This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Autism is a severe neurodevelopmental disorder that affects 1.5 million people in the United States. The etiology of autism is unknown but there is emerging evidence that autism is associated with abnormal immune responses. In regards to the adaptive immune response (T cell response), autism has been associated with elevations of both Th1 cytokines, often seen in organ specific autoimmune disorders, and Th2 cytokines that are associated with allergic disorders. Elevation of cytokines in both arms of the adaptive response in autism indicates a generalized over-activation of this response A specific subset of T cells is partly responsible for regulating this response. These regulatory CD4+CD25+FOXP3+(Treg) cells inhibit production of Th1 and Th2 cytokines by T effector cells through a mechanism involving interleukin (IL)-10 and transforming growth factor (TGF)-. Both IL-10 and TGF-are decreased in the peripheral blood of children with autism. Based on these findings, we hypothesize that inadequate regulation of T effector cells by Treg cells contributes to the immune dysregulation in children with autism.
Two specific aims have been developed to test this hypothesis.
Aim 1 is to compare the number and activity of Treg cells in peripheral blood of children with autism and age-matched controls. To address this aim we will conduct a case-control study comparing in vitro immune responses of 20 children with autism to responses of normally developing controls matched on age, race, gender and date of study visit. We will isolate Treg (CD4+CD25+brightFOXP3+) cells from periphral blood samples and compare the proportion of Treg cells to total CD4+ cells in cases and controls. We will compare the activity of Tregs by incubating T effector cells with different numbers of Tregs in the presence of plate-bound anti-CD3 and soluble anti-CD28 monoclonal antibodies. Proliferation of T effector cells and production of cytokines interferon-(Th1) and IL-13 (Th2) will be compared in cases and controls.
Aim 2 is to compare the amounts of IL-10 and TGF-produced by Treg cells and the responsiveness of T effector cells to these cytokines in children with autism and age-matched controls. To address this aim we will compare the levels of IL-10 and TGF-from co-cultures of Tregs and T effector cells from cases and controls with and without monoclonal antibodies against IL-10 and TGF-. The objective of this study is to determine the role of Treg cells in the pathway of immune dysregulation in autism. Understanding this mechanism will advance our understanding of the relationship between autism and immune dysfunction. This will provide important clues to the etiology of autism, identify potential immune biomarkers and direct research efforts toward possible immunologic therapies.
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