1) BIODEFENSE AND NEONATAL IMMUNITY Although there is a concerted national effort to find vaccines for potential bio-terrorism agents, and for newly emerging diseases, little is being done to protect the nation's infants. Most adult vaccines do not work for infants less than 6mo old, and many do not work for babies <1yr. We have been working with newborn mice, analyzing their responses to vaccination. Although newborn mice were thought to be immuno-incompetent, we had found that the early data supporting this idea had been mis-interpreted, and that newborns were fully capable of responding if immunized properly. We have therefore been testing immunization under different conditions. a) OPTIMAL DOSES FOR NEONATAL VACCINES: Our early studies had suggested that the dose of antigen and/or adjuvant is critical for obtaining a response from newborn mice. We therefore undertook a massive study in which we primed large groups of newborn mice with OVA at doses ranging from 0.01 to 100 ug, and then separated each primed group into boosting groups immunized over the same range. We found that very low doses of antigen were able to prime for a good secondary response after boosting. However a single dose of antigen at 100ug, given at three days after birth, resulted in a strong response that lasted at least three months. b) EFFECT OF MATERNAL ANTIBODIES: it is generally thought that the presence of maternal antibody inhibits newborn responses. We found, however, that neonatal mice respond perfectly well to the model antigen Ovalbumin (OVA), even if they have received passive anti-OVA antibody from their hyper-immunized mothers. By mating IgHb mothers to IgHa fathers, we are able to specifically follow the antibody responses of the babies, in the presence of antibody from their mothers. The immunity in babies from immunized mothers lasts for at least 18 months, and does not fade more rapidly than that of babies from control mothers. Thus, in mice, maternal antibodies are not inhibitory. c) VACCINATING FOR A REAL PATHOGEN: We found that maternal antibody can protect a neonate until about 30 days after weaning. We also found that neonates from hyperimmunized mothers, when immunized with Anthrax PA in adjuvant, made good responses and were protected from challenge. Some of the neonates were protected even though they did not produce neutralizing antibodies, suggesting that antibodies that neutralize in in vitro tests are not necessarily important for protection from Anthrax toxin. B cell deficient mice are not protected by similar vaccinations, thus antibodies (or at least B cells) are important for protection. d) NEONATAL RESPONSES TO MEASLES: having found that neonatal mice respond perfectly well to both OVA and Anthrax, we turned to the measles vaccine to ask why neonatal humans do not respond well. Because the Edmonston Vaccine strain of Measles does not use the TLR2 and Slam (the entry molecules for wild type Measles) but CD46, we looked at the expression of CD46 isotypes in cord blood. We found that the CD46 isotypes expressed by cord blood are not the same as those expressed by adults, and that the neonatal isoforms are not conducive to infection by the vaccine Measles strain. We also found that the CD46 isotypes change to the adult forms at about the same ages that children begin to become responsive to the Measles vaccine. We suggest that it is the vaccine, not the children, that are the problem in Measles vaccination. We also suggest that vaccines should be designed for, and tested on, the age groups for which they are destined. e) it is generally thought that neonates capture maternal antibody during pregnancy (across the placenta) and during the first two or three days after birth (from colostrum). we found, however, that the neonatal Fc receptor is expressed until weaning, and that pups fostered onto immunized mothers captured antibody until approximately weaning, after which the maternal antibodies waned. Thus neonates continue to capture maternal antibody from milk (both IgG and IgA) until weeks after birth. 2) CD4 T CELLS CLEAR TUMORS a) CELLULAR PARTNERSHIPS IN TUMOR CLEARANCE: Having found that CD4 T cells can be better at clearing tumors than CD8 cells (gainst six out of six tumors, from five different tissues, CD4 effectors were more potent than CD8s), we began stuyding the mechanisms used by the CD4 T cells. We found that the CD4 T cells partner with NK cells and with a macrophage population in tumors that has characteristics of both macrophage and dendritic cell. We are now studying these partnerships to determine which cells do what. Thus far, it seems that IFN-gamma production by the CD4 T cells is involved, and that tumor infiltrating macrophages can be educated by CD4 T cells to change from tumor-nurturing to tumorocytic. b) RECIRCULATION OF TUMORICIDAL LYMPHOCYTES: We found that CD4 T cells, when injected intraperitoneally, can leave the peritoneum and circulate to the tumor site. NK cells, however, are unable to do this. Following on these data, we found that the population of NK cells that resides in the peritoneum is different from NK cells in the spleen. And the peritoneal NK cells do not leave the peritoneum. We are currently asking what differences we might find in the function of splenic and peritoneal NK cells. c) COLLABORATION BETWEEN TUMORICIDAL LYMPHOCYTES AND TUMOR-RESIDENT MACROPHAGES. We found that activated CD4 T cells change the phenotype of tumor-resident macrophages from tumor-promoting to tumoricidal. 3) DENDRITIC CELL ACTIVATION: dendritic cells are thought to make pro-inflammatory cytokines in the first 24 hours after activation and then become """"""""exhausted"""""""" such that they no longer make such cytokines. We found, however, that they continue to make large quantitities of proinflammatory cytokines if allowed to interact with memory or effector T cells. Thus the dendritic cells are not pre-programmed, but respond to signals from their environment to make appropriate cytokines at appropriate times and in appropriate places.

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