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ARS Home » Northeast Area » Beltsville, Maryland (BARC) » Beltsville Agricultural Research Center » Environmental Microbial & Food Safety Laboratory » Research » Publications at this Location » Publication #282908

Research Project: ZOONOTIC PARASITES AFFECTING FOOD SAFETY AND PUBLIC HEALTH

Location: Environmental Microbial & Food Safety Laboratory

Title: CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome

Author
item Fan, X - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Upadhyaya, B - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Wu, L - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Koh, C - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Santin-duran, Monica
item Pittaluga, S - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Uzel, G - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Kleiner, D - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Williams, E - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Ma, Ca - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Bodansky, A - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Oliveira, J - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Edmonds, P - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Hornung, R - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Wong, D - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Fayer, Ronald
item Fleisher, T - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Heller, T - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)
item Prussin, C - National Instiute Of Allergy And Infectious Diseases (NIAID, NIH)

Submitted to: Clinical Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/27/2012
Publication Date: 5/9/2012
Publication URL: http://handle.nal.usda.gov/10113/56592
Citation: Fan, X., Upadhyaya, B., Wu, L., Koh, C., Santin, M., Pittaluga, S., Uzel, G., Kleiner, D., Williams, E., Ma, C., Bodansky, A., Oliveira, J., Edmonds, P., Hornung, R., Wong, D., Fayer, R., Fleisher, T., Heller, T., Prussin, C. 2012. CD40 agonist antibody mediated improvement of chronic Cryptosporidium infection in patients with X-linked hyper IgM syndrome. Clinical Immunology. 143(2):152-161.

Interpretive Summary: Patients with a genetic disorder that affects the immune system are susceptible to infection by opportunistic pathogens such as Cryptosporidium and usually present with respiratory infections, protracted diarrhea, and liver disease. The standard of care for these patients usually consists of antibiotics and immune globulin replacement. These therapies offer some benefit, but survival of patients with the specific genetic disorder referred to as XHM is limited. In these patients infection of the liver is generally not responsive to therapy. However, a targeted molecular approach that could restore deficient immune function in a specific manner and improve outcomes for XHM patients would be important. In this study, a highly targeted antibody was administered to two XHM patients with Cryptosporidium infection of the liver who were refractory to standard medical therapy. The treatment suppressed excretion of Cryptosporidium parasites. ARS scientists participated in this study by detection and identification of Cryptosporidium by microscopic and molecular testing of specimens.

Technical Abstract: X-linked hyper-IgM syndrome (XHM) is a combined immune deficiency disorder caused by mutations in CD40 ligand. We tested CP-870,893, a human CD40 agonist monoclonal antibody, in the treatment of two XHM patients with biliary Cryptosporidiosis. CP-870,893 activated B cells and APCs in vitro, restoring class switch recombination in XHM B cells and inducing cytokine secretion by monocytes. CP-870,893 infusions were well tolerated and showed significant activity in vivo, decreasing leukocyte concentration in peripheral blood. Although specific antibody responses were lacking, frequent dosing in one subject primed T cells to secrete IFN-g and suppressed oocyst shedding in the stool. Nevertheless, relapse occurred after discontinuation of therapy. The CD40 receptor was rapidly internalized following binding with CP-870,893, potentially explaining the limited capacity of CP-870,893 to mediate immune reconstitution. This study demonstrates that CP-870,893 suppressed oocysts shedding in XHM patients with biliary cryptosporidiosis. The continued study of CD40 agonists in XHM is warranted.