Research Highlights Mast Cell Involvement in cGVHD

Increased attention is being paid to the involvement of mast cells in fibrosis in chronic graft-versus-host-disease (cGVHD), a complication that threatens the effectiveness of allogeneic hematopoietic stem cell transplantation.

According to a recent review, data suggest mast cells have an important role in tissue homeostasis and wound healing, with mast cell dysregulation potentially leading to fibrotic disease. Notably, aberrant wound healing mechanisms lead to pathological fibrosis in cGVHD. While a better understanding of the cellular etiology causing this condition is warranted, some studies hint mast cells may contribute.

Research exploring the role of mast cells in cGVHD includes in vivo studies of fibrotic mast cells, but more comprehensive studies are needed.

“Expanding on these studies will be important, but there is now a significant body of literature demonstrating that mast cells can be important instigators of fibrotic disease. However, additional data are needed in diverse mouse models to further define their role,” researchers wrote, noting that most of the currently available studies involved B6.Cg-KitW-sh/HNihrJaeBsmGlliJ mast cell-deficient mice.

In their own lab, research has been carried out in mast cell-deficient mice in a murine model of cGVHD. The most commonly used strain of mast cell-deficient mice is those derived from the the C57BL/6 mouse. This led the lab to use the LP/J →C57BL/6 model, which is characterized by progressive and systemic dermal sclerosis. Evidence has previously indicated mast cells may have a hand in these processes.

In the model, the mice were conditioned with 8.5Gy TBI before engraftment of allogeneic donor cells. This revealed wild-type (WT) mice had significantly increased levels of cGVHD symptomology compared with mast cell-deficient (MCD) mice.

According to the researchers, the WT mice had a thicker and denser layer of collagen—a known feature of cGVHD—and exhibited a significant increase in pro-fibrotic gene expression. Meanwhile, the MCD mice exhibited a thin, diffuse, and well-ordered layer of collagen.

Notably, mast cell-dependent dysregulation of chemokine signaling and immune infiltration was found in the skin of the WT mice.

“Genes involved in chemokine signaling along with protein levels of CCL2, CCL3, CCL4, and CCL5 were broadly increased in allo-WT vs. allo-MCd recipients,” researchers wrote.

“We showed that mast cells could produce many of these same chemokines upon activation and that this was modulated by treatment with ibrutinib and ruxolitinib, drugs used clinically to treat steroid-refractory cGVHD. Given the clinical efficacy of these drugs in treatment of cGVHD and other fibrosing diseases, it is possible that modulation of mast cell function and chemokine production may be part of their mechanism of action,” they concluded.

Reference

Strattan E and Hildebrandt GC. Mast cell involvement in fibrosis in chronic graft-versus-host disease. Int J Mol Sci. 2021;22(5):2385. doi:10.3390/ijms22052385