On the mechanism of immunological tolerance in cyclophosphamide-treated mice.

The mechanism of immunological tolerance of sheep red blood cells (SRBC) in mice treated with a single dose of cyclophosphamide was studied. Specific tolerance lasted for as long as nine months in some animals, and its maintenance required the repeated administration of SRBC. Anti-SRBC antibody-forming cells were significantly reduced in the tolerant mice, and X-irradiated recipients of their spleens were specifically tolerant of SRBC. The smallest number of SRBC required for the induction of tolerance was 10; this was the smallest number of SRBC that could elicit antibody synthesis within 5 days in normal mice. Since the effects of cyclophosphamide on antibody-forming cells last only 5 days, it was concluded that the mechanism of tolerance induction involved destruction of antigen-stimulated cells. In support of this is the finding that mice treated with small doses of cyclophosphamide were rendered tolerant only when SRBC were given before the drug. Drug-induced immunological tolerance thus appears to differ significantly from both pneumococcal polysaccharide paralysis and classical, acquired tolerance. A central loss of immunocompetence does not occur in the former, while the latter requires for its induction the administration of antigen in a dose or form that does not stimulate antibody synthesis.