The objective of this project was to investigate effects of isometamidium (ISMM. Samorin®) on immune responses to Trypanosoma congolense infection in order to understand mechanisms of prophylaxis. (1) the efficacy of ISMM on T. congolense in vitro and in vivo was examined. (2) effects on sheep peripheral blood mononuclear cell (PBMC) phenotypes, proliferation, and IFN-y production were investigated. (3) effects on IL-12 and IFN-y production by mice splenic cells were studied. (4) effects on sheep PBMC phenotypes following BCG vaccination in sheep were also investigated in order to establish whether effects of ISMM were specific for trvpanosome antigens. Three groups consisting of four sheep were used in the trypanosome study. One group was prophylactically treated with ISMM and one was used as a normal control group. Four and half months later, all sheep were infected with T. congolense plus a third group that was later treated with ISMM 14 days post infection. Two groups of three sheep were used in BCG experiments: one was first treated with ISMM and 14 days after treatment both groups were inoculated with BCG vaccine. The efficacy of ISMM on T. congolense was studied on cultures in vitro and in sheep and mice in vivo. IL-12 and IFN-y production by mice splenic cells was investigated at different points after ISMM treatment Pre-infection results showed a significant increase in IFN-y production by sheep PBMC 14 to 21 days after ISMM administration when cultured with live tyrpanosomes. while cultures from the control group were negative. No significant amounts of IFN-y were detected in all groups during the infection period. ISMM prophylaxis suppressed polyclonal lymphocyte proliferation in vivo. Increases in B-cells in the control and treated groups 14 to 21 days after infection were significantly higher than in the prophy lactic group. A significant decrease in CD4" T-cells was recorded in the control and treated groups 14 to 21 days post infection, while in the prophylactic group no changes were observed. CD8~ T-cells increased only after treatment. The ratio of CD4LCD8" T-cells significantly dropped 21 days after infection in the control and treated groups, while it increased in the prophylactic group. There were no significant differences in CD5* and yS* T-cell responses. Trypanosome specific IgG antibodies in serum of the prophy lactic group were significantly higher than those in the control, while they were absent in the treated group. Following BCG vaccination, ly mphocy te proliferation in vivo was suppressed in the ISMM treated group. The ratio of CD4LCD8 T-cells was higher in the ISMM group than in the control. Also ISMM. prevented a decrease in the percentage of CD4~ T cells and suppressed polyclonal CD5" T cells and B cell expansion. Little or no differences were observed on yd'. CD8" T cells, and PPD skin test. ISMM was trypanostatic in vitro and T cell suppression decreased the prepatent period in prophylactically treated mice. In conclusion. ISMM prophylaxis modified cellular and antibody responses to T. congole infection probably via the IFN-y and 1L-12 feedback mechanisms. This immunomodulation enhanced prophylaxis and is not specific for trypanosome antigens since similar changes were observed following BCG vaccination, although the end result of an infection may depend on the type of host animal and nature of antigen.