A SYNGENEIC IDIOTYPE IS IMMUNOGENIC WHEN BORNE BY IGM BUT TOLEROGENICWHEN JOINED TO IGG

Some syngeneic monoclonal antibodies (mAb) elicit immune responses lik e conventional T-dependent antigens. To find out whether the heavy cha in class (isotype) plays a role for the immunogenicity of an idiotype (Id), we isolated rare subclones of an IgM mAb (termed Id3) in which t he variable region of the heavy chain (VH) is associated with a new co nstant region (CH) The V-H-Id3 gene is a member of the murine 36-60 fa mily and probably has three replacement mutations. The light chain V g ene is germ-line V lambda 2. IgM, IgG1, IgG2a and IgG2b variants of Id 3 were purified from protein-free medium and injected without adjuvant into BALB/c mice. The parental 19S IgM mAb given subcutaneously (s.c. ) elicited a vigorous humoral response against Id3; in comparison, mon omeric 8S IgM was a much weaker immunogen. Unlike IgM, multiple challe nges with the IgG switch variants failed to induce anti-Id3 Ab. IgG va riants gained immunogenicity if they were purified from medium contain ing fetal calf serum, mixed with complete Freund's adjuvant or injecte d into mice primed with IgM-Id3. Pretreatment with 100 mu g s.c. + 50 mu g of the IgG2a variant extinguished the Ab response to parental IgM , but the response to adjuvant-free bovine serum albumin was intact. T herefore, the tolerance induced by the IgG2a switch variant is antigen -specific and not due to toxicity. Significant inhibition of the Ab re sponse to parental IgM was observed after treatment with 4 mu g of the IgG2a switch variant. Administration of the IgG1 and IgG2b switch var iants also inhibited this response significantly. Thus, the outcome of an encounter with Id3 is strongly influenced by the CH isotype to whi ch the Id is joined. This suggests novel ways to minimize unwanted Ab responses against Id of human therapeutic mAb. In the context of the t heory of Id networks, we suggest that dominant B cell clones can preem pt anti-Id Ab responses against themselves by early switching from IgM to IgG secretion, before immunogenic IgM Ab have had time to activate anti-Id B cells.