Drug‐promoted B cell tolerance induction: a selective activity of cyclophosphamide dependent on the tolerogenicity of thymus‐independent antigens

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Abstract
Native levan and dextran B1355 induce equivalent IgM responses, specific for β(2→6) fructosyl or α(1→3) and α(1→6) glucosyl epitopes, respectively, in congenitally athymic and euthymic BALB/c mice. These can be suppressed to a varying extent by both alkylating agents (cyclophosphamide (CY), melphalan, chlorambucil) and other immunosuppressive drugs (6‐mercaptopurine, azathioprine, A‐methopterin). In contrast, the promotion of B cell tolerance to these thymus‐independent antigens, as measured by a reduction in the minimum tolerogenic dose, was found only during suppression with CY (or related compound Asta 5122) and with none of the other drugs.CY likewise reduced the tolerizing dose thresholds of 2,4‐dinitrophenyl (DNP)‐specific Bμ cells for feebly immunogenic dinitrophenylated pneumococcal polysaccharide type 3 and nonimmunogenic DNP‐D‐GL (D‐Glu, D‐Lys copolymer) by approximately 10‐ and 100‐fold, respectively, in CBA mice. This definitively verifies an implication from earlier variable epitope density studies (Desaymard and Howard, Eur. J. Immunol. 1975. 5: 541) that CY‐promoted tolerance with thymus‐independent antigens depends not on their immunogenicity, but on their inherent tolerogenicity. Evidence is discussed which suggests that this involves an increased susceptibility of B cells to normal tolerization by multivalent antigens.Spleen cells from mice 14 days after CY‐promoted tolerance induction were totally unresponsive to levan and devoid of demonstrable suppressor cell activity in mixed cell transfer experiments. As B cells are usually unaffected and suppressor T cells generated during analogous tolerance with thymus‐dependent antigens (Ramshaw, Bretscher and Parish, Eur. J. Immunol. 1977. 7: 180), we conclude that the mechanisms of tolerance promotion by CY are fundamentally dissimilar for these two classes of antigen.