ENHANCEMENT OF MUCOSAL IMMUNITY

THE RATE OF HETEROSEXUAL TRANSMISSION OF HIV-1 THROUGH SEXUAL CONTACTS IS INCREASING IN MOST COUNTRIES. LIKE MANY OTHER PATHOGENIC MICROORGANISMS, HIV-1 VIRIONS ENTER THE BODY THROUGH MUCOSAL SURFACE OF GENITAL TRACTS. HOWEVER, IT HAS BEEN SUGGESTED IN THE RHESUS MARCAQUE/SIV MODEL THAT THE VACCINES BEING DEVELOPED ARE POORLY PROTECTIVE AGAINST VIRAL CHALLENGES THROUGH THE MUCOSAL ROUTE. THE GOAL OF OUR STUDIES IS TO DEVELOP A METHOD THAT CAN ENHANCE MUCOSAL IMMUNITY TO HIV-1 BY INCREASING THE PRODUCTION OF SECRETORY IGA AT THE MUCOSAL SURFACE. OUR APPROACH IS TO USE MONOCLONAL ANTIBODIES (MABS) SPECIFIC FOR HUMAN MEMBRANE-BOUND IGA (MIGA) ONB CELLS TO ACTIVATE MIGA+ B CELLS AND INCREASE IGA PRODUCTION. WE HAVE DEVELOPED MABS THAT RECOGNIZE THE EXTERIOR PORTION OF THE MEMBRANE ANCHOR PEPTIDE OF MIGA AND SHOWN THAT THEY BIND ONLY TO MIGA+ B CELLS, NOT TO B CELLS EXPRESSING OTHER ISOTYPES, AND NOT TO SECRETED ANTIBODIESOF ALL ISOTYPES. THE SPECIFIC AIMS ARE: (1) TO CONSTRUCT HUMAN MIGA+ CELL LINES FOR EXAMINING ANTI-MIGA-MEDICATED CELL ACTIVATION, (2) TO ESTABLISH AN INVITRO CULTURE SYSTEM FOR EVALUATING IGA PRODUCTION, AND (3) TO INVESTIGATE WHETHER MABS SPECIFIC FOR MIGA, IN THE ABSENCE OR PRESENCE OF CERTAIN LYMPHOKINES, CAN ACTIVATE IGA-BEARING B CELLS AND/OR INDUCE IGA PRODUCTION.