The Genotype of the Donor for the (GT)n Polymorphism in the Promoter/Enhancer of FOXP3 Is Associated with the Development of Severe Acute GVHD but Does Not Affect the GVL Effect after Myeloablative HLA-Identical Allogeneic Stem Cell Transplantation.

Víctor Noriega,Ildefonso Espigado,Noemí Sánchez-Hernández,Carlos Solano,Mi Kwon,David Gallardo,Marjorie Pion,Carolina Martínez-Laperche,Ismael Buño,Beatriz Martín-Antonio,Vicent Guillem,Pascual Balsalobre,Rafael Rojas-Contreras,Elena Buces,Milagros González-Rivera,Anna Bosch-Vizcaya,Rafael De La Cámara,Jorge Gayoso,Leyre Bento,Antonio Jiménez-Velasco,Salut Brunet,José Luis Díez-Martín ,Antònia Sampol ,José Nieto ,Marcos González ,Carmen Martı́nez ,Álvaro Urbano-Ispízua ,Juan Carlos Vallejo ,David Serrano

doi:10.1371/journal.pone.0140454

Abstract

The FOXP3 gene encodes for a protein (Foxp3) involved in the development and functional activity of regulatory T cells (CD4+/CD25+/Foxp3+), which exert regulatory and suppressive roles over the immune system. After allogeneic stem cell transplantation, regulatory T cells are known to mitigate graft versus host disease while probably maintaining a graft versus leukemia effect. Short alleles (≤(GT)15) for the (GT)n polymorphism in the promoter/enhancer of FOXP3 are associated with a higher expression of FOXP3, and hypothetically with an increase of regulatory T cell activity. This polymorphism has been related to the development of auto- or alloimmune conditions including type 1 diabetes or graft rejection in renal transplant recipients. However, its impact in the allo-transplant setting has not been analyzed. In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08–0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients.

Highlights

Allogeneic stem cell transplantation is nowadays the therapy of choice for several neoplastic and non-neoplastic diseases [1]
In the present study, which includes 252 myeloablative HLA-identical allo-transplants, multivariate analysis revealed a lower incidence of grade III-IV acute graft versus host disease (GVHD) in patients transplanted from donors harboring short alleles (OR = 0.26, CI 0.08–0.82, p = 0.021); without affecting chronic GVHD or graft versus leukemia effect, since cumulative incidence of relapse, event free survival and overall survival rates are similar in both groups of patients
Donor versus recipient immune reactions harbor a beneficial effect since they mediate the immunological eradication of residual tumor cells, in the context of the so called graft versus leukemia (GVL) effect [3]

Summary

Introduction

Allogeneic stem cell transplantation (allo-SCT) is nowadays the therapy of choice for several neoplastic and non-neoplastic diseases [1]. Increased numbers of functional Tregs are known to lead to GVHD mitigation [9,10,11,12], an effect that is not necessarily associated with a decrease in the anti-tumor activity (GVL) of the allogeneic graft. This is still an open issue, since some authors have described attenuation of GVHD together with preservation of GVL mediated by Tregs [13,14], while others reported increased incidence of relapse in such cases [15]

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Results