Exercise Benefits in Chronic Graft versus Host Disease

A Murine Model Study

Carmen Fiuza-luces; Luisa Soares-miranda; ÁFrica Gonza; Lez-Murillo; Jesús Martínez Palacio; Isabel Colmenero; Fernando Casco; Gustavo J. Melén; Aitor Delmiro; María Morán; Manuel Ramírez; Alejandro Lucia

Disclosures

Med Sci Sports Exerc. 2013;45(9):1703-1711. 

In This Article

Abstract and Introduction

Abstract

Introduction: Chronic graft versus host disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation that generates considerable morbidity and compromises the physical capacity of patients. We determined the effects of an exercise training program performed after allogeneic hematopoietic stem cell transplantation on clinical and biological variables in a minor histocompatibility antigen–driven murine model of cGVHD treated with cyclosporine A.

Methods: Recipient BALB/C female mice (age 8 wk) received bone marrow cells and splenocytes from donor B10.D2 male mice and were randomly assigned to an exercise ( n
= 11) or control group ( n = 12). For approximately 11 wk after transplant, the exercise group completed a moderate-intensity treadmill program. Variables assessed were clinical severity scores, survival, physical fitness, cytokine profile, immune cell reconstitution, molecular markers of muscle exercise adaptations, and histological scores in affected tissues.

Results
: Exercise training increased survival ( P = 0.011), diminished total clinical severity scores ( P = 0.002), improved physical fitness ( P
= 0.030), and reduced blood IL-4 and tumor necrosis factor [alpha] levels ( P
= 0.03), while increasing circulating B220 ( P
= 0.008) and CD4 lymphocytes ( P
= 0.043).

Conclusions
: A moderate-intensity exercise program that mimics widely accepted public health recommendations for physical activity in human adults was well tolerated and positive effects on survival as well as on clinical and biological indicators of cGVHD.

Introduction

Recent advances in allogeneic hematopoietic stem cell transplantation (allo-HSCT) have led to an expanding population of long-term survivors, many of whom suffer severe side effects, particularly those related to graft versus host disease (GVHD).[13,20] GVHD encompasses several clinical and histological manifestations caused by activated donor T cells interacting with tissue antigens in the immunosuppressed host.[13] In the acute disease form (aGVHD), exacerbated inflammation leads to lesions in skin, liver, lungs, and the gastrointestinal tract, whereas virtually any organ can be affected in the chronic form (cGVHD).[40] The latter characteristically presents as autoimmune and alloimmune deregulation and a preferential cytokine production pattern linked to CD4+ T helper 2 cells (Th2).[36] cGVHD occurs in 30%–65% of allo-HSCT recipients and shows a 5-yr mortality rate of 30%–50% mainly due to immune deregulation and opportunistic infections.[5] In addition, this disease can be highly debilitating and lead to a poor health state, considerably impairing patients' quality of life and physical functioning.[8,16,22] Once the disease has developed, immunosuppressive drug treatment is the only current therapeutic option,[11] yet the likelihood of a good response decreases with the severity of disease.[26] When successful, survivors have to live with treatment side effects, particularly muscle toxicity and an increased risk of infections, which further deteriorates their health and physical capacity.[13,30]

There is strong evidence supporting a broad range of therapeutic benefits associated with regular, moderate-intensity aerobic exercise, including decreased systemic inflammation and improved immune function.[6] Despite numerous studies addressing the effects of exercise in human allo-HSCT recipients, no study has specifically examined the effects of exercise on cGVHD. To the best of our knowledge, only one previous study has assessed the effects of exercise in a murine GVHD model with no immunosuppressive treatment.[14] We hypothesized that adding an exercise intervention to the standard immunosuppressive therapy for GVHD could improve the clinical course of the disease and survival while minimizing impaired functional capacity with no harmful effects on immune function. Our study was designed 1) to assess the effect of an exercise program on the clinical course of the disease (severity), survival, and physical capacity (primary study outcomes) in mice with cGVHD receiving standard immunosuppressive treatment (cyclosporine A) compared with a control, nonexercise cGVHD group receiving the same drug; and 2) to evaluate the effects of this intervention on inflammatory markers, immune reconstitution, skeletal muscle molecular adaptations to exercise, and histological/clinical state of target organs of the disease (secondary outcomes).

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