HUMAN MONOCLONAL ANTIBODIES TO HLA-DR DETERMINANTS

THE HUMAN IMMUNE RESPONSE IS GOVERNED BY ORDERED INTERACTIONS BETWEEN FUNCTIONALLY AND PHENOTYPICALLY DISTINCT LYMPOID CELLS (T CELLS AND THEIR SUBSETS, B CELLS) AND MONOCYTES IN THE CONTEXT OF IA-LIKE MOLECULES ENCODED BY THE HLA COMPLEX OF GENES. THUS,THE PRODUCTS OF THESE HLA CLASS II GENES (DP,DQ AND DR) CONTROL THE PROLIFERATIVE RESPONSE OF T CELLS IN MIXED LYMPHOCYTE REACTIONS, ANTIGEN PRESENTATION TO T CELLS BY MACROPHAGES, AND COLLABORATION BETWEEN T AND B CELLS. IN ADDITION TO INFLUENCING ALLOGRAFTSURVIVAL, ALLELES OF SPECIFIC CLASS II GENES (DQ AND DR) HAVE BEEN ASSOCIATED WITH SUSCEPTIBILITY TO A NUMBER OF DISEASES INCLUDING SYSTEMIC LUPUS ERYTHEMATOSUS (SLE), RHEUMATOID ARTHRITIS (RA), AND MULTIPLE SCLEROSIS. PHASE I OF THIS PROPOSAL SUCCESSFULLLY DEMONSTRATED THAT A HUMAN MONOCLONAL IGM ANTIBODY TO HLA-DQWL COULD BE PRODUCED. IN PHASE II, A PANEL OF HUMAN MONOCLONAL ANTI-DQ AND ANTI-DR ALLOANTIBODIES WILL BE PRODUCED. IN ADDITION THE GENES FOR THESE ANTIBODIES WILL BE MANIPULATED BY A VARIETY OF DNA CLONING TECHNIQUES TO INCREASE AFFINITY AND TO SWITCH ISOTYPES. THE GENERATION OF THESE ANTIBODIES SHOULD HAVE AN IMMEDIATED PRACTICAL IMPACT IN FACILITATING CLINICAL HLA TYPING PERFORMED TO DETERMINE TRANSPLANTATION COMPATIBILITY.FURTHER, THEIR AVAILABILITY WILL ALLOW A GREATER UNDERSTANDING OF THE SPECIFICITY AND FUNCTIONAL EFFECTS ON IMMUNE FUNCTIONS OF NORMAL AND DISEASED INDIVIDUALS. ULTIMATELY, THESE ANTIBODIES MAY BE USEFUL IN THE DIAGNOSIS AND TREATMENT OF AUTOIMMUNE DISORDERS.