Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
A Chimeric Human-Mouse Model of Sjogren's Syndrome.
Young, Nicholas, Friedman, Alexandra, Jarjour, Wael N.
Sjogren's Syndrome (SjS) is a chronic autoimmune disorder that results in the persistent inflammation of moisture producing glands. In addition to the lacrimal and salivary gland response, systemic inflammation is also observed to different extents. Despite recent advances in the understanding of this disease, the pathogenic mechanisms remain to be elucidated. Although animal models have been useful in characterizing some disease aspects, an ideal model for early drug discovery is not available.
In this work, peripheral blood mononuclear cells (PBMCs) from healthy subjects and patients with SjS were isolated and injected into immuno-incompetent mice. This transgenic mouse strain is commonly known as NOD scid gamma (NSG) and can not produce functional T cells, B cells, and NK cells due to several induced mutations. Moreover, this mouse has been shown to have more successful engraftment of PBMCs than any other strain. Before initial injection, PBMCs from SjS patients and healthy controls were characterized though flow cytometry with markers directed against major cell subtypes. Upon euthanization, tissue from multiple organs was harvested and heparinized blood was collected for additional cytometric analysis.
Isolated PBMCs from SjS patients were found to contain approximately 65% CD3+ T cells, with approxiametely 55% being CD4+ and 8% CD8+. Monocytes (12%), NK cells (3%), and B cells (7%) were also detected in these samples. Isolated PBMCs were then adoptively transferred into NSG mice. H&E stains of tissues from SjS adoptive transfers revealed a dramatic multi-organ inflammatory response which pronounced infiltrate observed in the lacrimal and salivary glands. Tissue sections of mice transferred with healthy PBMCs showed significantly less infiltrate into these target organs. Interestingly, flow cytometry of the blood collected showed a slightly decreased presence in both CD3+/CD4+ and CD3+/CD8+ cells. However, no monocytes, NK cells, and B cells of human origin were detected. When the salivary and lacrimal glands of mice transferred with SjS PBMCs were examined further with immunohistochemistry (IHC), the infiltrate consisted largely of CD4+ cells with some CD8+ cells present. Notably, B cells were also detected in the infiltrate of these glands, but to a lesser extent. The localization of inflammation to the lacrimal and salivary gland targets may explain the presence of B cells in these organs, while not found using flow cytometry.
This adoptive transfer model of SjS uses PBMCs isolated from patients and displays pronounced target organ infiltrate. Continued efforts with this model will characterize the inflammatory response further, both in cellular infiltrate and organ involvement, and optimize experimental conditions. Ultimately, this novel chimeric human-mouse model using primary human SjS cells will offer a unique experimental environment in which to test therapeutics and investigate disease pathology.
To cite this abstract, please use the following information:
Young, Nicholas, Friedman, Alexandra, Jarjour, Wael N.; A Chimeric Human-Mouse Model of Sjogren's Syndrome. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :496