New lab findings support development of stem cell treatments for SSc-ILD
PD-1 receptor ID'd as target for slowing disease progression
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Mesenchymal stem cells (MSCs) — a type of regulatory cell found in various tissues — work to reduce lung scarring in systemic sclerosis (SSc) by suppressing the growth of certain immune T-cells that carry the PD-1 receptor, according to a new study.
PD-1 is an immune checkpoint protein receptor found on T-cells that normally functions to prevent overactive immune responses and autoimmunity. In SSc patients, however, a subset of T-cells that carry PD-1 appears to drive disease progression, particularly in SSc-related interstitial lung disease (SSc-ILD), the data suggested.
“These findings highlight PD-1 as a therapeutic target and support the clinical investigation of MSC-based interventions for SSc-ILD,” the researchers wrote.
Their study, “Mesenchymal stromal cells ameliorate systemic sclerosis-interstitial lung disease via PD-1/PD-L1 signalling axis,” was published in the journal RMD Open.
In SSc, or scleroderma, the immune system mistakenly attacks healthy connective tissue, driving excessive scarring (fibrosis) in the skin and, in more severe cases, the internal organs. When scarring affects the lungs, it’s called SSc-ILD.
Investigating mesenchymal stem cells for treating autoimmune diseases
MSCs are a type of stem cell known to calm the immune system by removing overactive immune cells and boosting protective immune cells. As such, MSCs, commonly harvested from bone marrow or umbilical cord, are being investigated as potential treatments for several autoimmune conditions, including SSc.
An earlier Phase 1/2 clinical trial (NCT00962923) conducted by a team in China tested umbilical cord-derived MSCs in 41 people with moderate to severe SSc. Data showed a one-time intravenous, or into-the-vein, infusion of MSCs reduced skin thickness, stabilized or reduced lung fibrosis in those with ILD, and increased five-year survival rates.
However, while MSC therapy shows promise as a treatment for SSc, scientists can’t fully explain how MSCs exert their therapeutic effects.
Recent studies have reported a link between SSc and the PD-1/PD-L1 pathway — an immune checkpoint that acts like a brake to prevent the immune system from becoming overactive and damaging the body’s own tissues.
PD-1 is a receptor found on immune T-cells, while PD-L1 is a matching molecule on healthy tissue. The binding of PD-1 to PD-L1 signals the immune system not to attack the healthy tissue. When a healthy cell is infected or diseased, however, PD-L1 production drops, and without PD-1/PD-L1 binding, the immune system will attack and kill the cell.
Even so, high levels of PD-1 have been found on a subset of T-cells in SSc patients, a finding associated with more active and severe disease, particularly SSc-ILD. Accordingly, blocking the PD-1/PD-L1 pathway in cell and animal models seemed to reduce scar-forming activity.
Using cell, mouse models to determine effects of MSCs
With these findings in mind, the Chinese team wondered whether MSCs exerted their beneficial effects by modulating the PD-1/PD-L1 pathway.
To find out, the researchers first measured the expression (production) of PD-1 in different subsets of T-cells isolated from the blood of 30 SSc patients and 15 healthy volunteers. The results confirmed higher levels of T-cells expressing the receptor CD4 that contained PD-1 among patients with SSc-ILD, compared with controls.
To further explore how these cells contribute to lung fibrosis, the team examined mice with induced SSc-ILD. In these mice, PD-1 was mainly found on immune cells in the lungs, especially CD4-positive T-cells. Over time, these cells steadily increased as lung scarring worsened, suggesting a role in disease progression.
Next, to assess MSC efficacy, the researchers infused MSCs into the tail veins of SSc-ILD mice after disease induction. Compared with untreated mice, those treated with MSCs had much less lung damage, reduced inflammation and scar tissue, and fewer fibrosis-driving cells in the lungs. The activity of key genes linked to scarring was also lowered after MSC treatment.
Importantly, MSCs reduced the number of T-cells carrying PD-1, with or without CD4, the researchers noted.
This study demonstrates that MSCs alleviate and reverse the fibrotic [scarring] process in SSc-ILD.
To test whether the benefits of MSCs in treating lung scarring depended on the PD-1/PD-L1 pathway, the team suppressed PD-L1 production in MSCs. In mice treated with these altered MSCs, lung damage didn’t ease, scar-promoting molecules remained high, as did the overall levels of collagen, the main protein in scar tissue.
These PD-L1-deficient MSCs also failed to suppress overactive immune cells in the lungs, including CD4-positive T-cells that drove lung fibrosis.
“We conclude that a pathway involving PD-L1 is a key contributor to the immunomodulation exerted by MSCs,” the researchers wrote.
To confirm these findings in patients, the scientists grew MSCs with immune cells collected from people with SSc-ILD. This reduced the number of CD4-positive T cells expressing PD-1 by slowing their growth rather than killing them.
“This study demonstrates that MSCs alleviate and reverse the fibrotic process in SSc-ILD by suppressing [CD4-positive, PD-1-positive] T cell proliferation through a PD-L1-dependent mechanism,” the team concluded. “Future studies should validate these mechanisms in larger SSc-ILD cohorts and explore PD-1 expression as a predictive biomarker for MSC responsiveness.”
