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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.

Noriega V, Martínez-Laperche C, Buces E, Pion M, Sánchez-Hernández N, Martín-Antonio B, Guillem V, Bosch-Vizcaya A, Bento L, González-Rivera M, Balsalobre P, Kwon M, Serrano D, Gayoso J, de la Cámara R, Brunet S, Rojas-Contreras R, Nieto JB, Martínez C, Gónzalez M, Espigado I, Vallejo JC, Sampol A, Jiménez-Velasco A, Urbano-Ispizua A, Solano C, Gallardo D, Díez-Martín JL, Buño I, Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GET - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

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.

No MeSH data available.


Related in: MedlinePlus

Results of the luciferase assays performed to test influence of the number of repeats in the (GT)n microsatellite polymorphism on the expression of the FOXP3 gene.The (GT)15 allele produces significantly higher expression of the FOXP3 gene than the (GT)16 allele.
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pone.0140454.g001: Results of the luciferase assays performed to test influence of the number of repeats in the (GT)n microsatellite polymorphism on the expression of the FOXP3 gene.The (GT)15 allele produces significantly higher expression of the FOXP3 gene than the (GT)16 allele.

Mentions: Polymorphisms in certain genes have shown to be implicated in the development of complications after allo-SCT [16,17]. In this context, our aim was to analyze the influence of the (GT)n polymorphism in the FOXP3 gene in the success of allo-SCT. Short alleles for such polymorphism have been shown to promote higher FOXP3 expression and hypothetically an increase of regulatory T cell activity [21]. In our hands, luciferase assays performed to test influence of the number of repeats in the (GT)n microsatellite polymorphism on the expression of the FOXP3 gene showed that the (GT)15 allele produces significantly higher expression of the FOXP3 gene than the (GT)16 allele (Fig 1).


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.

Noriega V, Martínez-Laperche C, Buces E, Pion M, Sánchez-Hernández N, Martín-Antonio B, Guillem V, Bosch-Vizcaya A, Bento L, González-Rivera M, Balsalobre P, Kwon M, Serrano D, Gayoso J, de la Cámara R, Brunet S, Rojas-Contreras R, Nieto JB, Martínez C, Gónzalez M, Espigado I, Vallejo JC, Sampol A, Jiménez-Velasco A, Urbano-Ispizua A, Solano C, Gallardo D, Díez-Martín JL, Buño I, Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group (GET - PLoS ONE (2015)

Results of the luciferase assays performed to test influence of the number of repeats in the (GT)n microsatellite polymorphism on the expression of the FOXP3 gene.The (GT)15 allele produces significantly higher expression of the FOXP3 gene than the (GT)16 allele.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608671&req=5

pone.0140454.g001: Results of the luciferase assays performed to test influence of the number of repeats in the (GT)n microsatellite polymorphism on the expression of the FOXP3 gene.The (GT)15 allele produces significantly higher expression of the FOXP3 gene than the (GT)16 allele.
Mentions: Polymorphisms in certain genes have shown to be implicated in the development of complications after allo-SCT [16,17]. In this context, our aim was to analyze the influence of the (GT)n polymorphism in the FOXP3 gene in the success of allo-SCT. Short alleles for such polymorphism have been shown to promote higher FOXP3 expression and hypothetically an increase of regulatory T cell activity [21]. In our hands, luciferase assays performed to test influence of the number of repeats in the (GT)n microsatellite polymorphism on the expression of the FOXP3 gene showed that the (GT)15 allele produces significantly higher expression of the FOXP3 gene than the (GT)16 allele (Fig 1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain.

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.

No MeSH data available.


Related in: MedlinePlus