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SOM Research Projects: Defining the Mechanism of Pregnancy induced arthritis amelioration by RA

Title

Defining the Mechanism of Pregnancy induced arthritis amelioration by RA

Status

Open

Project Description

 

Rheumatoid Arthritis (RA) is a chronic progressive disease that affects approximately 1% of the general population, and many patients do not achieve complete remission or cure with current therapies. Interestingly, nature has an effective treatment for RA—pregnancy. During pregnancy, 75% of women with RA have improvement or remission of their disease, often within the first trimester. Although the mechanism of this pregnancy-induced RA improvement is poorly understood, epidemiologic studies have demonstrated that increased genetic disparity between the mother and fetus correlates with more rapid and sustained RA remission. These studies suggest that increased genetic disparity leads to an enhanced negative regulation of the maternal immune system upon exposure to foreign fetal antigens, thereby leading to more robust arthritis amelioration. T cell activation by antigen presenting cells (APCs) is central to response to foreign antigens as well as arthritis development. Understanding how pregnancy impacts maternal APCs and therefore T cell function will provide insight into the mechanism by which pregnancy suppresses RA development, knowledge that should increase our capacity to manipulate the immune system to treat autoimmune diseases such as RA.  Mechanistic investigations of fetal tolerance and arthritis amelioration in early pregnancy are not possible in humans. Thus, we have developed a model of pregnancy-induced arthritis amelioration using SKG mice. During pregnancy, systemic maternal APCs encounter fetal antigen that is released as apoptotic trophoblast fragments from the placenta into the maternal circulation. Acquisition of apoptotic cell fragments by APCs can lead to an anti-inflammatory and tolerogenic phenotype. Thus, we hypothesize that acquisition of apoptotic trophoblast fragments by specific maternal APC subsets leads to the development of an anti-inflammatory and tolerogenic microenvironment that is a critical early event in the induction of arthritis amelioration by pregnancy. The test this hypothesis and define the mechanism of arthritis amelioration by pregnancy in this model we will perform the studies outlined in the following specific aims: Aim 1. To identify the maternal APCs that acquire fetal antigen in pregnant SKG mice and determine if they have a tolerogenic phenotype. Aim 2. To determine if trophoblast apoptotic fragments can simulate the immunologic changes of pregnancy and treat arthritis. The long-term goal of these studies will be to develop ways to manipulate APC development and/or function as novel treatments for autoimmune disease. Defining the mechanism by which pregnancy leads to the reestablishment of self-tolerance in SKG mice could elucidate general properties of the immune system that can be manipulated to treat not only RA, but potentially other autoimmune conditions. 

 

Mentor Name

Dragone, Lenny

Mentor Location

National Jewish Health 1400 Jackson Street Rm K1026A

Mentor Contact Number

303-398-1351

Mentor Contact Email

Dragonel@NJHealth.org

Specialty

Enter Choice #1

Preceptor Name

 

Student

 

Department

Pediatrics

Funding Department/Program

Rheumatology Grant

Area of Study

Immunology and Autoimmune Diseases

Populations

Pregnant Woman

Method(s)

Animal Models

Disease or Symptom

Arthritis; Pregnancy

Faculty/Lab Website

http://www.nationaljewish.org/research/programs-depts/pediatrics/labs/dragone/

Display on public listings?

Yes

Attachments

Created at 7/3/2012 2:09 PM by Watts, Katie
Last modified at 8/23/2012 11:32 AM by Watts, Katie