ADVANCES IN IMMUNOLOGY
CONTENTS MUCOSAL DELIVERY ROUTES FOR OPTIMAL IMMUNIZATION: TARGETING IMMUNITY TO THE RIGHT TISSUES MUCOSAL IMMUNE RESPONSES INDUCED BY TRANSCUTANEOUS VACCINES M CELL-TARGETED MUCOSAL VACCINE STRATEGIES VIRUS-LIKE PARTICLES FOR ANTIGEN DELIVERY AT MUCOSAL SURFACES RECENT ADVANCES IN MICROPARTICLE AND NANOPARTICLE DELIVERY VEHICLES FOR MUCOSAL VACCINATION PLANT-DERIVED ANTIGENS AS MUCOSAL VACCINES DRY POWDER VACCINES FOR MUCOSAL ADMINISTRATION: CRITICAL FACTORS IN MANUFACTURE AND DELIVERY MUCOSAL IMMUNITY AND HIV-1 INFECTION: APPLICATIONS FOR MUCOSAL AIDS VACCINE DEVELOPMENT MUCOSAL VACCINES FOR BIODEFENSE MUCOSAL DELIVERY ROUTES FOR OPTIMAL IMMUNIZATION: TARGETING IMMUNITY TO THE RIGHT TISSUES ABSTRACT THE MUCOSAL IMMUNE SYSTEM EXHIBITS A HIGH DEGREE OF ANATOMIC COMPARTMENTALIZATION RELATED TO THE MIGRATORY PATTERNS OF LYMPHOCYTES ACTIVATED AT DIFFERENT MUCOSAL SITES THE SELECTIVE LOCALIZATION OF MUCOSAL LYMPHOCYTES TO SPECI?C TISSUES IS GOVERNED BY CELLULAR ‘‘HOMING’’ AND CHEMOKINE RECEPTORS IN CONJUNCTION WITH TISSUE-SPECI?C ADDRESSINS AND EPITHELIAL CELL-DERIVED CHEMOKINES THAT ARE DIFFERENTIALLY EXPRESSED IN ‘‘EFFECTOR’’ TISSUES THE COMPARTMENTALIZATION OF MUCOSAL IMMUNE RESPONSES IMPOSES CONSTRAINTS ON THE SELECTION OF VACCINE ADMINISTRATION ROUTE TRADITIONAL ROUTES OF MUCOSAL IMMUNIZATION INCLUDE ORAL AND NASAL ROUTES OTHER ROUTES FOR INDUCING MUCOSAL IMMUNITY INCLUDE THE RECTAL, VAGINAL, SUBLINGUAL, AND TRANSCUTANEOUS ROUTES SUBLINGUAL ADMINISTRATION IS A NEW APPROACH THAT RESULTS IN INDUCTION OF MUCOSAL AND SYSTEMIC T CELL AND ANTIBODY RESPONSES WITH AN EXCEPTIONALLY BROAD DISSEMINATION TO DIFFERENT MUCOSAE, INCLUDING THE GASTROINTESTINAL AND RESPIRATORY TRACTS, AND THE GENITAL MUCOSA HERE, WE DISCUSS HOW SUBLINGUAL AND DIFFERENT ROUTES OF IMMUNIZATION CAN BE USED TO GENERATE IMMUNE RESPONSES IN THE DESIRED MUCOSAL TISSUE(S) INTRODUCTION MUCOSAL VACCINES: AN UNMET NEED CONSIDERATIONS IN SELECTING A MUCOSAL OR PARENTERALVACCINE DELIVERY ROUTE COMPARTMENTALIZATION AND CELL MIGRATION IN THE MUCOSAL IMMUNE SYSTEM INDUCTION OF MUCOSAL IMMUNE RESPONSES TISSUE-SPECIFIC HOMING OF MUCOSAL LYMPHOCYTES MUCOSAL EFFECTOR SITES ASSOCIATED WITHVACCINATION ROUTES INTESTINAL, NASAL, AND VAGINAL VACCINATION SUBLINGUAL VACCINATION TRANSCUTANEOUS VACCINATION PARENTERAL VACCINATION ‘‘TROPICAL BARRIERS’’ TO MUCOSAL VACCINES SURROGATES OF MUCOSAL VACCINE-INDUCED IMMUNITY PERSPECTIVES REFERENCES 1 INTRODUCTION THE GASTROINTESTINAL, RESPIRATORY AND UROGENITAL TRACTS, EYE CONJUNCTIVA, INNER EAR, AND DUCTS OF ALL THE EXOCRINE GLANDS ARE COVERED BY MUCOUS MEMBRANES ENDOWED WITH POWERFUL MECHANICAL AND CHEMICAL CLEANSING MECHANISMS THAT REPEL AND DEGRADE MOST FOREIGN MATTER (BRANDTZAEG AND PABST 2004; OGRA 1999) IN ADDITION, A HIGHLY SPECIALIZED INNATE AND ADAPTIVE MUCOSAL IMMUNE SYSTEM PROTECTS THESE SURFACES, AND THEREBY THE BODY INTERIOR, AGAINST INSULTS FROM THE ENVIRONMENT IN A HEALTHY HUMAN ADULT, THIS LOCAL IMMUNE SYSTEM IS ESTIMATED TO COMPRISE NEARLY 80% OF ALL LYMPHOCYTES, COMMENSURATE WITH THE CA 400 SQUARE METERS OF MUCOSAL SURFACES THAT IT HAS TO DEFEND THESE IMMUNE CELLS ARE ACCUMULATED IN, OR IN TRANSIT BETWEEN, VARIOUS MUCOSA-ASSOCIATED LYMPHOID TISSUES (MALTS), WHICH TOGETHER FORM THE LARGEST MAMMALIAN LYMPHOID ORGAN SYSTEM THE MALT REPRESENTS A HIGHLY COMPARTMENTALIZED IMMUNOLOGICAL SYSTEM THAT FUNCTIONS INDEPENDENTLY OF THE SYSTEMIC IMMUNE APPARATUS AT VARIANCE WITH THE SYSTEMIC IMMUNE SYSTEM, WHICH NORMALLY FUNCTIONS IN A STERILE MILIEU AND CAN THUS AFFORD TO RESPOND VIG- OROUSLY TO INVADERS, THE MALT GUARDS ORGANS THAT ARE REPLETE WITH FOREIGN MATTER ONLY A LIMITED PROPORTION OF THESE FOREIGN ANTIGENS ARE DERIVED FROM PATHOGENS; MOST ARE COMMENSALS, FOOD PROTEINS, AND OTHER INGESTED OR INHALED FOREIGN MATE- RIALS THIS MEANS THAT UPON ENCOUNTER WITH THIS BROAD RANGE OF ANTIGENIC STIMULI, THE MALT MUST SELECT APPROPRIATE EFFECTOR MECHANISMS AND REGULATE THEIR INTEN- SITY TO AVOID BYSTANDER TISSUE DAMAGE AND IMMUNOLOGICAL EXHAUSTION THERE IS A GREAT NEED TO DEVELOP VACCINES AGAINST MANY BACTERIAL AND VIRAL PATHOGENS THE MAJORITY OF MICROBIAL PATHOGENS HAVE A MUCOSAL PORT OF ENTRY ALTHOUGH PARENTERAL VACCINATION CAN PROVIDE PROTECTION IN SOME INSTANCES, A MUCOSAL VACCINATION ROUTE IS NECESSARY IN MOST CASES IN ADDITION, AS COMPARED TO INJECTABLE VACCINES, MUCOSAL VACCINES WOULD BE EASIER TO ADMINISTER, CARRY LESS RISK OF TRANSMITTING INFECTIONS, AND COULD SIMPLIFY MANUFACTURING, THEREBY INCREASING THE POTENTIAL FOR LOCAL VACCINE PRODUCTION IN DEVELOPING COUNTRIES (HOLMGREN AND CZERKINSKY 2005) ADVANCES IN IMMUNOLOGY