Systemic lupus erythematosus (SLE), or simply lupus, is characterized by the production of anti-nuclear autoantibodies (autoAbs) that form immune complexes and induce widespread inflammatory damage including skin rashes, chronic joint pain and arthritis, anemia, inflammation of the heart and lungs and kidney disease. Follicular T helper cell (Tfh) dysregulation is thought to contribute significantly to autoAb production and subsequent tissue damage. Mesenchymal stem cell (MSC) therapy is one promising therapeutic approach for treating for SLE. Indeed, in one recent study, MSC treatment showed positive therapeutic effects in some severe and refractory SLE patients. Further, MSC therapy has been able to prevent SLE-associated abnormalities in experimental models, but results have been variable, possibly due to the origins of the MSCs used. A group of researchers led by Dr. Jeehee Youn of Hanyang University in Seoul, Korea set out to fully evaluate the therapeutic effects of human bone marrow-derived MSCs (hBM-MSCs) in an animal model of SLE and to also examine the effects of hBM-MSC therapy on the pathogenic Tfh numbers and function (Jing et al. 2016).
Why are follicular helper T (Tfh) cells so important in SLE?
Although the environmental and genetic factors that cause SLE have not been fully elucidated, the pathogenic anti-nuclear autoABs found in SLE patients are mainly produced by self-reactive B cells in lymphoid germinal centers (GCs). GCs are where mature B lymphocytes proliferate, undergo antibody class switching and affinity maturation, and, ultimately, differentiate into either plasma cells (PCs) or durable memory B cells that respond to infectious agents. PCs migrate to bone marrow and inflamed tissues where they complete maturation into long-lived PCs that are resistant to immunosuppressive treatments. Tfh cells play a direct role in long-lasting PCs formation by signaling to B cells to undergo antibody class-switching and affinity maturation and supporting their survival. Tfh cells were proposed as disease markers for SLE after high levels of circulating Tfh cell precursors were observed in some SLE patients. Further, increased levels of dysregulated Tfh cells with excessive GC formation, high autoAB titers and organ damage due to chronic inflammation have been observed in both SLE mouse models and SLE patients.
MSCs derived from bone marrow can differentiate into many cells types, including osteoblasts, chrondrocytes, adipocytes and myoblasts. They can modulate T and B lymphocytes, natural killer cells, and dendritic cells via both contact-dependent and independent mechanisms lending to their therapeutic potential in autoimmune disease. In SLE patient studies, MSCs derived from human bone marrow prevented autoAb production, proteinuria and nephritis. In another study, mouse bone marrow-derived MSCs attenuated nephritis. With the knowledge that Tfh cells play an important role in SLE pathology, Dr. Youn's group investigated whether hBM-MSCs affected the activity of pathogenic Tfh cells in a mouse model of SLE.
huBM-MSC treatment delays the onset of kidney nephritis in a mouse model of SLE
New Zealand Black (NZB) and New Zealand White (NZW) F1 hybrid mice (NZBWF1/J, Stock 100008) are widely-used SLE mouse models that, like SLE patients, produce antinuclear antibodies in sufficiently high levels to induce progressive immune complex glomerulonephritis, hemolytic anemia, and proteinuria. Dr. Youn's group infused NZBWF1/J female mice with vehicle or with hBM-MSCs at 17, 19 and 21 weeks of age. Both anti-double-stranded DNA antibody and urinary albumin levels progressively rose from 22-28 weeks in vehicle-treated mice, but such increases were delayed until 30-34 weeks in huBM-MSC-treated mice. Cumulative proteinuria and survival, also, were significantly improved in the huBM-MSC-treated mice compared to vehicle-treated controls. These results suggest that MSC therapy administered before the onset of SLE symptoms could delay the onset and progression of kidney nephritis.
huBM-MSC treatment suppresses auto-antibody production in a mouse model of established SLE
NZBWF1/J female mice also were treated with hBM-MSCs or vehicle after disease onset (at ~28 weeks) once per week for five weeks to determine if MSC therapy could inhibit the progression of an already-established disease. huBM-MSC treatment reduced anti-double-stranded DNA antibody levels, but had no effect on urinary albumin accumulation. These results indicate that MSC therapy could suppress autoAB production in an established disease, but did not prevent proteinuria or the progression of nephritis.
A closer histopathological examination of huBM-treated NZBWF1/J mice revealed:
- Splenomegaly and splenic hypercellularity
- An absence of immune complexes and complement factor C3 in the kidneys (which were observed in vehicle-treated controls)
- Reduced percentages of proliferating kidney glomeruli
- Reduced infiltrates of CD4+T cells and B220+ cells in the kidney
In addition, cellular studies in huBM-treated versus vehicle-treated NZBWF1/J mice revealed:
- Reduced proportions of Tfh cells, their precursors, and germinal center B cells in the spleen
- An increase in the proportion of small versus large germinal centers
- Significantly fewer long-lived PCs in the kidney
By tracking labeled huBM-MSCs after injection, Dr. Youn's team showed that not only do the huBM-MSCs migrate to the liver, bone marrow, spleen, kidney, lymph nodes, brain, and blood, but also that the MSCs remain in the lymphoid system for at least 8 days, long enough to elicit a humoral immune response.
Taken together, these results demonstrate that treatment with huBM-MSCs can significantly attenuate lupus-related nephritis in the NZBWF1/J SLE mouse model. Because huBM-MSC treatment also decreased splenic Tfh cells and precursors, germinal center B cells, PCs, and autoAB production, the data suggest that MSCs improves SLE pathology by targeting the pathogenic Tfh cell functions.