body wt X 100) were significantly increased (p=0.05) in all infected mice (n=24). We conclude that immune reconstitution of M. PTB infected SCID bg mice with spleen cells from BALB/c mice (naive or M. PTB sensitized) reduces the severity of the experimental disease. Given this abrogation in disease and the much larger number of CD4+ compared to CD8+ cells identified after reconstitution, we attribute this largely to the CD4+ population of lymphocytes. This model should permit further evaluation of independent and cooperative interactions of cells and mediators of the immune system responding to M. PTB infection.