Johne's disease is an important disease that results in great economic losses for both dairy and beef production in the US and worldwide. The disease progresses through distinct stages, a subclinical stage where there are no clinical signs and a clinical stage that is characterized by progressive symptoms associated with chronic shedding of high levels of bacteria in the feces along with severe diarrhea and concomitant weight loss. The host immune response to M. paratuberculosis is paradoxical with strong cell-mediated immune responses during subclinical stages and strong humoral responses during clinical stages of the disease. It is possible that immune modulation of an effective cell-mediated immune response in paratuberculosis may play an important role in disease progression. We hypothesized that the clinical stage of Johne's disease is mediated by production of cytokines such as TGF-beta and IL-10 that downregulate IFN-gamma production and interfere with an effective cell-mediated immune response. Therefore, ileum, ilealcecal junction, ilealcecal lymph node and mesenteric lymph node tissues from healthy, subclinical or clinical animals were collected and analyzed for the presence of TGF-beta, IL-10 and IFN-gamma mRNA by quantitative RT-cPCR. The results show that TGF-beta and IL-10 mRNA levels in animals that have progressed to the clinical stage of disease is higher than that found in subclinical or healthy animals, whereas, IFN-gamma is higher in subclinical animals. A change in the balance of cytokines at the site of infection may have an important effect on the microbicidal activity of macrophages.