2020 Gina M. Finzi Memorial Student Fellow
Cleveland Clinic Lerner Research Institute
Project title: Investigation of the differentiation of male and female derived stem cells to pro-inflammatory and anti-inflammatory cells in a chimeric lupus mouse model
Mentor: Trine N. Jorgensen Dept. of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic Foundation Associate Director of Research, Cleveland Clinic Lerner College of Medicine at CWRU
Project Title: Lupus disproportionately affects women compared to men in a 9:1 ratio. Many other autoimmune diseases show a similar tendency towards women. While previous studies have suggested that testosterone may promote an anti-inflammatory response and estrogen may promote pro-inflammatory responses, the mechanisms through which this is accomplished remains unknown.
Our current therapies for lupus rely on conventional disease-modifying anti-rheumatic drugs (eg, azathioprine, methotrexate, mycophenolate mofetil), however, these treatments have variable efficacy and side effect profiles. Newer, more targeted therapies are needed to improve the quality of life of lupus patients. The yet to be determined mechanisms that drive the female predisposition towards autoimmunity pose a promising area of research for the development of new therapies.
Two cell populations of particular interest to our lab include plasmacytoid dendritic cells (pDCs), which have enhanced function in IFN-a production within an estrogen rich environment, and myeloid derived suppressor cells (MDSCs) whose development are driven by testosterone and have immunosuppressive effects. We and others have previously observed apparent roles for either genetic (female vs male hematopoietic stem cell (HSC) dependent) cues, as well as hormonal (estrogen vs testosterone dependent) cues in shifting the activity of these cells. However, the relative role that genetic signaling versus hormonal signaling plays, and the specific pathways through which each function to ultimately lead to the development of lupus is not well understood.
We hypothesize that female hematopoietic stem cells (HSCs) and estrogens together favor the differentiation of pDCs, while male HSCs and testosterone favor differentiation of MDSCs, hence driving autoimmunity in females and less so in males. We aim to tease out the relative roles of both sex hormones and HSCs by using mixed male and female hematopoietic stem cell chimeras with red/green photo-labeled cells.
We will create 1:1 female to male donor chimeras in female or male host lupus mice and determine the subsequent populations and distributions of donor derived pro and anti-inflammatory cells using flow cytometry markers. We will compare our chimera models to female-into-female and male-into-male chimera mice and unmanipulated age-matched mice.
Using this novel method, we will have the advantage of distinguishing between the activity of sex hormones and male and female derived HSCs within the same environment. This work will be extended into a year long project that will also look at the functionality of these cells.
Our research will provide a foundation to clarify the role of sex hormones in lupus, elucidate the intrinsic effect of male or female HSCs, and ultimately expose previously unrecognized mechanisms within the pathogenesis of lupus that will lead to the development of new, highly targeted therapies.