Inhibitor antibody development and T cell response to human factor VIII in murine hemophilia A.

In order to understand better the mechanism of inhibitor formation in hemophilia A patients, we have characterized the immune response to human factor VIII in a murine model of hemophilia A. Mice with severe factor VIII deficiency caused by targeted gene disruptions in exons 16 and 17 were injected intravenously with human factor VIII. Anti-factor VIII was absent or was detected at only very low levels in hemophilic mice of both strains after a single injection of 0.2 microg factor VIII, but it was present in most mice after a second exposure. Subsequent exposures led to high titer anti-factor VIII antibodies in both ELISA and inhibitor assays. A human factor VIII-specific T cell proliferative response was detected with spleen cells obtained three days after a single injection with human factor VIII, before mice had detectable anti-factor VIII antibodies. Subsequent exposures to factor VIII were followed by an increased T cell proliferative response. These studies indicate that murine hemophilia A is a good model for the study of the immune response to human factor VIII, especially the role of the T cell in the early steps in inhibitor antibody formation.

[Effect of thymagen, thymalin and vilosen on the cAMP and cGMP levels and phosphodiesterase activity in spleen lymphocytes during sensitization and anaphylactic shock]. / Vliianie timagena, timalina i vilozena na soderzhanie cAMP, cGMP i aktivnost' fosfodiésteraz v limfotsitakh selezenki pri sensibilizatsii i anafilakticheskom shoke.

It is established that the effect of thymus-derived species is connected with the cyclic nucleotide system. The action of thymus-derived immunocorrectors (thymalin, thymagen, vilosen) on catabolic processes of cyclic nucleotides has been observed under conditions of anaphylaxy and sensibilization. They show that sensibilization of the animal is bound up with a decrease of the cAMP/cGMP ratio. Anaphylaxis induces levelling of the cAMP/cGMP ratio up to the reference level. So, activity of enzymes of cyclic nucleotide catabolism grows due to the influence of thymogen, thymalin and vilosen in lymphocytes of sensibilized guinea pigs and tends to an increase in lymphocytes of anaphylaxis-treated animals.

[Effect of thymic immunomodulators on the system of cyclic nucleotides of splenic T-lymphocytes after BCG vaccination]. / Vliianie timicheskikh immunomoduliatorov na sistemu tsiklicheskikh nukleotidov T-limfotsitov selezenki pri vaktsinatsii BTsZh.

The experiments on guinea pigs was performed to study the effects of thymogen , thymalin and vilosene on the activity of cAMP, cGMP, adenylate cyclase, guanylate cyclase, cAMP- and cGMP-phosphodiesterases in T lymphocytes during BCG vaccination. It was shown that the disease was accompanied by increased activity of enzymes of anabolism and catabolism of cyclic nucleotides. Thymogen and thymalin mainly activated the synthesis of cGMP, thus causing the shift of cAMP/cGMP value below the reference level. At the same time vilosene increased this value in the process of a repeated BCG injection.

[Decrease in adenylate cyclase activity in spleen T- and B-lymphocytes and thymus T-lymphocytes in CBA mice treated with levamisole]. / Snizhenie adenilattsiklaznoi aktivnosti T- i B-limfotsitov selezenki i T-limfotsitov vilochkovoi zhelezy myshei linii CBA pod vliianiem levamizola.

The influence of various concentrations of levamisole on the activity of the membrane adenylate cyclase complex of lymphocytes is analyzed. It is ascertained that levamisole decreases the activity of adenylate cyclase at a concentration of 10(-9)-10(-7) M in thymic lymphocytes, and that the activity of the enzyme in spleen T- and B-lymphocytes remains constant. The influence of levamisole on the activity of adenylate cyclase thymocytes is studied under conditions of its stimulation by NaF, GTF and adrenaline. It is ascertained that levamisole at a concentration of 10(-9)-10(-7) M decreases the activity of the enzyme stimulated by NaF, GTF and adrenaline.