Mature B cells accelerate and improve healing of chronic diabetic wounds

John Murphy, MDLinx | October 27, 2017

A single topical application of mature B lymphocytes significantly sped up the healing of acute and chronic wounds in both diabetic and non-diabetic mice—closing the wounds days earlier, improving the quality of regenerated tissue, and reducing scarring in treated mice, reported Harvard researchers in an early online article in Wound Repair and Regeneration.

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B cells speed healing in diabetic ulcers

Topical application of mature B cells accelerated healing of chronic wounds in diabetic mice—a finding that could one day be used to treat diabetic foot ulcers in humans.

“Our demonstration that B lymphocytes…can accelerate wound healing in both healthy and diabetic skin potentially opens up an exciting path to a new treatment for chronic wounds, such as diabetic foot ulcers,” said lead author and research fellow Ruxandra Sîrbulescu, PhD, Massachusetts General Hospital Vaccine and Immunotherapy Center (VIC), Harvard Medical School, Boston, MA.

“Diabetic foot ulcers are the most common cause of non-traumatic major amputations around the world and the costliest type of chronic wound to care for, so an inexpensive and safe way to accelerate healing would have great benefits,” she added.

In a previous study in rats, members of this research team and others found that injecting bone marrow-derived B cells into cardiac tissue damaged by heart attack improved cardiac function.

For this study, the researchers isolated mature naïve B cells—immune cells known for producing antibodies—from the spleens of diabetic and nondiabetic mice. When they tested the B cell treatment, they found that a single topical application resulted in full closure in 43% of chronic diabetic wounds, compared to full closure in only 5% of control wounds treated with saline.

The B cell treatment significantly accelerated acute wound closure by 2 to 3 days in wild-type mice. Wound closure was accelerated by 5 to 6 days using B cells derived from older, obese, diabetic mice that were applied to acute wounds in similarly aged, obese, diabetic mice.

Additionally, the treatment was associated with significantly reduced scar size, increased collagen deposition and maturation, enhanced angiogenesis, and increased nerve growth into and under the healing wound, the researchers reported.

To confirm these effects, the researchers applied equivalent doses of T cells and disrupted B cells. But these didn’t generate any of the pro-healing responses that the live B cells produced.

“The improved healing associated with B cell treatment was supported by significantly increased fibroblast proliferation and decreased apoptosis in the wound bed and edges, altered kinetics of neutrophil infiltration, as well as an increase in TGF-β and a significant reduction in MMP2 expression in wound granulation tissue,” Dr. Sîrbulescu and colleagues reported in their study.

Obtaining B cells to use for wound applications in humans shouldn’t pose a challenge, Dr. Sîrbulescu noted. A single standard blood pheresis procedure could collect enough B cells for several treatments. She and the other researchers are now collaborating with colleagues at the Dana-Farber Cancer Institute, Boston, MA, to define B cell collection procedures for treatment in human patients.

“Having a novel therapeutic that is based on the immediate isolation of a patient’s own cells, with minimal manipulation, will represent an attractive option for the wound care field; and a successful option that accelerates healing would greatly benefit patients, as diabetic ulcers typically need up to a year or more heal,” said the study’s senior author Mark Poznansky, MD, PhD, director of the Massachusetts General Hospital Vaccine and Immunotherapy Center.

Dr. Sîrbulescu added: “While more work is required to elucidate the cellular and molecular mechanisms through which B cells exert their beneficial function in wound healing, we are in the process of obtaining the required regulatory approvals to conduct a first clinical study in patients with diabetic foot ulcers.”

“With adequate funding, we believe we could apply this technology clinically within 1 to 2 years,” she said.

Support for this study was provided by grants from the Trinity Innovation Fund of Holy Cross Hospital, the VIC Innovation Fund, and National Institutes of Health.

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