FIG. 7.

Influence of OdDHL on the immune system. The mammalian T-helper (Th) cell response can be subdivided into two distinct arms, Th-1 and Th-2; the development of T cells along these distinct lineages is stimulus dependent and results in the release of cytokines characteristic of each lineage. (a) bacterial pathogens induce a Th-1 response, characterized by the secretion of IL-12 and gamma interferon. This developmental pathway results in the generation of activated macrophage populations, which are bactericidal and proinflammatory. (b) TNF-α is a key player in the establishment of this inflammatory process. It causes neutrophil activation, adhesion and extravasation, and the secretion of further inflammatory cytokines and chemokines (IL-6 and IL-8). Conversely, environmental allergens and helminth parasites induce a Th-1 contrasuppressive Th-2 response, characterized by the secretion of IL-4, IL-5, and IL-13, which induce a state of immediate hypersensitivity. Given the demarcation of these developmental pathways into antibacterial and anthelminthic, it would be of evolutionary advantage to bacterial pathogens to suppress the Th-1 response. This would in turn be supportive of the Th-2 response. It can be envisaged that OdDHL, by influencing both T-cell and macrophage functions at the points indicated in panel a, modulates host inflammatory responses to a degree which may promote the growth and survival of the pathogen. Compounds with this type of immunological activity could have applications in disease states, such as toxic shock syndrome and cerebral malaria, which have a significant TNF-α component.