Felix M. Prof. Dr. Dietrich

Enhancement of host resistance against virus infections by MTP-PE, a synthetic lipophilic muramyl peptide--I. Increased survival in mice and guinea pigs after single drug administration prior to infection, and the effect of MTP-PE on interferon levels in sera and lungs.

Muramyl tripeptide-phosphatidylethanolamine (MTP-PE, CGP 19835) displays prophylactic antiviral activity in mice infected with influenza viruses A and B, parainfluenza 1 virus or herpes simplex type 1 viruses (HSV/1) and in guinea pigs infected with herpes simplex type 2 viruses (HSV/2). MTP-PE is effective when given in a single intranasal dose as early as 1-4 weeks before infection. In the case of HSV/2 infections, prophylactic effectiveness can be demonstrated after a single topical application into the vagina seven days before infection. Antiviral effects are observed in response to doses as little as 0.001 mg/kg bodyweight. The activity of the substance seems to be inversely related to the size of the viral inoculum, but poor dose-effect relation is demonstrable in a dose-range extending over four to five orders of magnitude. Furthermore, the compound is devoid of antiviral effects in vitro. MTP-PE does not induce interferon (IFN) in serum and lung, nor does it influence kinetics or quantity of serum and lung IFN content in the course of viral infections. However, when given intranasally 7 days before an oral dose of tilorone, increased levels of IFN in lung suspensions are observed.

New developments in drugs enhancing the immune response: activation of lymphocytes and accessory cells by muramyl-dipeptides

Recently, stimulation of host defence mechanisms has become a major goal of pharmacotherapeutic research. Immunopotentiating compounds exert their effects in different ways. On the one hand, they may enhance non-specific effector mechanisms operative in the resistance of infectious agents and to neoplastic cells. On the other hand, they may non-specifically increase specific immune responses elicited by the recognition of antigenic determinants. Of course, the two mechanisms operative in the resistance to infectious agents and to neoplastic cells. On may be mediated by the pharmacological activation of common target cells, that is macrophages and other accessory cells, such as polymorphonuclear leucocytes.

Tuberculin Shock in Mice: Relationship Between Systemic Reactions to Tuberculin and Endotoxin and Lack of Correlation Between Tuberculin Shock and Cellular Immunity to Tuberculin:

Summary Systemic reactivity to tuberculin was regularly induced after two injections of living BCG. In contrast, only a small proportion of mice was fatally shocked with PPD after a single iv or ip inoculation of mycobacteria. Single treatments with high doses of bacteria given either ip or into the foot pads together with Freunds adjuvant caused anaphylaxis rather than delayed tuberculin shock upon challenge with PPD. With regard to the conditions of induction and the time of occurrence there was a strict correlation between systemic hypersensitivity to PPD and sensitivity to endotoxin. In the period of increased sensitivity to endotoxin, PPD shock and endotoxin shock had an identical symptomatology. On the other hand, there was a complete lack of correlation between systemic tuberculin reactivity and manifestations of cell-mediated immunity such as skin reactivity, in vitro transformation of lymphocytes and inhibition of the migration of peritoneal exudate cells. These facts, as well as the demonstration of a small but decisive endotoxin activity in the PPD preparations used in this study, corroborate the view that systemic tuberculin reactivity is fundamentally a nonimmunological phenomenon.

Hemodynamic Changes in Systemic Tuberculin Reaction, Active Anaphylaxis and Shock Caused by Histamine-Serotonin or Endotoxin

Summary Systemic hypersensitivity to tuberculin in mice is compared with anaphylaxis and shock reactions following the injection of histamine-serotonin or endotoxin. Time of occurrence, symptomatology and cardiovascular parameters demonstrate a striking similarity between tuberculin shock and reactivity to bacterial endotoxin in tuberculous mice and clearly differentiate these reactions from anaphylaxis and from shock caused by histamine-serotonin or by endotoxin administered to nontuberculous mice. The findings are compatible with the view that nonimmunological mechanisms may underlie the pathogenesis of systemic tuberculin reactivity. A greatly increased susceptibility to bacterial lipopoly-saccharides in mycobacterial infections and the fact that endotoxins are common contaminants of tuberculin preparations may play a decisive role. The skilled technical assistance of Mrs. H. Scherrer, Miss M. Gut, Mr. N. Kaufmann and Mr. L. Criscione is gratefully acknowledged.