Poly I-Mercapto Poly C: antiviral, anticellular, and pharmacologic effects.

Thiolation of position 5 of some of the cytosine bases in polycytidylic acid results in the formation of mercaptopolycytidylic acid (MPC). Annealing of MPC to polyinosinic acid (Poly I) results in the formation of double-stranded Poly I-MPC. In this study we investigated the interferon inducing ability, in vivo toxic effects, effect on DNA synthesis, and the effects in human tumor cell lines of Poly I-MPC. Poly I-MPC was capable of inducing human alpha, beta and gamma interferons in the appropriate cell systems. In vivo toxicity was measured in mice, guinea pigs, and rabbits according to FDA guidelines. Weight loss and lethal and pyrogenic effects were markedly lower in Poly I-MPC treated animals than in those that received unmodified Poly I-Poly C. In contrast to the lack of an effect of Poly I-Poly C in human lymphocytes, Poly I-MPC inhibited DNA synthesis. It also inhibited colony formation and was cytotoxic in several human tumor cell lines. Poly I-MPC's ability to induce human alpha, beta and gamma interferons, to inhibit DNA synthesis and its effects in human tumor cell lines demonstrate the potential of this drug for future clinical studies, both as an antiviral and antitumor agent.

Identification of the T cell subset that produces human gamma interferon.

Positive and negative selection procedures combined with cytofluorographic analysis and lysis with monoclonal antibodies were utilized to identify the T lymphocyte subset that produces human gamma interferon (gamma-IFN) (formerly referred to as "immune" or "type II" interferon) in response to mitogen stimulation. Lymphocytes were separated on the basis of their Fc receptors for IgG or IgM, their nonreactivity with IgM or IgG antibodies, and their reactivity with the monoclonal antibodies OKT4, OKT8, OKT11a, and OKM1. Isolated T cell subsets were incubated with the gamma-IFN inducer, phytohemagglutinin. Three days after induction, the cell supernatants were harvested and assayed for interferon. The T cell subset that produces gamma-IFN was identified as E rosette positive with the phenotype: T gamma, T non-micro, OKM1+, OKT4-, OKT8- and OKT11a+. gamma-IFN production by cells was resistant to doses of x-irradiation that abrogate mitogen-induced T suppressor function but was highly sensitive to low doses of 4-hydroperoxycyclophosphamide. These data demonstrate that gamma-IFN is produced by the T gamma, OKM1+ lymphocyte subset, but these cells may also require the presence of accessory monocytes for elaboration of gamma-IFN. The anti-proliferative activity of gamma-IFN may be responsible for the previously described suppressor function of this subset, and gamma-IFN production by T gamma cells may distinguish this subset from the suppressor/cytotoxic functions of the OKT8+ subset or the mitogen-induced OKT4+ suppressor.