IMMUNOREGULATION /IMMUNE RECOGNITION IN FILARIAL/NONFILARIAL PARASITIC INFECTIONN

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Regulation of parasite-specific immune responses in filarial infection- Because chronic filarial infections may alter immune reactivity to other (nonparasite) antigens and because these alterations may have profound implications for vaccine programs worldwide, a community-based study in Esmeraldas province of Ecuador was performed in which 200 individuals (mostly children) with microfilaria-positive onchocerciasis, along with ethnically similar but uninfected individuals, were vaccinated with common, commercially available vaccines (tetanus toxoid as a ?recall? protein antigen, pneumococcal vaccine as a new and/or a recall polysaccharide, hepatitis B as a new protein), and their subsequent cellular (cytokine profile) and humoral (isotype, subclass) responses were compared. The data suggest that the presence of active onchocerciasis blunts significantly the proliferative response along with IFN-gamma production to tetanus toxoid and changes the isotype profile of the antibody responses postvaccination to hepatitis B and to tetanus. A second, more comprehensive study, in which oral cholera vaccine was administered to patients with heavy intestinal helminth infection, has demonstrated even more dramatically that the immune response induced by these parasites alters not only the immune response to the orally administered vaccine, but also the take of the vaccine.Because systemic helminth infection (e.g., filarial infections) can alter the cytokine milieu of the surrounding cells, its effect on HIV entry and replication was performed using an in vitro model. Acute helminth infection was very clearly associated with increased in vitro HIV replication compared to normal controls. Moreover, following definitive treatment with antiparasitic drugs, the increased replication seen in vitro returned to the normal levels. Predisposition to Infection and Disease - To examine the possibility that there is a genetic predisposition to a given immune response or to a given pathological outcome of infection, novel methods of examining the MHC class II genetic diversity have been developed and utilized in the fine mapping of the DQ, DP and DR locus in >600 patients with varying forms of filarial infections. To date, almost all of the HLA Class II alleles have been typed in these many individuals. Of note, there is a statistically significant difference between putatively immune (PI) and infected (INF) Amerindian subjects. This finding appears to be the result of a polarization of HLA-DR -DQ haplotypes DRB1*08042-DQA1*0401- DQB1*0402 (PI) and DRB1*0404-DQA1*0301-DQB1*0302 (INF). The presence of an association between HLA class II genes and immunity or infection has not been observed within the South American Black population subset that cohabit this onchocerca-endemic region, however.Modeling the early immune response to parasitic helminth infection - We have developed a model to examine both priming and induction of an immune response to parasite antigen in CD4+CD45RA+ (naive) T cells obtained from unsensitized donors. We have shown that these ?naive? CD4+ cells were able to proliferate and produce IL-5 and IFN-g when primed with microfilarial antigen using B-cells/monocytes as APCs. This same microfilarial Ag in the presence of IL-4 induces a strong IL-5 (Type-2) response whereas in its absence a Th0 (both IL-5 and IFN-g) occurs. On secondary stimulation with microfilarial antigen, cells originally primed with Mf Ag or Mf Ag + IL-2 produced IFN-g whereas cells primed in the presence of IL-4, induced a Th2-type response. This model has been extended to examine the role of antigen dose on the differentiation of na?ve T cells and the role of the important costimulatory molecues on skewing the immune response toward a Th2- dominated response.We have been able to isolate in pure form from normal, unsensitized blood donors both dendritic cells (the first cell likely to encounter a parasite antigen) and monocytes and shown that, upon stimulation with the larval stage antigen, parasite antigen induces these cells to produce IL-10 in significantly greater amounts than is produced to the nonhelminth protozoal antigen, soluble Toxoplasma antigen. Further, in response to filarial antigens, these dendritic cells and monocytes produce RANTES, one of the major eosinophil chemoattractant chemokines. Most recently, we have shown that parasite antigen and live parasites can (under some conditions) induce IL-4 production by dendritic cells, a finding that has profound implications for understanding why the T cell response in these infections invariably leads to immune responses characterized by IL-4 and IL-5. Using dendritic cells infected with Leishmania metacyclic promastigotes, we have also been able to demonstate the IL-12p70 (the major cytokine involved in immunity to this parasite) is only induced in a CD40-dependent manner. This has major implications for the biological role of IL-12 in mediating protection to infectious organisms.