Lymphocyte Depleting and Modulating Therapies for Chronic Lung Allograft Dysfunction

Abstract

Chronic lung rejection, also called chronic lung allograft dysfunction (CLAD), remains the major hurdle limiting long-term survival after lung transplantation, and limited therapeutic options are available to slow the progressive decline in lung function. Most interventions 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 treatments 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 strategies. Modalities used include anti-thymocyte globulin, alemtuzumab, methotrexate, cyclophosphamide, total lymphoid irradiation, and extracorporeal photopheresis, and to explore possible future strategies. When considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin and total lymphoid irradiation appear to offer the best treatment options currently available for progressive CLAD patients. SIGNIFICANCE STATEMENT: Effective treatments to prevent the onset and progression of chronic lung rejection after lung transplantation are still a major shortcoming. Based on existing data to date, considering both efficacy and risk of side effects, extracorporeal photopheresis, anti-thymocyte globulin, and total lymphoid irradiation are currently the most viable second-line treatment options. However, it is important to note that interpretation of most results is hampered by the lack of randomized controlled trials.

Fig. 1

Overview of main mechanisms of several lymphocyte depleting and/or modulating therapies for CLAD. APC, antigen-presenting cell (e.g., dendritic cell, macrophage, B cell); AZA, azathioprine; Bregs, regulatory B cells; CNI, calcineurin inhibitor; DC, dendritic cell; JAK-I, janus kinase inhibitor; MEK-I, mitogen-activated protein kinase kinase inhibitor; MMF, mycophenolate mofetil; MTX, methotrexate; TNFα-I, tumor necrosis factor alpha inhibitor; Tregs, regulatory T cells. Created with BioRender.com.

Fig. 2

Lymphocyte depleting and/or modulating therapies in CLAD. (A) Suggested treatment algorithm for CLAD based on existing data taking into account the efficacy and risk of side effects as well as some potential safer future options that require more investigation. (B) Overview of features associated with ATG, TLI, and ECP treatment. Which therapeutic option is chosen mainly depends on local resources and patient profile (e.g., risk of infection, CLAD phenotype, rapid versus slow lung function decline) and preferences. AZA, azathioprine; CsA, cyclosporine A; IS, immunosuppressive; L-CsA, liposomal cyclosporine A; MMF, mycophenolate mofetil; TAC, tacrolimus.