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Impact of Maternal Infection on Neurodevelopment – Structural and Functional Changes Geoffrey B.C. Hall, Ph.D., McMaster University, Canada (Pilot Research Award) Not only has Autism a strong genetic component, but early exposure to environmental insult may be a significant risk factor for the disorder. Exposure to known viruses during the first trimester of pregnancy has been connected to higher rates of autism. Animal models built on these observations present striking neurological similarities to human data as well as some behavioural deficits that mimic those seen in autism. Because autism is a developmental disorder, we are interested in using an animal model to study the behaviour of mice that have been exposed to viral infection in-utero, across pre-adolescent, adolescent and adult time-points. Importantly, we wish to assess the neurological origins of these behaviours. Using recently available animal imaging methods we plan to assess the neurodevelopmental outcomes of maternal infection in brain pathways key to autism. These methods offer the advantage over other techniques in that animals need-not be killed, and therefore the same animal can be studied across time. This provides the exciting opportunity to also study the effects of environmental enrichment on behavioural outcomes, and connect these results to the neurological changes seen throughout in development. We have outlined is a series of studies that will use an animal model of maternal infection, small animal imaging, social behaviour analyses and conditions of environmental enrichment to explore the neural mechanisms behind autism. This work is novel, exciting and holds promise for the development of new diagnostic tools and improvements in intervention. Investigating the Overlap between Celiac Disease and Autism - Potential Inflammatory Responses Exacerbated by Exposure to Toxicants such as Mercury Allen J. Rosenspire, Ph.D., Wayne State University (Pilot Research Award) The aim of this grant is to research the connection between autism and celiac disease (CD). Celiac disease (CD), a digestive disorder that is characterized by intolerance to dietary gluten, is primarily recognized as an autoimmune disease of the small intestine. There is some evidence that individuals suffering from a variety of neurological disorders, including autism, often also suffer from CD, although the link needs to be better established. It is now clear that a particular antibody, anti-transglutaminase2 (anti-TG2), is strongly associated with having CD. A systematic survey for anti-TG2 in the blood of autistic children and their families has not yet been done. Therefore, Dr. Rosenspire will now test for anti-TG2 antibodies in serum samples archived in the Cure Autism Now AGRE repository. His hypothesis is that autistic children will have higher anti-TG2 titers than the general population, as well as their non-autistic siblings and parents. Knowledge of whether or not autism and CD are linked will advance our understanding of autism and disorders of the gut. Moreover, although CD clearly has a genetic basis, exactly how celiac disease could be connected to neurological disorders has been a mystery. Establishing an unambiguous link to autism will allow Dr. Rosenspire to pursue his hypothesis that CD may lead to inappropriate inflammation in the brain, and that patients with CD may therefore also be especially prone to adverse inflammatory responses upon exposure to environmental toxicants such as mercury. Blood Genomic Studies of Children with Idiopathic Autism Frank R. Sharp, M.D., University of California, Davis (Pilot Research Award) Autism appears to be a complex neurodevelopmental disease that may be caused by the interaction of inherited genes with still unknown factors in the environment. We have demonstrated that RNA expression in blood that is detected using newly developed microarrays can reliably detect the effects of a given genetic disease on gene expression in the blood. In addition, environmental agents like medications and infectious agents like bacteria and viruses also produce characteristic genomic profiles in blood. We have applied this approach to children with autism ages 2 to 5. Blood was obtained from the children, the RNA isolated, and the expression of ten thousand RNAs assessed in each child. We discovered genomic profiles – RNA expression patterns - in blood that correlate with the age of onset of children with autism, and correlate with high expression of genes associated with Natural Killer (NK) cells and cytotoxic T lymphocytes, CD8+ cells in peripheral blood. In this project we propose to study 100 children with autism as compared to controls. We will test whether the genes found to be regulated in children 2-5 years old are also regulated in children 5 to 18 years old. We will confirm that age at onset produces characteristic blood genomic profiles in children with autism at all ages, and that the genes regulated in Natural Killer cells – the cells that normally kill viruses when they enter the blood stream – are also up regulated in a large subgroup of children with autism. Finally, the results of the first half of the patients will be used to predict the subgroups in the second half of the patients. This study should help identify different types of autism, and possibly point to abnormalities of NK and/or CD8 cells that might affect the ability of the developing fetus or newborn child to deal with certain types of viruses. Contribution of Calcium Channel Mutations to Autism Risk and Mercury Susceptibility Isaac Pessah, Ph.D., University of California, Davis (Environmental Initiative Innovator Award) The goal of this research is to understand the genetic and environmental risk factors contributing to the incidence and severity of core symptoms and comorbidity seen in childhood autism. Dr. Pessah hypothesizes that mutations in specific types of calcium (Ca2+) channels may contribute to certain forms of autism and significantly increase susceptibility to adverse effects of environmental toxicants. This hypothesis is based on evidence from the Pessah lab that organic mercury, polychlorinated biphenyls, and flame retardants (PBDEs) can alter the intracellular Ca2+ signals generated by ryanodine receptors, an important type of calcium channel, and that these are essential for normal maturation and function of both the immune and nervous systems. To attain these goals, mice that contain mutations for calcium channels will be studied for abnormal social behavior and their possible heightened susceptibility to organic mercury compounds such as thimerosal will be studied in detail. One mouse currently being developed possesses a mutation within a specific calcium channel (Cavl.2) that has been found to cause Timothy Syndrome (TS). Children with TS have a 60% rate of an autism diagnosis, with up to 80% of the children showing some signs of autism. Two additional mouse strains are currently being studied which possess a mutation within the type 1 or type 2 ryanodine receptor Ca2+ channel (RyR1 and RyR2, respectively). Dr. Pessah's lab has found that mice possessing mutations in RyR channels have heightened susceptibility to chemically-induced adverse reactions of the immune and nervous systems. Together, the Cavl .2 and RyR2 receptors form a signaling unit in heart, neurons and T lymphocytes. This project will investigate whether these three lines of mice, which have an underlying genetic defect in Ca2+ signaling, will have increased behavioral and immunological problems when exposed to mercury, and will also examine whether mercury directly affects the development of nerve cells from these animals. Finally, the Pessah lab will determine whether children with autism have a higher frequency of Cavl .2 or RyR mutations. Collectively these experiments will provide important new information on the possible contribution of Cavl .2 or RyR mutations to autism risk in humans and launch studies of enhanced susceptibility of the developing nervous and immune systems to organic forms of mercury in micecarrying mutations relevant to autism. Immunological Phenotyping in Autism: A Screen for Potential Early Biomarkers of Activation Paul Ashwood, Ph.D., M.I.N.D. Institute, University of California, Davis (Pilot Research Award) Clinicians, schools, and service agencies worldwide have reported a dramatic increase in the number of children identified with autism spectrum disorders (ASD). Currently, autism is believed to be a complex genetic disorder with the combination of multiple events leading to disease cause. It is thought that the interaction of genetic susceptibility and exposure to nongenetic influences during critical periods of neurodevelopment plays a part in the development of autism. Virtually the entire research literature on autism emphasizes the multiple facets of this disorder. This includes for example, varying degrees of large head circumference, small head circumference, loss of language and social skills (regression), mental retardation, savant abilities, seizures, serious sleep problems and overt gastrointestinal problems . Taken together, these data indicate that ASD is, in reality, a group of disorders that share a common behavioral profile. To make progress in identifying the causes of these disorders it will be essential to develop diagnostic markers that will lead to unequivocal differentiation of the various phenotypes. One area that has consistently been discussed as an important factor in autism is the presence of an altered or dysregulated immune system. The interface between the cellular immune and nervous systems is exceedingly complex with extensive communication occurring between them in both health and disease. Immune cells and neuroimmune molecules such as cytokines and chemokines modulate brain function affecting cognitive and emotional processing. Cytokines are mediators of cell-cell communication that demonstrate assorted effects on neuronal tissue such as the modulation of systemic and central nervous system (CNS) responses to infection, injury, and inflammation. Thus, these molecules can have profound effects on mood and behavior. Researchers have recently shown the presence of immune activation in both brain specimens and cerebrospinal fluid from subjects with autism suggesting that abnormal immune responses in the CNS may influence neural function and development in autism. The adaptive immune response involves the proliferation and differentiation of T lymphocytes into functional effector cells. Cell surface receptors and proteins can be utilized as phenotypic markers to identify and classify stages of cellular differentiation and activation. In this way, a detailed definition of the cells involved in the adaptive immune responses can be performed. Moreover, T cells may develop along separate lines, resulting in distinct immune phenotypes characterized by the particular pattern of cytokines they produce, (i.e. activated TH1 and TH2 subsets, and/or regulatory subsets TH3) and the immune response these cytokines mediate. We aim to demonstrate the presence of distinct immune phenotypes in ASD based on the level of activation of their immune response. We will identify and characterize the immune response in ASD by comparing the activation status and function of lymphocyte cell populations and their cytokine/chemokine profiles, firstly in, peripheral blood and secondly in isolated cell cultures that receive immunological challenge. Comparisons will be made not only between the autism cases and typically developing controls but also within the autism group based on clinical behavioral and medical characteristics. Immunological findings will be correlated with behavioral and biomedical factors to examine the relationship between the immune responses and clinical characteristics of autism. Particular attention will be paid to the key cytokines and chemokines that may affect neurodevelopment and immune function. By elucidating the medical and biological correlates of autism, we hope to contribute to a clearer understanding of the early biological processes underlying this increasingly common disorder. Results from this study will guide further targeted investigations into the pathobiology of autism. A better understanding of the underlying biology may contribute to earlier identification and the development of more individual-based treatment regimens. Histologic, Microbiological and Molecular Analyses of Bowel Disease in ASDs W. Ian Lipkin, M.D., Columbia University (Pilot Research Award) Debilitating gastrointestinal (GI) dysfunction is described in some autistic children, possibly at higher frequency in individuals with a regressive phenotype. Its cause is unknown; however, some studies have implicated inflammation or infection. The significance of gastrointestinal dysfunction for brain dysfunction is controversial; some investigators have proposed that differences in GI microflora induce inflammation, influence permeability of the GI tract, or release novel neuroactive peptides that have remote effects in brain. Our project will use sensitive new assays for gene expression, microbiology and immunology to survey GI tract biopsies and blood from two groups of children: one group with GI dysfunction and autism, and one group with GI dysfunction but no neurological disturbance. The implication of an infectious agent (or agents) as factors (or cofactors) in autism or associated GI comorbidity could lead to new strategies for prophylaxis or therapeutic intervention. Discovery of distinct profiles of gene expression in GI tract or of soluble factors in peripheral blood may provide insights into pathogenesis; inform genetic analyses; and facilitate management by providing therapeutic targets and objective criteria for diagnosis and treatment response. A Role for Immune Proteins in Early Stages of Neural Development: Possible Implications for the Pathogenesis of Autism A. Kimberley McAllister, Ph.D., University of California, Davis (Pilot Research Award) Proper formation of connections in the brain during childhood provides the substrate for adult perception, learning, memory, and cognition. Tragically, improper formation or function of these connections leads to many neurodevelopmental disorders, including autism. Autism spectrum disorder is a highly prevalent severe neurobehavioral syndrome with a heterogeneous phenotype. Although there is a strong genetic component to autism, the syndrome can also be caused or influenced by nongenetic factors. Specifically, maternal viral infection has been identified as the principle nongenetic cause of autism. Several studies have even indicated a genetic link between autism and immune system genes. Since immune molecules are increased following infection and are present in the developing brain, it is possible that changes in these immune molecules lead to changes in neuronal connectivity that underlie some forms of autism. This proposal will test this idea by studying the function of altered levels of a specific kind of immune molecule on the initial formation of connections and their subsequent plasticity in the developing brain. Thus, our results should reveal a mechanism for the primary nongenetic cause of autism and thereby illuminate potential preventive therapies for this devastating disease. Genetic Susceptibility to Mercury-induced Immune Dysfunction in Autism and Autism- Spectrum Disorders Ellen K. Silbergeld, Ph.D., Johns Hopkins Bloomberg School of Public Health (Pilot Research Award) The goal of this project is to examine gene that may affect responses to environmental risk factors in autism and autism spectrum disorders (ASD). These are complex diseases that are known to involve interactions between genetic susceptibility and acquired (or environmental) exposures. However, most research on autism/ASD development has not examined these interactions, but rather focused on either genetic or environmental risk factors, including mercury compounds. The failure to include geneenvironment interactions may be one reason why we have not yet identified either key genes or significant environmental risk factors associated with autism/ASD. We plan to examine whether there are differences in how children with autism/ASD respond to one environmental contaminant (mercury) compared to their unaffected siblings and parents. We hypothesize that mercury does not cause autism by itself, but that individuals who carry certain variations in specific genes may have heightened responses to mercury, and that these variations will increase the likelihood that those children exposed to mercury will develop autism/ASD. In order to accomplish our goal, we will first develop and validate a panel of tests using immune cells found in human blood to quantitate immune responses to mercury in vitro by using the blood of healthy volunteers. Then we will apply this panel to cells obtained from children diagnosed with autism/ASD, their unaffected siblings, their parents, and unrelated community controls. This project will be the first study on this topic conducted in cells from human subjects. Eventually, we hope to identify variations in specific genes related to these responses to mercury for use in epidemiological studies of autism/ASD. Immune Genes and Abnormal Brain Development in Autism Lisa Boulanger, Ph.D., University of California, San Diego (Pilot Research Award) Autism is the result of a combination of genetic and environmental influences. Many studies have linked to immune genes and immune abnormalities, but the source of these links has remained unclear. Maternal viral infection during the second trimester of pregnancy dramatically increases the risk of the child developing autism, suggesting that immune challenges may be an important environmental contributor to autism. Indeed, viral infection of pregnant mice induces a syndrome in the offspring with striking anatomical and behavioral parallels to autism. These effects are seen following a wide variety of immune challenges, and despite a lack of virus in the fetal circulation, suggesting that a relatively nonspecific aspect of the maternal immune response affects the developing fetal brain. Cytokines are key components of this nonspecific immune response, and have been the focus of a number of recent studies on autism. Cytokines are altered in the fetal brain following maternal immune challenge, and they play an important role in brain development and function. In the immune system, cytokines' effects are mediated in part through changes in the levels of members of the major histocompatibility complex (MHC) class I family of proteins. Unexpectedly, these proteins-famous for their role in the immune system-are also expressed by normal neurons and required for specific, key events in brain development. Thus cytokines may affect fetal brain development by changing MHC class I expression in the brain. It is unknown if MHC expression is altered in the autistic brain, or if MHC is involved in the origin or expression of this devastating disorder. We will investigate this possibility in both the immune challenge mouse model of autism, as well as in autistic children. The mouse model will allow us to better understand the molecular mechanisms by which maternal infection can functionally or structurally disrupt critical brain regions involved in autism. These studies will add to our understanding of the origins of autism and may suggest novel, immune-based measures for its diagnosis, treatment, and prevention. Evaluation of Intestinal Inflammation and Carbohydrate Digestion in Children with Autistic Spectrum Disorders and the Effect of Anti-Inflammatory Therapy on their Behavior Rafail I. Kushak, Ph.D., Dr. Sc., Massachusetts General Hospital (Pilot Research Award) Gastrointestinal disorders such as abdominal pain, diarrhea, constipation, and flatulence may contribute to the behavioral problems observed in children with autism. The effects of intestinal inflammation on neurological disorders experienced by autistic children remains unclear. We will study this problem using recently developed non-invasive tests based on the analysis of two proteins (calprotectin and lactoferrin) found in the stool of children with intestinal inflammation. Since the absorption of biologically active proteins may affect cognitive and behavioral function, these surrogate markers of inflammation will be correlated with intestinal permeability. The study will provide valuable information for understanding the association between gastrointestinal disease and behavioral problems in autistic children. Prevention of Autism Spectrum Disorders by Modulating T Cell Responsiveness David A. Ostrov, Ph.D., University of Florida-College of Medicine (Treatment Award) This proposal aims to prevent autism by the development of drugs that bind to nervous system and immune response proteins. Links between immune system dysfunction and autism suggest that events within the first few years of life offer a brief window of opportunity to intervene with disease progression. The proposed research builds on recent discoveries made as the direct result of the Human Genome Project. A portion of the human genome associated with autism by genetic studies has been identified and provides the basis for the proposed study. The proposed research utilizes the cutting edge techniques to design compounds capable of blocking events that initiate and promote autism spectrum disorders. Immune Phenotypes in Autism Spectrum Disorder Cynthia A. Molloy, M.D., M.S., Cincinnati Children’s Hospital (Pilot Research Award) This research focuses on the association between Autism Spectrum Disorder and the body’s immune responses. Previous studies have suggested that autoimmunity or allergy may be associated with ASD. This study is designed to compare children with ASD to children with other developmental disorders and children with neurotypical development with respect to a history of allergy or family history of autoimmunity. The levels of cytokines, substances in the blood that direct immune responses toward allergy or autoimmunity, will also be measured and compared between children with ASD and controls. Neuroimmune Reactions in the Pathogenesis of Autism Carlos A. Pardo-Villamizar, M.D., Johns Hopkins University School of Medicine (Pilot Research Award) Autism is a complex neurological and behavioral disorder in which the cause remains unknown. The participation of the immune system as a possible factor that determines the presence of autism has been proposed. Immunological reactions are mediated by immune cells such as white blood cells and immunoglobulins that participate in the defense mechanism against infection or other type of injuries to the human body. Under some circumstances, these immunological reactions may produce damage of specific tissues in the body. Our research focuses in the study of immunological changes in the brain of patients with autism. By examining brain tissues obtained from patients with microscopical techniques we are evaluating whether immune reactions such as infiltration of the brain by white blood cells or immunoglobulins are associated with the presence of autism. We are also studying how the supporting cells of the brain, called neuroglial cells, may be affected in autism. This research is relevant to the study of the brain mechanisms that are implicated in the presence of neurological abnormalities observed in autism. Characterization of a Mouse Model for Autism Paul H. Patterson, Ph.D., California Institute of Technology (Pilot Research Award) While autism is usually considered to be a disorder of early childhood, recent behavioral observations and some neuropathological studies argue that the origin of this disease may lie in altered brain development during fetal life. While there is a strong genetic component to this disorder, it is also clear that environmental factors can play a role as well. For instance, there is evidence that viral infection of the mother at the appropriate stage of pregnancy can increase the likelihood of the child getting this disease. In fact, maternal viral infection has been cited as “the principal non-genetic cause of autism” (Ciaranello and Ciaranello, 1995). Moreover, some of the genetic studies suggest that immune dysfunction may contribute to the development of some cases of autism. Such genes could play a role in the viral infection or in the reaction of the mother or the fetus to such an infection. Given this background, and the need for more animal models for autism research, we are exploring the utility of a mouse model involving maternal infection with a virus that infects man and mouse. Thus far, we have found that the adult offspring of infected mothers display striking behavioral abnormalities that are relevant to autism, including increased anxiety in stressful situations, strong reluctance to investigate novel objects, and diminished social interactions. Moreover, we have recently obtained evidence that mice born to infected mothers exhibit a highly localized abnormality in the cerebellum, which is a specific and very common finding in the autistic brain. A Comparative Study Evaluating the Dose-Responsive Effects of Methylmercury and Thimersal on Select Nervous, Immune and Enzyme Parameters Deborah Keil, Ph.D., Medical University of South Carolina (Environmental Factors) Infantile autism (IA) is a neurodevelopmental syndrome found in 1-5 cases of every 10,000 children with boys acquiring this syndrome 3-5 times more than girls. The spectrum of disorders of autism includes a range of impaired development of language and communication, unusual behaviors, and mental retardation. A diversity of pathophysiological effects also exist to include hyperserotoninemia, decreased T-cell proliferative function and activation, increased soluble IL-2 levels in serum, decreased CD8+ cells, decreased NK cells, development of anti-brain autoantibodies, decreased cerebellum volume and Purkinje cell number. Several studies indicate that the etiology of IA is multi-factorial and includes exposure to environmental chemicals. In particular, mercury exposure during infant and child development has been implicated in IA; especially in the case of vaccines containing mercury. Although mercury exposure from vaccines has been implicated in autism, this association has been criticized due to a lack of supportive experimental dose-response data. Thus, the proposed study will assess the possible role of methylmercury (MeHg) and thimerosal (TH) in contributing to the pathophysiology of IA using a mouse model to assess dose-responsive effects in cognitive and physiological parameters that encompass nervous, immune and enzyme pathways. This comparative approach will permit increased understanding of deficits due to MeHg or TH after acute exposure during early developmental stages and facilitate understanding of etiological causes of autism or other neurodevelopmental diseases. Furthermore, this study will also improve our understanding of the health effects attributed to different forms of mercury and contribute to the development of toxicological risk assessment models for detecting environmental contaminants that would adversely impact children’s health. Role of Cytokines in Developmental Neurotoxicity Ellen Silbergeld, Ph.D., University of Maryland School of Medicine (Environmental Factors of Autism) Identifying preventable causes or risk factors for autism is of the highest importance for children's health. Methylmercury exposure has been associated with autism, and is known to cause profound neurobehavioral dysfunctions in children exposed in utero. A hallmark of methylmercury neurotoxicity is the disruption of neural migration, a critically tinled process in which specific nerve cells move to their appropriate locations in brain regions. We hypothesize that methylmercury may interfere with this movement by inhibiting the action of specific molecules released by brain cells during development. These molecules include the cytokines, which are a family of cell signals utilized by the immune system to combat infections. In the brain, there is evidence that these same molecules also direct the movement of nerve cells during development. Since methylmercury interferes with cytokines in the immune system, it is possible that this toxic agent may act in the same way in the brain. This research has implications beyond understanding methylmercury, since autism has also been associated with maternal infections. The response of the brain to infection involves production of anti-inflammatory cytokines, and this response may indirectly affect the development of the brain. Confirmation of the Association and Linkage of HLA Genes in Autism Anthony Torres, M.D., Utah State University (Contracted Research) Numerous immune abnormalities have been noted in subjects with autism. The Reed Warren Memorial Laboratory at Utah State University has reported associations between autism and genes in the human leukoctye antigen (HLA) region on chromosome 6. Besides being the most gene rich region in the human genome, HLA genes encode many proteins with critical immune response functions. More diseases have associations with HLA genes than any other region in the human genome. Recently we have been able to link HLA-DR4 to autism by HLA-typing entire families. The transmission disequilibrium test (TDT) indicates that the probands inherit the HLA-DR4 allele more often from the fathers than would be expected. Linking HLA-DR4 to autism expands out knowledge between the immune system and autism. Our project with Cure Autism Now is very important, as research until this time has been with a limited number of probands and families mainly from Utah. Increasing the HLA database with several hundred additional families through Cure Autism Now and the Autism Genetic Resource Exchange (AGRE) will add significant power to our theory of autoimmune mechanisms in autism. A Study of Behaviors Associated with Fever in Children with Autism Andrew Zimmerman, M.D., Kennedy Krieger Institute (Pilot Research) Evidence from case reports suggests that behavioral improvements in children with autism may be associated with fever onset and may decline toward baseline when the fever subsides. The purpose of this proposal is to investigate the potential association between fever and behavioral changes in children with autism. The overall objective of this study is to increase our understanding of the neurobiology of autism and stimulate future avenues of research and treatment. The Autism Diagnostic Observation Schedule (ADOS) will be performed with children with autism in their homes on three days: 1) when the child has fever 2) one to two days later when the fever is going down, and 3) on the first day the child has not had a fever for a full week. The ADOS targets behaviors related to social interaction and communication. ADOS scores across home visits will be compared to see if behaviors are different during episodes of fevers. ADOS data will also be collected on a similar schedule with children with autism who do not get fevers. Non-autistic siblings of febrile children who also have fevers at the first home visits will provide comparison data as well. Studies of the Relationship Between Autism and Colonization of the Intestinal Tract by Neurotoxigenic Clostridial Species Sydney M. Finegold, M.D., University of California, Los Angeles, VA Medical Center (Bridge Grant) This group has been investigating the possibility that neurotoxin-producing bacteria could cause or significantly contribute to autistic symptoms in a subset of children with autism. Previous qualitative and quantitative analysis of stools indicated that there were differences between the stool flora of children with autism compared to that of control children. They are closing examining the Clostridium species isolated from the stools of children with autism. Using polymerase chain reaction (PCR) they will specifically test these isolates for the production of tetanus neurotoxin. A Double-Blind Placebo-Controlled Crossover Study of the Effects of Intravenous Immunoglobulin (IVIG) in Autism Sudhir Gupta, M.D., University of California, Irvine (Bridge Grant) Autism is a disease of unknown cause. A number of treatment approaches have been used with varied success. A majority of these have been open trials (subject to personal bias). Earlier in an open study we reported that a subset of children with autism show a beneficial effect to the treatment with intravenous immune globulin (IVIG). In order to avoid any bias, we conducted a double-blind, placebo-controlled study to examine the effect of IVIG in autism. Twenty children were enrolled, and the study was divided into phases. In Phase 1, 12 children were randomly assigned with placebo and the other 12 with IVIG. Treatments were given at 4-week intervals for a total of 6 treatments. In Phase 2, those children who were receiving placebo treatments were switched to IVIG treatment, and those receiving IVIG treatment were switched to placebo. During Phase 2, children were treated for 6 treatments as in Phase 1. Psychometric analysis was done using number measurements and a large number of immunological evaluations were also done. Ass a group, there was no significant difference between the effect of placebo and IVIG. Some children did show improvement on IVIG; however the significance of improvement could not be demonstrated because of the small study size. A number of limitations were noted in the design of the study, which may have resulted in not reflecting true beneficial potential of IVIG in autism.