By Ramsey Hachem, M.D.
Washington University School of Medicine Barnes-Jewish Hospital
Division of Pulmonary and Critical Care
December, 2010
Over the past 20 years, lung transplantation has become an accepted treatment for patients with a variety of end-stage lung diseases. Indeed, it has not only improved the quality of life but also prolonged life for most recipients. However, the long-term survival after lung transplantation remains disappointing. Worldwide, the average survival is approximately 5 years, and unfortunately, this has not improved substantially over the past 10 years. Chronic rejection, or bronchiolitis obliterans syndrome, has clearly emerged as the primary obstacle to better long-term outcomes and is the leading cause of death beyond the first year after transplantation. In fact, the average survival after the diagnosis of chronic rejection is only 2 to 3 years. Chronic rejection damages and scars the walls of small airways in the lungs, narrowing their lumens. There is a great number of small airways in the lungs and these have a very large total cross-sectional area. So, each small airway contributes little resistance to airflow and a large proportion may be damaged before symptoms appear, highlighting the importance of frequent pulmonary function testing. Chronic rejection manifests as a decrement in lung function that is often progressive and relentless.
The mainstay of treatment has been directed at intensifying the immunosuppressive regimen. The maintenance immunosuppressive regimen is usually optimized; tacrolimus is substituted for cyclosporine and/or mycophenolate mofetil or sirolimus is substituted for azathioprine. In some cases, when the decrement in lung function is small or slowly progressive, this adjustment alone is sufficient to stabilize lung function. However, in cases where the decrement in lung function is larger or rapid, more intensive treatments are necessary. At our program, a 5 to 7 day course of an anti-lymphocyte globulin preparation is the next step. There are two commercially available preparations; one is derived from horses and the other from rabbits. These preparations are synthesized by immunizing an animal with the human immune cells that can cause rejection. The animal then mounts an immune response against these cells that consists of antibodies, or small immune proteins, directed against human cells. These antibodies are then isolated from the animal and purified for therapeutic use. The results of this treatment for chronic rejection have been variable; some patients have a good response and their lung function stabilizes. Unfortunately, others don’t respond and have a progressive decline in lung function. Photopheresis has emerged as a salvage, or second-line, treatment for chronic rejection at our program.
Photopheresis was initially introduced in the 1980s as a treatment for cutaneous T-cell lymphoma and is currently FDA approved for this indication. Not surprisingly because of the treatment’s effects on lymphocytes, the primary immune cells responsible for rejection, it was soon introduced as a potential therapy in organ transplantation. While photopheresis’s exact mechanism of action remains somewhat unclear, important progress to elucidate this has been made in recent years. A sample of whole blood is removed from the patient and immune cells are separated from red blood cells. Plasma and red blood cells are then returned to the patient. The immune cells remain in the photopheresis machine where they are treated with methoxsalen, which is a photosensitizing agent, and irradiated with ultraviolet light. Upon irradiation with ultraviolet light, methoxsalen disrupts the immune cells’ DNA and results in programmed cell death, or apoptosis. These cells are then returned to the patient’s blood stream. They are then phagocytosed, or eaten, by specialized cells. This results in a state of better graft tolerance. Exactly how this happens and the specific biologic events that lead to this remain unclear. A potential explanation is that the introduction of apoptotic immune cells into the blood stream results in the expansion of regulatory T-cells. These are key cells of the immune system that control or dampen the immune response thereby limiting any collateral damage. As such, they are considered immunosuppressive immune cells. In fact, recent studies suggest that the number of circulating regulatory T-cells is decreased in chronic rejection after lung transplantation. So, expanding these cells’ numbers would probably be advantageous in the setting of rejection.
Unfortunately, there have been very few clinical studies examining the efficacy of photopheresis for lung transplant rejection. However, there are case series that have demonstrated an important benefit. Our program’s experience with photopheresis has been consistently positive. Many patients have seen stabilization in lung function and very few have had adverse effects. The treatment is generally very well tolerated, and the major potential serious complication is a catheter related blood stream infection, although some patients don’t need an indwelling venous catheter.