Project 176418

TL1A is a molecule that can stimulate T lymphocytes. In our pilot study, we showed that mice injected with this molecule had severer rheumatoid arthritis (RA). This molecule could increase antibody production, which is a RA-causing factor. We further proved that TL1A was produced in human joints. In an attempt to understand how this molecule causes RA, we generated genetically manipulated mice which do not have the TL1A gene. The objective of this project is to understand how TL1A causes RA. Hypotheses: 1) Local TL1A production in the joints is a component of a vicious circle in aggravating RA. 2) In rheumatoid arthritis, TL1A production in lymphoid organs promotes autoantibody production, which is a cause of the disease. Specific aims 1. To assess whether mice without TL1A gene have reduced severity and penetrance of collagen-induced arthritis (CIA). 2. To study whether a lack of TL1A expression in non-hematopoietic cells would reduce the severity of CIA. 3. To evaluate whether blocking TL1A activity can ameliorate CIA. 4. To investigate whether a lack of TL1A expression results in reduced IL-17 production in RA joints. 5. To understand how TL1A enhances Ab production and germinal center formation. Significance This study will address the question whether TL1A is a novel mediator involved in RA development, and is a possible therapeutic target for the disease.