Plasma histamine but not anaphylatoxin levels correlate with generalized urticaria from infusions of anti-lymphocyte monoclonal antibodies

Anti-lymphocyte monoclonal antibodies have shown promise in trials for therapy of lymphocyte malignancies but are associated with a high frequency of immediatetype anaphylactoid reactions. We have previously demonstrated that these immediate-type anaphylactoid reactions are not mediated by immunoglobulin E to anti-lymphocyte monoclonal antibodies. To gain insight into the mechanisms of these immediate-type anaphylactoid reactions, we measured plasma levels of histamine and anaphylatoxins (C3a, C4a, C5a) during 11 infusions in eight patients who received anti-lymphocyte monoclonal antibodies (T101 and Lym-1). Three patients experienced generalized urticaria (two with severe angioedema); a fourth patient had three isolated hives but without generalized manifestations of an immediate-type anaphylactoid reaction. Plasma histamine levels after infusions that were associated with generalized urticaria were significantly higher than those during infusions that were not associated with generalized urticaria (mean, 3.47 vs 0.18 ng/ml, p < 0.001). Increases in C3a and C4a levels were observed after some infusions, but these did not correlate with generalized urticaria. Measurable rises in plasma C5a levels after infusions were not detected. Although these data should be viewed as preliminary considering the limited number of patients studied, the observed histamine release demonstrates that mast cell or basophil activation that is not mediated by immunoglobulin E to anti-lymphocyte monoclonal antibodies occurs in the pathogenesis of immediate-type anaphylactoid reactions from anti-lymphocyte monoclonal antibodies. Although activation of the classical complement pathway may occur in some anti-lymphocyte monoclonal antibody infusions, this does not appear to explain immediate-type anaphylactoid reactions. Mechanisms that involve interactions between lymphocytes and mast cells or basophils, possibly including the production of histamine-releasing factors from lymphocytes, may be involved in the pathogenesis of immediate-type anaphylactoid reactions from anti-lymphocyte monoclonal antibodies.