|JOHNSON, W. CARL|
|Cluff, C - RIBI IMMUNOCHEM INC.|
Submitted to: Annals of the New York Academy of Sciences
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 15, 1997
Publication Date: N/A
Interpretive Summary: The immune response of cattle to babesiosis, a tick-transmitted disease caused by a protozoa (one celled animal) that resides in the red blood cells, is complex. There are basically two primary forms of immunity. Type-1 involves killing of the invading microorganisms directly by effector cells or by the release of soluble mediators from effector cells, and type-2 involves the production of antibody. In some cases, cellular responses can be augmented when the pathogen is coated with a certain class of antibody. This special class of antibody is called an opsonin. It has been shown recently that opsonic antibody production is regulated by a molecule called interferon gamma. Interferon gamma also activates a certain kind of effector cell called a mononuclear phagocyte. We have demonstrated that opsonic antibody and activated mononuclear phagocytes are involved with the resolution of a Babesia infection, and that the immune response is best characterized as type-1. The mononuclear phagocyte not only kills the organism directly by engulfing it, a mechanism augmented by opsonic antibody, but by the release of a soluble mediator. In addition, we have also identified another molecule (interleukin-10) that regulates the production of interferon gamma (dampens the effectiveness of a type-1 response), and may be associated with an increase in severity of the disease. Thus we have identified that a vaccine needs to prevent the overproduction of interleukin-10 until a type-1 immune response is induced.
Technical Abstract: Interferon-g is an important regulatory molecule associated with type-1 immune responses. Among the several regulatory activities are the induction of IgG2 production in B-cells, and the activation of mononuclear phagocytes (MP). IgG2 is important as an opsonic isotype enhancing MP phagocytosis and nitric oxide, which is generated from activated MP, is babesiacidal. We have demonstrated that the apparent lack of specific IgG2 in convalescent serum from adult cattle coincides with the lack of opsonic activity in this serum. We also demonstrate the babesiacidal nature of nitric oxide generated from IFN-g plus TNF-a- stimulated MP, and the downregulation of both IFN-g and iNOS by IL-10. Finally, we provide evidence that a type-1 response may not always result from an initial B. bovis infection, that the failure may be related to high and persistent levels of IL-10 mRNA, and that this condition may be associated with severe disease. Together, the data suggest that IL-10 and IFN-g are critical molecules involved in the response to this protozoan infection, and that studies to futher define their roles be accomplished.