FW: Dr. Harumi Jyonouchi's abstracts

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[AutismRecoveryNetwork] Dr. Harumi Jyonouchi's abstracts

1) Innate and Adaptive Immune Responses in Children With Regression Autism:Evaluation of the Effects of Environmental Factors Including VaccinationJournal of Allergy and Clinical ImmunologyFebruary 2001, part 2 * Volume 107 * Number 2Harumi Jyonouchi; Sining Sun; Hoa LeUniversity of Minnesota, Minneapolis, MNEtiology of autism is unknown. However, there appears to be a causal association between onset of regression/autistic behavior and infant immunization/viral infection/adverse reactions to common food antigens (gluten and cow's milk). Previous literature indicates the presence of autoantibodies against neuronal cells in autistic children and subtle immune abnormalities such as skewed T2 responses. In this study, we hypothesized that children with regression autism may have aberrant immune responses against these common, usually benign environmental factors, resulting in inflammatory and/or autoimmune conditions in the CNS. As a first step to examine our hypothesis, we determined innate and adaptive immune responses in children with autism spectrum disorders (N=35, Age 2-14 yrs, median: 6 yr, 24 males and 9 females). Innate immune responses are assessed by measuring production of TNF-a, IL-1ß, IL-6, sTNFRI, and sTNFRII after incubating peripheral blood mononuclear (PBMN) cells overnight with endotoxin (LPS: 0.1 to 10 µg/ml). Adaptive immune responses are assessed by measuring T cell cytokine (IFN-g, IL-4, IL-5 and IL-10) production in response to recall antigens (tetanus and dust mite), mitogens (PHA and Con A) and IFN-g inducing cytokines (IL-12p70 and IL-18) after culturing cells for 4 days with these stimuli. Production of IL-12p40, IL-18, and TGF-ß was also measured in this setting. Controls were obtained from healthy normal children (N=17, Age 2-16 yrs, median: 11 yrs). Onset of autism/developmental regression with immunization was reported in 27/35 patients and 32/35 patients were reported to have improvement of behavior by parents/teachers/therapists with a casein-free/gluten-free diet. Autistic children produced higher TNF-a (p<0.01), sTNFRII (p=0.038), and IL-6 (p=0.01) with a low dose of LPS (0.1 µg/ml) than controls. This is due to the presence of a subset of patients who produced large amounts of these cytokines. In fact, 27/35 (77.1%) study subjects produced higher than the maximum levels of TNF-a, sTNFRII, IL-6 and/or IL-1ß observed in controls with a low dose of LPS. We also observed elevated serum levels of these cytokines in 8/18 autistic children. Our results thus indicate a high frequency of excessive innate immune responses in children with regression autism. These results may partly explain apparent casual association between onset of regression/autistic behavior and immunization in these children. Production of IFN-g, IL-5, IL-10 and IL-12p40 was highly variable in autistic children. IL-4, IL-18, and TGF-ß production by PBMN cells were generally low and did not differ between the study subjects and controls. We also assessed T1/T2 responses by comparing the ratio of IFN-g/IL-5 levels produced with recall antigens. The ratio of IFN-g/IL-5 did not differ between autistic children and controls. However, 7 and 8 out of 35 autistic children produced significantly high IL-12p40 with recall antigens and IL-12/IL-18, respectively. IL-10 production was markedly variable in autistic children: 10 and 11 out of 35 subjects produced high amounts of IL-10 with PHA and tetanus, respectively, while 12/34 subjects produced significantly low IL-10 with PHA as compared to controls. These results also indicate aberrant production of regulatory cytokines for T cell responses in subsets of autistic children.2) Experimental Biology AbstractProinflammatory/regulatory cytokine production in children with regression autism: Evidence of dysregulated innate/adaptive immune responses in subsets of children.Harumi Jyonouchi, Sining Sun, and Hoa Le, University of Minnesota, Minneapolis, MNAutism is a complex developmental disorder and its etiology is poorly understood. Onset of regression and autistic behavior are often preceded by infant and immunization and benign viral infection. Many autistic children also suffer from chronic diarrhea/constipation and demonstrate adverse reactions to common food antigens (Ags; gluten and cow's milk). Previous literature indicates possible autoimmunity and subtle immune abnormalities such as skewed T2 responses in autistic children. We hypothesized that children with regression autism may have aberrant immune responses against common, usually benign environmental factors including food Ags and vaccines. In this study, we determined innate and adaptive immune responses in children with autism spectrum disorders (ASD) (N=50, Age 2-14 yrs, median: 5.5 yrs, 36 males and 14 females) by measuring production of a variety of cytokines involved in immune network. Onset of autism and developmental regression following immunization was reported in 37/50 patients and parents /teachers/therapists observed improvement of behavior/GI symptoms with a casein-free and/or gluten-free diet in 46/50 (92%) patients. Innate immune responses are assessed by measuring production of TNF-a, IL-1b IL-6, sTNFRI, and sTNFRII after incubating peripheral blood mononuclear (PBMN) cells overnight with endotoxin (LPS). Adaptive immune responses are assessed by measuring production of T cell cytokines (IFN-g, IL-4, IL-5, IL-10) in response to recall antigens (tetanus and dust mite), mitogens (PHA and Con A) and IFN-g inducing cytokines (IL-12p70 and IL-18) after culturing PBMN cells for 4 days with these stimuli. Production of IL12p40, IL-18, TNF-a, and TGF-B was also measured in this setting. Controls were obtained from healthy normal children (N=17, Age 2-16 yrs, median: 11yrs). Autistic children produced larger amounts of TNF-a (p<0.01), sTNFRII (p< 0.05), and IL-6 (p<0.01) without stimuli and with LPS (0.1 ug/ml) than controls. IL-1b production without stimuli was also higher in autistic children (p<0.05). This is due to the presence of subsets of patients who produced large amounts of these cytokines. With LPS (0.1 ug/ml), 40/50 (80%) study subjects produced higher than the maximum levels of TNF-a, sTNFRII, IL-6, and/or IL1b observed in controls. Production of IFN-g, IL-5, and IL12p40 was highly variable in autistic children. The ratio of IFN-g/IL-5 produced with recall antigens did not differ between autistic children and controls. IL-10 production with Con A and IL-18 stimuli was lower in autistic children than controls (p<0.01) due to the presence of a subset of patients with low IL-10 production. T his is also reflected in higher ratios of IL-12/IL-10 produced with Con A, PHA, and IL-18 in autistic children (p< 0.02). IL-4, IL-18, and TGF-B production by PBMN cells were generally low and did not differ between the study subjects and controls. Taken together these results indicate a high frequency of excessive innate immune responses in children with regression autism and the presence of a subset(s) of autistic children with aberrant production of regulatory cytokines for T cell responses. These findings may be associated with high frequency of adverse reactions to infant immunizations and food Ags in children with regression autism. However, further studies are required to determine how such subtle immunodysregulation can be associated with development of ASD.Visit the ARN Homepage! http://www.geocities.com/ARNFL