Stem cell therapy for graft dysfunction in lung transplant

Mayo Clinic researchers have demonstrated the safety and feasibility of stem cell therapy for lung transplant recipients with moderate obstructive chronic lung allograft dysfunction (CLAD). A larger clinical study is planned, which might eventually yield regenerative-medicine options for managing acute or chronic CLAD.

"The primary purpose is to improve lung function, or at least arrest the rate of decline in lung function, in transplant patients with progressive obstructive disease that is refractory to medical therapy," says Cesar A. Keller, M.D., emeritus professor at Mayo Clinic in Jacksonville, Florida.

Although lung transplantation is a life-saving treatment option, chronic rejection is considerably more common than in other solid organ transplants, due to the lungs' continuous exposure to environmental factors. Within five years of lung transplant, 45 percent of recipients develop obstructive CLAD, also known as bronchiolitis obliterans syndrome (BOS) — which has an associated mortality rate ranging from 25 percent to 56 percent. There is no standardized therapeutic protocol for BOS, and the existing therapies have had variable success.

The Mayo Clinic study used allogeneic mesenchymal stem cells, which were infused into nine recipients with moderate BOS who were refractory to standard therapy and weren't candidates for retransplantation. Each patient received a single stem cell infusion and was medically evaluated for evidence of infusion-related adverse events and tolerance of therapy at 24 hours, one week and one month after the procedure.

Among the study's findings:

  • Vital signs and oxygen saturation didn't significantly change during or up to two hours after stem-cell infusion.
  • Gas exchange variables, pulmonary function test results and laboratory values weren't significantly changed after infusion.

Regenerating lung tissue

Mesenchymal stem cells have long been known to regulate the cellular immune system. They suppress T cells and are thought to shift immune response toward an anti-inflammatory, tolerogenic phenotype.

Mesenchymal stem cells also have the capacity to engraft into lung tissue. Once implanted, stem cells can interact with the surrounding microenvironment and are believed to facilitate regeneration of neighboring tissue — by secreting various factors and renewing biologic functions, or by acting directly to support and revive cell function and repair damage.

Intravenously infused cells are naturally trapped in the lung with few cells reaching systemic circulation. "This facilitates the stem cells' access to the pathology site," Dr. Keller says.

He notes that, having established the safety and feasibility of stem-cell infusion for obstructive CLAD refractory to medical therapy, future studies could examine stem-cell therapy for acute graft failure. "Another opportunity might involve the early administration of autologous or allogeneic mesenchymal stem cells after transplant to prevent severe primary graft dysfunction, which is known to be associated with early mortality and late morbidity," Dr. Keller says.

Administering the stem cells early after lung transplant might help reduce the need for heavy immunosuppressive therapy. "That could decrease the high incidence of infectious complications and adverse events associated with calcineurin inhibitors and corticosteroids," Dr. Keller says.

These studies and others are now facilitated by Mayo Clinic's ability to rapidly produce stem cells using an automated bioreactor-based stem cell production platform. The Food and Drug Administration recently allowed this cell manufacturing method to be used in this trial at Mayo Clinic's campus in Florida, representing a major step forward in regenerative medicine research.

The next phase of research will be directed by David B. Erasmus, M.D., M.B., Ch.B., a lung transplant surgeon at Mayo Clinic's campus in Florida, and Abba C. Zubair, M.D., Ph.D., a pathologist at that Mayo Clinic campus. Dr. Zubair was also co-principal investigator with Dr. Keller on the previous study.

For more information

Keller CA, et al. Feasibility, safety, and tolerance of mesenchymal stem cell therapy for obstructive chronic lung allograft dysfunction. Stem Cells Translational Medicine. 2018;7:161.