Abstract
Immunoglobulin secretion onto mucosal surfaces is a major component of the mucosal immune system. We hypothesized that chronic gastrointestinal (GI) disturbances associated with autistic disorder (AD) may be due to an underlying deficiency in mucosal immunity, and that orally administered immunoglobulin would be effective in alleviating chronic GI dysfunction in these individuals. In this pilot study, twelve male subjects diagnosed with AD were evaluated using a GI severity index (GSI) while receiving daily dosing with encapsulated human immunoglobulin. Following eight weeks of treatment, 50% of the subjects met prespecified criteria for response in GI signs and symptoms and showed significant behavioral improvement as assessed by the Autism Behavior Checklist and parent and physician rated Clinical Global Impression of Improvement.
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Anthony, A., Bjarnason, I., Sigthorsson, G., Montgomery, S. M., Murch, S. H., & Thompson, M., et al. (2000). Faecal calprotectin levels correlate with acute inflammation in autistic enterocolitis. Gut, 46(Suppl II), A3.
Arnold, L. E., Aman, M. G., Martin, A., Collier-Crespin, A., Vitiello, B., & Tierney, E., et al. (2000). Assessment in multisite randomized clinical trials of patients with autistic disorder: The Autism RUPP Network. Research Units on Pediatric Psychopharmacology. Journal of Autism and Developmental Disorders, 30(2), 99–111.
Ashwood, P., Anthony, A., Pellicer, A. A., Torrente, F., Walker-Smith, J. A., & Wakefield, A. J. (2003). Intestinal lymphocyte populations in children with regressive autism: Evidence for extensive mucosal immunopathology. Journal of Clinical Immunology, 23(6), 504–517.
Barnes, G. L., Doyle, L. W., Hewson, P. H., Knoches, A. M., McLellan, J. A., & Kitchen, W. H., et al. (1982). A randomised trial of oral gammaglobulin in low-birth-weight infants infected with rotavirus. Lancet, 1(8286), 1371–1373.
Casswall, T. H., Hammarstrom, L., Veress, B., Nord, C. E., Bogstedt, A., & Brockstedt U., et al. (1996). Oral IgA–IgG treatment of chronic non-specific diarrhoea in infants and children. Acta Paediatrica, 85(9), 1126–1128.
Chez, M. G., Buchanan, C. P., Bagan, B. T., Hammer, M. S., McCarthy, K. S., & Ovrutskaya, I., et al. (2000). Secretin and autism: A two-part clinical investigation. Journal of Autism and Developmental Disorders, 30(2), 87–94.
Comi, A. M., Zimmerman, A. W., Frye, V. H., Law, P. A., & Peeden, J. N. (1999). Familial clustering of autoimmune disorders and evaluation of medical risk factors in autism. Journal of Child Neurology, 14(6), 388–394.
Connolly, A. M., Chez, M. G., Pestronk, A., Arnold, S. T., Mehta, S., Deuel, R. K. (1999). Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders. Journal of Pediatrics, 134(5), 607–613.
Dalakas, M. C. (1997). Intravenous immune globulin therapy for neurologic diseases. Annals of Internal Medicine, 126(9), 721–730.
Daniels, W. W., Warren, R. P., Odell, J. D., Maciulis, A., Burger, R. A., & Warren, W. L., et al. (1995). Increased frequency of the extended or ancestral haplotype B44-SC30-DR4 in autism. Neuropsychobiology, 32(3), 120–123.
Eibl, M. M., Wolf, H. M., Furnkranz, H., & Rosenkranz, A. (1988). Prevention of necrotizing enterocolitis in low-birth-weight infants by IgA–IgG feeding. New England Journal of Medicine, 319(1), 1–7.
Furlano, R. I., Anthony, A., Day, R., Brown, A., McGarvey, L., & Thomson, M. A., et al. (2001). Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. Journal of Pediatrics, 138(3), 366–372.
Harvey, R. F., & Bradshaw, J. M. (1980). A simple index of Crohn’s-disease activity. Lancet, 1(8167), 514.
Horvath, K., Papadimitriou, J. C., Rabsztyn, A., Drachenberg, C., & Tildon, J. T. (1999). Gastrointestinal abnormalities in children with autistic disorder. Journal of Pediatrics, 135(5), 559–563.
Horvath, K., & Perman, J. A. (2002). Autism and gastrointestinal symptoms. Current Gastroenterology Reports, 4(3), 251–258.
Hyams, J. S., Mandel, F., Ferry, G. D., Gryboski, J. D., Kibort, P. M., Kirschner B. S., et al. (1992). Relationship of common laboratory parameters to the activity of Crohn’s disease in children. Journal of Pediatric Gastroenterology and Nutrition, 14(2), 216–222.
Jyonouchi, H., Sun, S., & Le, H. (2001). Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. Journal of Neuroimmunology, 120(1–2), 170–179.
Kanfer, E. J., Abrahamson, G., Taylor, J., Coleman, J. C., & Samson, D. M. (1994). Severe rotavirus-associated diarrhoea following bone marrow transplantation: treatment with oral immunoglobulin. Bone Marrow Transplantation, 14(4), 651–652.
Kazatchkine, M. D., & Kaveri, S. V. (2001). Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. New England Journal of Medicine, 345(10), 747–755.
Korvatska, E., Van de Water, J., Anders, T. F., Gershwin, M. E. (2002). Genetic and immunologic considerations in autism. Neurobiology of Disease, 9(2), 107–125.
Krug, D. A., Arick, J., & Almond, P. (1980). Behavior checklist for identifying severely handicapped individuals with high levels of autistic behavior. Journal of Child Psychology and Psychiatry, 21(3), 221–229.
Krug, D. A., Arick, J., & Almond, P. (1993). Autism screening instrument for educational planning. Examiner’s manual (1st ed.). Austin, Texas: Pro-ed.
Kuddo, T., Nelson, K. B. (2003). How common are gastrointestinal disorders in children with autism?. Current Opinion in Pediatrics, 15(3), 339–343.
Lichtiger, S., Present, D. H., Kornbluth, A., Gelernt, I., Bauer, J., & Galler, G., et al. (1994). Cyclosporine in severe ulcerative colitis refractory to steroid therapy. New England Journal of Medicine, 330(26), 1841–1845.
Melamed, I., Griffiths, A. M., & Roifman, C. M. (1991). Benefit of oral immune globulin therapy in patients with immunodeficiency and chronic diarrhea. Journal of Pediatrics, 119(3), 486–489.
Melmed, R. D., Schneider, C. K., Fabes, R. A., Phillips, J., & Reichelt, K. (2000). Metabolic markers and gastrointestinal symptoms in children with autism and related disorders. Journal of Pediatric Gastroenterology and Nutrition, 31(Suppl 2), A116.
Messahel, S., Pheasant, A. E., Pall, H., Ahmed-Choudhury, J., Sungum-Paliwal, R. S., & Vostanis, P. (1998). Urinary levels of neopterin and biopterin in autism. Neuroscience Letters, 241(1), 17–20.
Molloy, C. A., & Manning-Courtney, P. (2003). Prevalence of chronic gastrointestinal symptoms in children with autism and autistic spectrum disorders. Autism, 7(2), 165–171.
Money, J., Bobrow, N. A., & Clarke, F. C. (1971). Autism and autoimmune disease: a family study. Journal of Autism and Childhood Schizophrenia, 1(2), 146–160.
Myren, J., Bouchier, I. A., Watkinson, G., Softley, A., Clamp, S. E., & de Dombal, F. T. (1984). The O.M.G.E. Multinational Inflammatory Bowel Disease Survey 1976–1982. A further report on 2,657 cases. Scandinavian Journal of Gastroenterology. Supplement, 95, 1–27.
NIMH, (1985). CGI (Clinical Global Impression) scale. Psychopharmacology Bulletin, 21, 839–840.
Piven, J. (1997). The biological basis of autism. Current Opinion in Neurobiology, 7(5), 708–712.
Roberts, W., Weaver, L., Brian, J., Bryson, S., Emelianova, S., & Griffiths, A. M., et al. (2001). Repeated doses of porcine secretin in the treatment of autism: A randomized, placebo-controlled trial. Pediatrics, 107(5), E71.
Schott, J. M., Harkness, K., Barnes, J., della Rocchetta, A. I., Vincent, A., & Rossor, M. N. (2003). Amnesia, cerebral atrophy, and autoimmunity. Lancet, 361(9365), 1266.
Singh, V. K. (1996). Plasma increase of interleukin-12 and interferon-gamma. Pathological significance in autism. Journal of Neuroimmunology, 66(1–2), 143–145.
Singh, V. K., Warren, R., Averett, R., & Ghaziuddin, M. (1997). Circulating autoantibodies to neuronal and glial filament proteins in autism. Pediatric Neurology, 17(1), 88–90.
Sweeten, T. L., Bowyer, S. L., Posey, D. J., Halberstadt, G. M., & McDougle, C. J. (2003). Increased prevalence of familial autoimmunity in probands with pervasive developmental disorders. Pediatrics, 112(5), e420.
Sweeten, T. L., Posey, D. J., & McDougle, C. J. (2003). High blood monocyte counts and neopterin levels in children with autistic disorder. American Journal of Psychiatry, 160(9), 1691–1693.
Szatmari, P., Jones, M. B., Zwaigenbaum, L., MacLean, J. E. (1998). Genetics of autism: Overview and new directions. Journal of Autism and Developmental Disorders, 28(5), 351–368.
Takai, T. (2002). Roles of Fc receptors in autoimmunity. Nature Reviews Immunology, 2(8), 580–592.
Torrente, F., Anthony, A., Heuschkel, R. B., Thomson, M. A., Ashwood, P., & Murch, S. H. (2004). Focal-enhanced gastritis in regressive autism with features distinct from Crohn’s and Helicobacter pylori gastritis. American Journal of Gastroenterology, 99(4), 598–605.
Torrente, F., Ashwood, P., Day, R., Machado, N., Furlano, R. I., & Anthony, A., et al. (2002). Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Molecular Psychiatry, 7(4), 375–382.
Torres, A.R., Maciulis, A., & Odell, D. (2001). The association of MHC genes with autism. Frontiers in Bioscience, 6, D936–D943.
Vincent, A., Lily, O., & Palace, J. (1999). Pathogenic autoantibodies to neuronal proteins in neurological disorders. Journal of Neuroimmunology, 100(1–2), 169–180.
Wakefield, A. J., Anthony, A., Murch, S. H., Thomson, M., & Montgomery, S. M., Davies, S., et al. (2000). Enterocolitis in children with developmental disorders. American Journal of Gastroenterology, 95(9), 2285–2295.
Warny, M., Fatimi, A., Bostwick, E. F., Laine, D. C., Lebel, F., & LaMont, J. T., et al. (1999). Bovine immunoglobulin concentrate—Clostridium difficile retains C. difficile toxin neutralising activity after passage through the human stomach and small intestine. Gut, 44(2), 212–217.
Acknowledgments
The authors would like to thank the subjects and parents for their participation in the study, the Southwest Autism Research and Resource Center for making its facility available during the study, and Janet Kirwan, RN and Monica McCabe, RN, OCN for their skill and dedication in ensuring that the study was conducted in compliance with the study protocol and regulatory guidelines. Funding for the study was provided by Protein Therapeutics, Inc.
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Schneider, C.K., Melmed, R.D., Barstow, L.E. et al. Oral Human Immunoglobulin for Children with Autism and Gastrointestinal Dysfunction: A Prospective, Open-Label Study. J Autism Dev Disord 36, 1053–1064 (2006). https://doi.org/10.1007/s10803-006-0141-y
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DOI: https://doi.org/10.1007/s10803-006-0141-y