Regulation of the Immune System by Synthetic Polynucleotides

Abstract

Equimolar complexes of the synthetic polyribonucleotides, polyadenylic and polyuridylic acid (poly(A:U)), or polyinosinic and polycytidylic acid (poly(I:C)) were shown to be adjuvants for antibody formation in mice. A decreased induction period and increases in 19S and 7S antibody titers and in immunologic memory were noted. Poly(A:U) increased the antibody response to a variety of antigens including both soluble and particulate proteins, sheep red blood cells, and a polysaccharide, the Vi antigen of Escherichia coli. In addition, antibody formation to bovine γ globulin was enhanced in mice, rabbits and guinea pigs. Antigenicity was increased considerably in that poly(A:U) was capable of rendering 1 ng of bovine γ globulin immunogenic. When injected 0.5 to 1 day before antigen, poly(A:U) was found to be immunosuppressive. However, a second injection of poly(A:U) given with antigen abolished the immunosuppression induced by the first dose of poly(A:U). Study of various physical and chemical factors necessary for the adjuvant action of poly(A:U) revealed that no polynucleotide alone acted as an adjuvant nor were other known interferon-inducing polymers effective. Complexes composed of altered molar proportions were no more effective than an equimolar complex, and neither purine nor pyrimidine mono- and oligonucleotides could replace their respective polynucleotides in the poly(A:U) complex. Decreasing the hydrogen bonding in the complex through use of chemically modified poly A and poly U caused a reduction in the adjuvant action. In addition, neither repeated freeze-thawing nor prolonged incubation at room temperature minimized the adjuvant action of poly (A:U). Heat denaturation rendered the complex ineffective, as did treatment with ribonuclease or incubation in normal mouse serum.