Silverman Laboratory Research Overview
Dr. Silverman launched his research program at CHOP in 2016 to study the long-term impacts of early-life interactions between commensal microbes and the developing immune system. His research accomplishments leverage knowledge of how these interactions with the immune system could prevent autoimmunity.
A growing lab team is working on four lines of investigation:
- Early-life microbial and genetic protection from T1D
- Modeling early-life host microbiome interaction using the first gnotobiotic mouse model of the pediatric microbiome (PedsCom)
- Defining the microbiome and immune system response to commensal microbes in patients with selective IgA deficiency
- Leveraging the host antibody responses to screen for immunomodulatory microbes using microbial flow cytometry coupled with metagenomic sequencing
This ongoing project aims to discover the mechanisms by which the host immune system impacts the development of commensal microbiota, and further how commensal microbes educate the immune system to prevent autoimmunity. Exploring the development and antigen-specificity of microbe-induced regulatory T-cells is an area of focus. Modeling of HLA class II dominant protection from T1D supports the lab’s long-term goal of developing early-life microbiota-based therapies to prevent T1D in humans.
A gnotobiotic mouse model with a small, defined community is a powerful tool to study the complex and dynamic host-microbiota interactions. However, the currently available consortia (e.g. Altered Schaedler’s Flora) were not designed to model the unique composition and function of the pediatric microbiome. The lab developed a simplified community of bacteria derived from pre-weaning mice that recapitulates the composition and function of the early-life microbiome.
The Silverman Lab recruited 16 families with one child with selective IgA deficiency and one healthy control. The lab uses fecal samples to define the impact of IgA deficiency on the intestinal microbiome composition. Further, the lab team predicts that these patients will have poor intestinal barrier function resulting in microbial translocation and induction of a systemic immune response including elevated IgG antibody response against commensal microbes. The lab developed a technique called mFLOW-SEQ to assess the degree of anti-commensal antibody binding and to identify the specific microbes inducing this systemic response.
For this project, the lab uses diabetes-susceptible NOD and diabetes-resistance Eα16/NOD mice to identify fecal microbes that specifically induce a systemic IgG response in Eα16/NOD compared to NOD mice. Candidate immunomodulatory microbes are then introduced into germfree NOD and Eα16/NOD mice and assessed for induction of regulatory T cells and development of autoimmune diabetes.