IDENTIFICATION OF PATHOGENIC AUTOANTIBODIES

SLE IS AN AUTOIMMUNE DISEASE OF UNKNOWN ETIOLOGY WHICH AFFLICTS, PRIMARILY, WOMEN OF CHILD-BEARING AGE. PRODUCTION OF AUTOANTIBODIES, PARTICULARLY THOSE SPECIFIC FOR DNA AND OTHER POLYNUCLEOTIDES ARE CENTRAL TO THE PATHOGENESIS OF THE DISEASE. THE OVERALL OBJECTIVE IS TO REGULATE AUTOANTIBODY RESPONSES USING ANTI-IDIOTYPIC (ANTI-ID) ANTIBODIES. DURING THE COURSE OF GENERATING MURINE MONOCLONAL ANTI-IDS FOR THE TREATMENT OF B CELL LYMPHOMA, WE OBSERVED THAT MANY OF THESE REAGENTS RECOGNIZE DETERMINANTS ON WELL-CHARACTERIZED HUMAN AUTOANTIBODIES. WE WILL EXPLORE THE POSSIBILITY OF USING THESE ANTI-IDS TO MODULATE AUTOANTIBODY PRODUCTION IN SLE AND RELATED AUTOIMMUNE DISORDERS. IN PHASE I OF THIS STUDY, WE WILL USE SELECTED ANTI-IDS TO AFFINITY-PURITY PUTATIVE AUTOANTIBODIES FROM THE SERA OF PATIENTS WITH SLE. THE PURIFIED ANTIBODIES WILL BE CHARACTERIZED FOR ANTIGENIC SPECIFICITY (DNA, POLYNUCLEOTIDES, ETC.), ISOTYPE AND CHARGE IN ORDER TO CONFIRM THAT THE ANTI-IDS RECOGNIZE PATHOGENIC AUTOANTIBOD- IES. RENAL BIOPSY SPECIMENS WILL ALSO BE EXAMINED FOR THE PRESENCE OF DEPOSITED IDIOTYPE-SPECIFIC IMMUNOGLOBULINS. WE WILL COMPARE THE REACTIVITY OF CANDIDATE ANTI-IDS WITH OTHER WELL-DEFINED ANTI-IDIOTYPIC REAGENTS USING A PANEL OF INTERNATIONAL REFERENCE SERA WITH ANTI-DNA REACTIVITY. FINALLY, WE WILL EXAMINE SERA FROM AUTOIMMUNE-PRONE STRAINS OF MICE FOR CROSS-REACTIVE INTERSPECIES IDIOTYPES IN ORDER TO EXPLORE THE FEASIBILITY OF ESTABLISHING AN ANIMAL MODEL.