Requirements for induction of activation and proliferation of human B cells analysed with anti-idiotype monoclonal antibodies

We have produced five monoclonal antibodies (MoAb) directed against idiotypic determinants of surface immunoglobulins (sIg) expressed on malignant B cells from a patient suffering from prolymphatic leukaemia (B-PLL). The anti-idiotype MoAb were characterized by immunofluorescence-binding studies, allotype reactivity, and immunoprecipitation studies and were found to recognize at least two distinct epitopes on the sIg of the neoplastic B cells. Differential effects of the soluble anti-idiotype MoAb on phorbol myristate acetate (PMA)-induced B-PLL-cell proliferation were found; three types of anti-idiotype MoAb could be distinguished: (1) MoAb that enhanced the PMA-induced B-PLL-cell proliferation, (2) MoAb without effect, and (3) MoAb that inhibited the PMA-induced B-PLL-cell proliferation. Addition of the calcium ionophore A23187 could abolish the differential effects of the anti-idiotype MoAb on PMA-induced B-PLL-cell proliferation. The negative effect of the type 3 MoAb on PMA-induced B-PLL-cell proliferation was associated with a more than 10-fold stronger binding to sIg expressed on the B-PLL cells, compared with the other anti-idiotype MoAb. The differential effects of the types 1 and 2 MoAb cannot be explained solely by differences in the Fc portion of the MoAb and binding characteristics. Neither did differences in epitope specificity necessarily lead to differential effects on PMA-induced B-PLL-cell proliferation. In contrast to the clear differences found in the proliferation induction experiments, all MoAb were equally able to induce an early rise in free intracellular Ca2+ concentration. Our data suggest that for B-cell proliferation to occur, apart from early rises of intracellular Ca2+, more prolonged [Ca2+]i elevations or additional intracellular activation signals are required. The differences in proliferative responses of B-PLL cells to anti-idiotype MoAb may be relevant for immunotherapy of B-cell tumours with anti-idiotype MoAb