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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

Influence of the genotype of the donor for the polymorphism (GT)n in the promoter/enhancer of FOXP3 on the outcome of allo-SCT.(A) Cumulative incidence of grade III-IV GVHD. (B) Cumulative incidence of relapse. (C-D) Kaplan-Meier curves of event free survival (B) and overall survival (C).
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pone.0140454.g002: Influence of the genotype of the donor for the polymorphism (GT)n in the promoter/enhancer of FOXP3 on the outcome of allo-SCT.(A) Cumulative incidence of grade III-IV GVHD. (B) Cumulative incidence of relapse. (C-D) Kaplan-Meier curves of event free survival (B) and overall survival (C).

Mentions: The genotype of the recipient for the (GT)n polymorphism did not influence SCT outcome (data not shown) supporting previous observations [11] that showed that the amount of Tregs in the donors influenced SCT outcomes. Indeed, as expected from the reported observations mentioned above, the presence of short alleles in the donor was associated with a lower incidence of grade III-IV acute GVHD with statistically significant association (OR = 0.36, CI = 0.16–0.82, p = 0.016; Table 2). After multivariate analysis introducing all potentially confounding variables (Table 3), the presence of short alleles in the donor remained as an independent protective factor for the development of grade III-IV acute GVHD (OR = 0.26, CI = 0.08–0.82, p = 0.02). Total body irradiation (TBI) used within the conditioning regimen for ALL patients has shown to be associated with the development of GVHD [28] and these two factors (ALL and TBI) are also identified in the present study (Table 3). Additionally, CI of grade III-IV acute GVHD was significantly lower in patients transplanted from short allele donors (CI 100 days 8.3% vs. 20.7%, p = 0.016, Fig 2A). On the other hand, no significant association was observed for moderate-severe chronic GVHD (OR = 1.1, CI = 0.56–2.19, p = 0.86; Table 2).


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)

Influence of the genotype of the donor for the polymorphism (GT)n in the promoter/enhancer of FOXP3 on the outcome of allo-SCT.(A) Cumulative incidence of grade III-IV GVHD. (B) Cumulative incidence of relapse. (C-D) Kaplan-Meier curves of event free survival (B) and overall survival (C).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140454.g002: Influence of the genotype of the donor for the polymorphism (GT)n in the promoter/enhancer of FOXP3 on the outcome of allo-SCT.(A) Cumulative incidence of grade III-IV GVHD. (B) Cumulative incidence of relapse. (C-D) Kaplan-Meier curves of event free survival (B) and overall survival (C).
Mentions: The genotype of the recipient for the (GT)n polymorphism did not influence SCT outcome (data not shown) supporting previous observations [11] that showed that the amount of Tregs in the donors influenced SCT outcomes. Indeed, as expected from the reported observations mentioned above, the presence of short alleles in the donor was associated with a lower incidence of grade III-IV acute GVHD with statistically significant association (OR = 0.36, CI = 0.16–0.82, p = 0.016; Table 2). After multivariate analysis introducing all potentially confounding variables (Table 3), the presence of short alleles in the donor remained as an independent protective factor for the development of grade III-IV acute GVHD (OR = 0.26, CI = 0.08–0.82, p = 0.02). Total body irradiation (TBI) used within the conditioning regimen for ALL patients has shown to be associated with the development of GVHD [28] and these two factors (ALL and TBI) are also identified in the present study (Table 3). Additionally, CI of grade III-IV acute GVHD was significantly lower in patients transplanted from short allele donors (CI 100 days 8.3% vs. 20.7%, p = 0.016, Fig 2A). On the other hand, no significant association was observed for moderate-severe chronic GVHD (OR = 1.1, CI = 0.56–2.19, p = 0.86; Table 2).

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