IMMUNOTHERAPY OF CRYPTOSPORIDIOSIS USING MONOCLONALS

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Cryptosporidium parvum is a major cause of persistent diarrheal illness among AIDS patients. Current estimates are that from 15-20% of AIDS patients may eventually contract this infection. The true number of such patients, however, is currently unknown and likely to be underreported. The problem with cryptosporidiosis in AIDS patients is exacerbated by the absence of an effective chemotherapy. Recent studies have provided evidence, however, that hyperimmune antibody preparations given orally may reduce the severity of disease. Following through on this idea, we have focused on a monoclonal antibody (MAb) approach to prophylaxis and treatment because these reagents have uniformity, can be produced in unlimited quantity, can identify important parasite antigens, can be exhaustively tested using in vitro and in vivo model systems, and may be useful in opening up alternate preventive or treatment strategies. In this continuing Program Project proposal we will focus on an integrated approach to developing an immunologic strategy aimed at preventing and treating cryptosporidiosis in the AIDS patient. Core facilities will be established to provide parasite reagents to all projects (9001 Arizona), to provide a means of testing MAbs useful against intestinal and extraintestinal cryptosporidiosis, and to identify protective antigens and responses through use of immune deficient mice (9002 Washington). Projects 1 and 2 at Arizona will interact extensively and focus on work relating to identifying and characterizing neutralizing MAbs directed against the merozoite and sporozoite stages respectively. Project 3 at Washington will focus on recombinant strategies aimed at producing and characterizing sporozoite and merozoite proteins that induce protective responses against C. parvum. Project 4 at Arizona will focus on deriving murine dimeric IgA MAbs against antigens of sporozoites known to be neutralization sensitive and which can be used in a strategy to control extraintestinal cryptosporidiosis. The entire project will be directed by Arizona.