IMMUNOMODULATORY ACTIVITIES OF EXTRACELLULAR METALLOTHIONEIN .1. METALLOTHIONEIN EFFECTS ON ANTIBODY-PRODUCTION

Extracellular metallothionein (Zn,Cd-MT) has previously been shown to be a potent inducer of lymphocyte proliferation and to synergize with polyclonal activators in proliferation assays. In this report, the eff ects of metallothionein on the development of humoral responsiveness a re examined. In vivo, the specific anti-ovalbumin (OVA) IgG response w as diminished by co-injection of Zn, Cd-MT, while total:IgG levels rem ained unchanged. A similar reduction was also observed when Zn,Cd-MT; was administered during the development of an anti-sheep red:blood cel l (sRBC)humoral response. When amounts of Zn and Cd equimolar to that associated with the Zn, Cd-MT were co-injected with OVA, humoral respo nsiveness was enhanced, in contrast to the suppression seed with Zn, C d-MT. Apothionein lacking the available thiols associated with native Zn, Cd-MT had no effect on the development of humoral immunity. These results point to the thiols associated with the protein as the importa nt determinants in the observed immunosuppression and this is supporte d by the capacity of UC1MT, a new monoclonal anti-MT antibody; to reve rse MT mediated immunosuppression. No evidence was found to suggest th at Zn,Cd-MT was interacting directly with OVA. Finally, in vitro exper iments with, LPS-stimulated splenocyte production of IgM correlated wi th the in vivo observations of Zn,Cd-MT. These data provide evidence f or a significant role for MT in the development of metal-mediated immu nomodulation and suggest that MT may also possess immunomodulatory fun ctions under circumstances where MT is synthesized in the absence of h eavy metal stress. Furthermore, it may be possible to take advantage o f this system to exogenously manipulate the development of the immune response.