HUMAN INTERLEUKIN-1

INTERLEUKIN-1 (IL-1) HAS BEEN DETECTED IN THE SERUM OF PATIENTS WITH FEVER AND IN THE JOINT EFFUSIONS OF PATIENTS WITH RHEUMATOID ARTHRITIS, SUGGESTING THAT IL-1 MAY FUNCTIONIN VIVO AS A MEDIATOR OF ACUTE AND CHRONIC INFLAMMATION. THESE DELETERIOUS EFFECTS OF IL-1 COULD BE COUNTERACTED BY SPECIFIC HUMAN MONOCLONAL ANTIBODIES TO IL-1. THIS PROJECT PROPOSES TO DEVELOP NEUTRALIZING HUMAN MONOCLONAL ANTIBODIESTO HUMAN IL-1 THAT MAY BE USEFUL IN THE DIAGNOSIS AND TREATMENT OF AUTOIMMUNE DISORDERS SUCH AS LUPUS, RHEUMATOID ARTHRITIS, AND OTHER INFLAMMATORY DISEASES MEDIATED IN PART BY THIS MONOKINE. IN PHASE I, HUMAN MONOCLONAL ANTIBODIES TO IL-1 WILL BE GENERATED BY FUSIONS OF SENSITIZED HUMAN B- CELLS SECRETING IL-1 ANTIBODIES FROM A GROUP OF LUPUS PATIENTS SHOWN TO POSSESS SUCH AUTOANTIBODIES TO IL-1. THE FEASIBILITY OF THIS PROJECT IS BASED ON (1) THE AVAILABILITYTO THE ASSEMBLED TEAM OF LARGE QUANTITIES OF RECOMBINANT ANDMONOCYTE-DERIVED IL-1; (2) AN EXISTING SENSITIVE ELISA WHICHDETECTS HUMAN IL-1 ANTIBODIES; (3) THE OBSERVATION THAT SOMEPATIENTS WITH SLE HAVE HIGH TITERS OF SUCH ANTIBODIES; AND (4) EXPERIENCE WITH THE GENERATION OF HUMAN HYBRIDOMAS THAT PRODUCE ANTICYTOKINE ANTIBODIES. THE ANTI-INFLAMMATORY AND IMMUNO-SUPPRESSIVE EFFECTS OF NEUTRALIZING HUMAN MONOCLONAL IL-1 ANTIBODIES WILL BE EVALUATED IN A SERIES OF FUNCTIONAL IN VITRO ASSAYS IN PREPARATION FOR CLINICAL TRIALS IN PATIENTS WITH CHRONIC INFLAMMATORY DISEASES.