Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction

Chronic lung rejection, also called chronic lung allograft dysfunction (CLAD), remains the major hurdle limiting long-term survival after lung transplan-tation, and limited therapeutic options are available to slow the progressive decline in lung function. Most in-terventions are only temporarily effective in stabilizing the loss of or modestly improving lung function, with disease progression resuming over time in the majority of patients. Therefore, identification of effective treat-ments that prevent the onset or halt progression of CLAD is urgently needed. As a key effector cell in its pathophysiology, lymphocytes have been considered a therapeutic target in CLAD. The aim of this review is to evaluate the use and efficacy of lymphocyte depleting and immunomodulating therapies in progressive CLAD beyond usual maintenance immunosuppressive strate-gies. Modalities used include anti-thymocyte globulin, alemtuzumab, methotrexate, cyclophosphamide, total lymphoid irradiation, and extracorporeal photophere-sis, and to explore possible future strategies. When considering both efficacy and risk of side effects, ex-tracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation appear to offer the best treatment options currently available for pro-gressive CLAD patients. Significance Statement--Effective treatments to prevent the onset and progression of chronic lung re-jection after lung transplantation are still a major shortcoming. Based on existing data to date, consider-ing both efficacy and risk of side effects, extracorpo-real photopheresis, anti-thymocyte globulin, and total lymphoid irradiation are currently the most viable second-line treatment options. However, it is impor-tant to note that interpretation of most results is ham-pered by the lack of randomized controlled trials.