Manganese chelation therapy extends survival in a mouse model of M1000 prion disease.

Previous in vitro and in vivo investigations have suggested manganese (Mn(2+)) may play a role in pathogenesis through facilitating refolding of the normal cellular form of the prion protein into protease resistant, pathogenic isoforms (PrP(Sc)), as well as the subsequent promotion of higher order aggregation of these abnormal conformers. To further explore the role of Mn(2+) in pathogenesis, we undertook a number of studies, including an assessment of the disease modifying effects of chelation therapy in a well-characterized mouse model of prion disease. The di-sodium, calcium derivative of the chelator, cyclohexanediaminetetraacetic acid (Na(2)CaCDTA), was administered intraperitoneally to mice inoculated intra-cerebrally with either high or low-dose inocula, with treatment beginning early (shortly after inoculation) or late (at the usual mid-survival point of untreated mice). Analyses by inductively coupled plasma-mass spectrometry demonstrated brain Mn(2+) levels were selectively reduced by up to 50% in treated mice compared with untreated controls, with copper, iron, zinc and cobalt levels unchanged. In mice administered high-dose inocula, none of the treatment groups displayed an increase in survival although western blot analyses of early intensively treated mice showed reduced brain PrP(Sc) levels; mice infected using low-dose inocula however, showed a significant prolongation of survival (p = 0.002). Although our findings support a role for Mn(2+) in prion disease, further studies are required to more precisely delineate the extent of pathogenic involvement.

Plant-derived medicines: a novel class of immunological adjuvants.

Plant-derived medicines have a long history of use for the prevention and treatment of human disease. Today, many pharmaceuticals currently approved by the Food and Drug Administration (FDA) have origins to plant sources. A major role for plant-derived compounds based on the reported immunomodulatory effects has emerged in recent times and has led to the rigorous scientific examination to determine efficacy and safety. The discovery of novel plant compounds with immune system modulating activities has become an increasingly important area of research, particularly in the search for new-generation vaccine adjuvants. This review discusses the important role of plant-derived medicines as immunomodulators and provides evidence in support of the continued investigation of this new class of drugs for the maintenance of human health. The identification and characterization of plant compounds that augment new or existing vaccines, and in particular mucosally administered vaccines, will be of significant interest to vaccinologists and immunologists.

Identification of a novel vaccine adjuvant that stimulates and maintains diphtheria toxoid immunity.

Immunomodulation by plant-derived medicines is well-documented with effects on both innate and adaptive immunity. This study reports potent and long-lasting diphtheria toxoid-specific immunity by the botanical medicinal, Rehmannia Six Formula, using an in vivo mouse model of vaccine immunity. A significant vaccine adjuvant effect was observed with an increase in serum anti-diphtheria toxoid total and IgG antibodies following oral administration of Rehmannia Six Formula to mice. This response was antigen-specific and was still detectable six months following botanical medicinal treatment, suggesting that Rehmannia Six Formula could help maintain protective antibody levels in populations where vaccine coverage is low. Rehmannia Six Formula was well-tolerated with no adverse effects on mouse weight or survival observed in this study and suggests a potential role as a novel vaccine adjuvant preparation.

A novel foregut mucin characterized by a murine monoclonal autoantibody.

Autoantibodies to gastric cellular antigens and glycoproteins including mucins and Lewis X and Y antigens have been implicated in the induction of autoimmune gastritis. Monoclonal antibody D10 (D10 MAb) recognizes a highly conserved mucin expressed in the foregut of mammals and other vertebrates. The objective of this study was to biochemically characterize the autoantigen identified by D10 MAb and examine its autoimmunogenicity in the mouse. Characterization of the mucin autoantigen was undertaken following purification, by amino acid and carbohydrate analyses, deglycosylation, SDS-PAGE, and immunoblotting using D10 MAb. Autoimmune reactivity and specificity of D10 MAb were validated by immunohistochemistry and ELISA using mouse tissue. Induction of autoimmune gastritis was investigated following immunization of mice with D10 MAb-reactive heterologous mucin. D10 MAb was shown to be a murine anti-mucin autoantibody with a unique pattern of immunohistochemical staining of Brunner's glands of the duodenum and the cardiac glands, mucous neck cells, and pyloric glands of the stomach from inbred Balb/c mice in patterns identical to that previously reported in human tissue. Amino acid and carbohydrate analysis of purified D10 mucin reflected a compositional profile of a typical mucin molecule. Confirmation that D10 MAb recognizes a mucin was also provided by demonstration that the carbohydrate epitope resides on a high molecular weight (>1x10(6)Da), high-density (>1.40 g/mL) molecule comprised of greater than 60% carbohydrate. Mice immunized with D10 MAb-reactive, purified, heterologous mucin produced autoantibodies of identical specificity to the original D10 MAb. These data demonstrate the autoimmunogenic properties of a novel foregut mucin and raise the potential of anti-mucin autoantibodies in the induction of autoimmune gastritis.

Stimulation of tetanus toxoid-specific immune responses by a traditional Chinese herbal medicine.

The immunomodulatory properties of botanical medicinals are well-documented. In this study, the capacity for the traditional Chinese herbal medicine, Rehmannia Six Formula (R6F), to stimulate anti-tetanus toxoid (TT) immunity following oral administration to mice was examined. A significant rise in serum anti-TT antibody levels were observed in R6F-treated mice immunized with a minimum immunogenic dose of 10 microg TT suggesting an oral adjuvant effect. No such enhancement was found for unimmunized mice treated with R6F. This anti-TT response was preferentially IgG and antigen-specific in relation to antibody reactivity to a panel of unrelated antigens. The R6F used was safe with no adverse effects on mouse weight or survival, providing evidence for the use of R6F as an oral adjuvant.