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HLA (A*0201) Mimicry by Anti-Idiotypic Monoclonal Antibodies¹

William J. Burlingham^2,*, Ewa Jankowska-Gan^*, Lynn DeVito-Haynes^*, John H. Fechner, Jr.^*, Kevin T. Hogan, Frans H. J. Claas, Arend Mulder^,§, Xinhui Wang^¶ and Soldano Ferrone^¶

^* Department of Surgery, University of Wisconsin, Madison, WI 53792; Argonex Pharmaceuticals, Charlottesville, VA 22903; Department of Immunohaematology and Bloodbank, Leiden University Hospital, Leiden, The Netherlands; ^§ SVM-Foundation for the Advancement of Public Health and Environmental Protection, Bilthoven, The Netherlands; and ^¶ Department of Microbiology and Immunology, New York Medical College, Valhalla, NY 10595

Soluble MHC Ags and anti-Id (anti-anti-MHC) Abs have both been shown to inhibit MHC alloantigen-specific B cell responses in vivo. We hypothesized that some anti-idiotypic Abs function as divalent molecular mimics of soluble HLA alloantigen. To test this idea, we studied two well-defined anti-idiotypic mAbs, T10-505 and T10-938, elicited in syngeneic BALB/c mice by immunization with CRll-351, an HLA-A2,24,28-specific mAb. Each anti-Id induced "Ab-3" Abs in rabbits that cross-reacted with HLA-A2 but not with HLA-B Ags. Furthermore, each anti-Id could bind to and block Ag recognition by Ha5C2.A2, a human homologue of mAb CRll-351. Both anti-Id mAb displayed weak reactivity with the human mAb SN66E3, which recognized an overlapping but distinct determinant of HLA-A2 Ags; neither reacted with human mAb MBW1, which recognized a nonoverlapping HLA-A2 determinant. Amino acid sequence comparison of mAb CRll-351 heavy and light chain variable region complementarity-determining regions (CDRs) with those of mAb Ha5C2.A2 and SN66E3 revealed short regions of homology with both human mAb; a large insert in the light chain CDR1 of mAb SN66E3 distinguished it from both CRll-351 and Ha5C2.A2. The amino acid sequences of mAb T10-505 and T10-938, which differed markedly from each other, revealed no homology to the 2 domain sequence of HLA-A*0201 that contains the CRll-351 mAb-defined epitope. We conclude that structurally different anti-Id Abs can mimic a polymorphic conformational epitope of an HLA Ag. In the case of T10-505 and T10-938 mimicry was not based on exact replication of the epitope by the hypervariable loops of the anti-Id mAb.