Abstract
Regulatory T (Treg) cells are essential to maintain immune homeostasis in the intestine and Treg cell dysfunction is associated with several inflammatory and autoimmune disorders including inflammatory bowel disease (IBD). Efforts using low-dose (LD) interleukin-2 (IL-2) to expand autologous Treg cells show therapeutic efficacy for several inflammatory conditions. Whether LD IL-2 is an effective strategy for treating patients with IBD is unknown. Recently, we demonstrated that LD IL-2 was protective against experimental colitis in immune humanized mice in which human CD4+ T cells were restricted to human leukocyte antigen (HLA). Whether HLA restriction is required for human Treg cells to ameliorate colitis following LD IL-2 therapy has not been demonstrated. Here, we show that treatment with LD IL-2 reduced 2,4,6-trinitrobenzensulfonic acid (TNBS) colitis severity in NOD.PrkdcscidIl2rg-/- (NSG) mice reconstituted with human CD34+ hematopoietic stem cells. These data demonstrate the utility of standard immune humanized NSG mice as a pre-clinical model system to evaluate therapeutics targeting human Treg cells to treat IBD.
Highlights
inflammatory bowel disease (IBD) is a chronic relapsing and remitting disorder broadly classified as either Crohn’s disease (CD) or ulcerative colitis (UC) [1,2,3]
We reported that LD IL-2 may be an effective therapy to treat IBD based on our results whereby LD IL-2 induced human Treg cell expansion and attenuated experimental colitis in immune humanized NSG mice expressing human human leukocyte antigen (HLA)-DQ8 in a setting devoid of murine MHCII [28]
While there was no difference in mortality between the LD IL-2 treated or PBS treated groups (Figure 1B), humanized NSG mice treated with LD IL-2 exhibited accelerated recovery from trinitrobenzensulfonic acid (TNBS)-induced weight loss compared to mice treated with PBS as a control (P < 0.05) (Figure 1C)
Summary
IBD is a chronic relapsing and remitting disorder broadly classified as either Crohn’s disease (CD) or ulcerative colitis (UC) [1,2,3]. Over 1.4 million individuals are afflicted with IBD in the United States alone, carrying an annual economic burden of nearly $30 billion and an estimated 6–8 million patients world-wide [4,5,6,7]. Dysfunctional regulatory mechanisms of the immune system can trigger disease onset or exacerbate IBD. Genome-wide association studies have identified polymorphisms that confer increased risk for IBD with many occurring to genes involved in immune regulation or host defense [9, 10]. The molecular mechanisms driving IBD are not fully understood [10,11,12,13]
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