Relationships between the Effects of Poly I . Poly C and Endotoxin

Abstract

RECENT communications^1–3 have called attention to the toxicity of poly I . poly C and noted the resemblance of some of these effects to known endotoxin effects. The fact that “although poly I . poly C and endotoxin share many similarities, they are not identical in action”¹ is also documented by the ability of endotoxin and poly I . poly C to stimulate specific antibody responses when administered with an antigen^4,5 whereas only endotoxin, but not poly I . poly C, can activate a large variety of nonspecific antibody responses when administered alone^4,6. We previously furnished evidence⁴ indicating that the latter effect may be attributable to the ability of endotoxin to alter lymphocyte permeability, whereas the adjuvant action seems to result from cytotoxicity and the attendant release of endogenous stimulators^5,7. Poly I . poly C, like endotoxin. pyran copolymer⁸, and a number of other polyanions, appears to damage cell membranes, specifically those of rnacrophages, and thereby can release a number of endogenous materials, including pyrogeii, interferon and stimulators of lymphocytes. Double stranded polynucleotides that are rather rapidly changed to oligomers in vivo (for example, poly A . poly U) seem to produce only transient effects on membranes and therefore produce strikingly less toxicity, no or little pyrogenicity, little elevation of interferon levels, but good stimulation of antibody-forming lymphocytes⁵. Thus the biological effects of polynucleotides seem to involve at least two events: those associated with the highly polymerized form and those produced by oligomers. Poly I . poly C appears to produce pronounced effects attributable to the polymer, namely cytotoxicity—possibly selective—and with it endotoxin-like effects. Current studies with macrophages and lymphocytes in vitro (unpublished data of L. Jimenez, D. Webb and W. B.) support this conclusion.