DNA graphic

Natalia Giltiay, PhD

Research Assistant Professor

University of Washington

Medicine

https://rheumatology.uw.edu/faculty/natalia-giltiay-phd

Anti-BDCA 2-Targeted Therapy for SLE

Our cells store their DNA by wrapping it around proteins called histones. People with lupus show abnormal immune system responses against their own DNA and against histones. She thinks that histones are a little like the substances that cause allergies — they stimulate the immune system inappropriately, but controlled exposure to them may reduce this reaction. Their strategy to prevent these “allergic” reactions involves delivering small bits of self-proteins to key immune cells known as dendritic cells, which control the responses of other immune cells. They have developed molecules known as antibodies that home in on dendritic cells and bring the histone fragments along with them. They hypothesize that exposing dendritic cells to the fragments will curb the immune system reaction against histones, and the new study will test this approach in mice that are prone to lupus. The goal is to apply their work to the development of a new therapy for lupus patients.

 

What this study means to people with lupus

Dr. Giltiay’s team plans to teach the immune system to tolerate the body’s own cells in much the same way that allergy shots curb abnormal reactions to allergens. This novel approach to inducing immune system “tolerance” has never been applied to lupus before and may lead to a new effective treatment.

Lupus is a complex disease characterized by increased production of type I IFNs, activation of autoreactive T and B cells and the production of anti-nuclear autoantibodies. In previous studies we have found that targeting antigens (Ag) by coupling them to an antibody specific for BDCA2, a pDC-specific C-type lectin receptor inhibited T and B cell immune responses while promoting the activation of Ag-specific regulatory T cells (Tregs). We hypothesize that targeting of nuclear Ags to pDCs through BDCA2 can be used to induce Ag-specific tolerogenic immune responses and stop the activation of pathogenic T and B cell in lupus. We have developed a new recombinant anti-human BDCA2 Ab, which can be used to deliver a range of auto-Ags to pDCs in vivo. In our study, we will test if targeting of histone peptides to BDCA2+ pDCs can protect lupus-prone mice from the development of anti-nuclear auto-Abs and promote the activation of Ag-specific Tregs. Since BDCA2 crosslinking also inhibits pDCs’ activation, anti-BDCA2-Ag targeting might be an effective way to suppress disease progression by both inhibiting type I IFN production and promoting Ag-specific immune tolerance. Our study may provide a rationale to bring forward a novel immunotherapy for the treatment of lupus.

Learn and connect with our community!