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

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

Antígens menors d'histocompatibilitat en el trasplantament al·logènic de progenitors hematopoètics. Modulació de la resposta en funció del genotip CTLA-4

Minor histocompatibility antigens (mHAgs) are peptides derived from polymorphic intracellular proteins that can be recognized in an allogeneic setting by the donor T-lymphocytes leading to the appearance of graft-versus-host disease (GvHD); however, the correlation between mHAgs and this complication is a matter of debate. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with GvHD or relapse after allogeneic transplant. There are no studies exploring if these polymorphisms may modulate the ability of the immune system to develop responses in the presence of a specific antigen; and nor studies regarding the effect of CTLA-4 polymorphisms on alloimmune recognition when the allogeneic hematopoietic stem cell transplant (allo-HSCT) is performed with exhaustive T cell depletion through CD34-positive selection (allo- HSCT-CD34), where the immune response will depend on the newly generated T cells from the infused stem. Our hypothesis was that mHAgs disparities have an impact in clinical outcome after allo-HSCT from sibling donor; that the CTLA-4 genotype of the donor may modulate the ability of the allogeneic T lymphocytes to respond in front of mHAg mismatches, even when the graft is T cell depletedEls antígens menors d’histocompatibilitat (AgsmH) són pèptids precedents de proteïnes polimòrfiques endògenes que poden ser reconegudes en un context al·logènic pels limfòcits T del donant, donant lloc al desenvolupament de malaltia d’empelt contra l’hoste (MECH); tot i així, la correlació entre els AgsmH i l’aparició d’aquesta complicació és encara tema de debat. Els polimorfismes del gen CTLA-4, han estat relacionats amb malalties autoimmunitàries, predisposició a recaigudes de leucèmies, i amb MECH i recidives post-trasplantament de progenitors hematopoètics (al·lo-TPH). La hipòtesi del present treball és que les disparitats en antígens menors d’histocompatibilitat tenen un impacte en el resultat clínic de trasplantament al·logènic a partir d’un germà HLA-idèntic; i que el genotip de CTLA-4 dels limfòcits T del donant podrien estar modulant la resposta immunitària davant d’aquestes disparitats, inclús, quan el pacient rep un empelt lliure de limfòcits T per selecció positiva de CD34

Antígens menors d'histocompatibilitat en el trasplantament al·logènic de progenitors hematopoètics. Modulació de la resposta en funció del genotip CTLA-4

Minor histocompatibility antigens (mHAgs) are peptides derived from polymorphic intracellular proteins that can be recognized in an allogeneic setting by the donor T-lymphocytes leading to the appearance of graft-versus-host disease (GvHD); however, the correlation between mHAgs and this complication is a matter of debate. Polymorphisms on the CTLA-4 gene have been previously associated with autoimmune diseases, predisposition to leukemic relapse, and with GvHD or relapse after allogeneic transplant. There are no studies exploring if these polymorphisms may modulate the ability of the immune system to develop responses in the presence of a specific antigen; and nor studies regarding the effect of CTLA-4 polymorphisms on alloimmune recognition when the allogeneic hematopoietic stem cell transplant (allo-HSCT) is performed with exhaustive T cell depletion through CD34-positive selection (allo- HSCT-CD34), where the immune response will depend on the newly generated T cells from the infused stem. Our hypothesis was that mHAgs disparities have an impact in clinical outcome after allo-HSCT from sibling donor; that the CTLA-4 genotype of the donor may modulate the ability of the allogeneic T lymphocytes to respond in front of mHAg mismatches, even when the graft is T cell depletedEls antígens menors d’histocompatibilitat (AgsmH) són pèptids precedents de proteïnes polimòrfiques endògenes que poden ser reconegudes en un context al·logènic pels limfòcits T del donant, donant lloc al desenvolupament de malaltia d’empelt contra l’hoste (MECH); tot i així, la correlació entre els AgsmH i l’aparició d’aquesta complicació és encara tema de debat. Els polimorfismes del gen CTLA-4, han estat relacionats amb malalties autoimmunitàries, predisposició a recaigudes de leucèmies, i amb MECH i recidives post-trasplantament de progenitors hematopoètics (al·lo-TPH). La hipòtesi del present treball és que les disparitats en antígens menors d’histocompatibilitat tenen un impacte en el resultat clínic de trasplantament al·logènic a partir d’un germà HLA-idèntic; i que el genotip de CTLA-4 dels limfòcits T del donant podrien estar modulant la resposta immunitària davant d’aquestes disparitats, inclús, quan el pacient rep un empelt lliure de limfòcits T per selecció positiva de CD34

Donor CTLA-4 Genotype Modulates the Immune Response to Minor Histocompatibility Antigen Mismatches.

Minor histocompatibility antigen (miHA) mismatches have been related to graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, but this association remains controversial due to the lack of consistency in the results obtained by different groups. The CTLA-4 genotype of the donor has been reported to be relevant in the appearance of acute GVHD. We explored the effect of the donor's CTLA-4 genotype in the incidence of acute GVHD associated with HA-1, HA-8, or H-Y miHA mismatches in a large cohort of 1295 patients receiving an allogeneic transplant from an HLA-identical sibling donor. The incidence of acute GVHD was higher if the donor and recipient were mismatched for HA-1, HA-8, or H-Y, but only when the donor had the CTLA-4 rs231775 AA genotype (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.27 to 3.75; P = .005; HR, 2.11, 95% CI, 1.06 to 4.18; P = .033; and HR, 1.50; 95% CI, 1.05 to 2.15; P = .025, respectively). In contrast, this increased risk of developing acute GVHD was not found when the donor presented the CTLA-4 rs231775 AG or GG genotypes. We conclude that the immune response to specific miHA mismatches is modulated by the CTLA-4 genotype of the donor

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.

Journal Article; Research Support, Non-U.S. Gov't;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.This work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI08/1463, PI11/00708, PI14-01731 and RD12/0036/0061, co-financed by ERDF (FEDER) Funds from the European Commission, the Fundación LAIR and Asociación Madrileña de Hematología y Hemoterapia (AMHH). ISCIII-FIS grants PI01-3624, PI08- 36173 and The Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM).Ye

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

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

Univariate and multivariate analysis for variables potentially associated with the development of grade III-IV aGvHD.

<p>ALL: acute lymphoblastic leukemia; AML acute myeloid leukemia; MDS: myelodysplastic syndromes; MM: multiple myeloma; CML: chronic myeloid leukemia; SCT: stem cell transplantation; TBI: total body irradiation.</p><p>* p<0.05</p><p>Univariate and multivariate analysis for variables potentially associated with the development of grade III-IV aGvHD.</p

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.

<p>The (GT)₁₅ allele produces significantly higher expression of the FOXP3 gene than the (GT)₁₆ allele.</p

Influence of the genotype of the donor for the polymorphism (GT)_n in the promoter/enhancer of <i>FOXP3</i> on the outcome of allo-SCT.

<p><b>(A)</b> Cumulative incidence of grade III-IV GVHD. <b>(B)</b> Cumulative incidence of relapse. <b>(C-D)</b> Kaplan-Meier curves of event free survival (B) and overall survival (C).</p

Univariate analysis of the association between the presence of FOXP3 short alleles in the donor and the development of post-SCT complications.

<p>aGVHD: acute graft versus host disease; cGVHD: chronic GVHD.</p><p>(1)Seventeen patients died from infections. Data available for 12 patients, all of them due to bacterial infections, 5 died during the first year (range 2–10 months) and 7 died beyond the first year (range 15–48 months).</p><p>* p<0.05</p><p>Univariate analysis of the association between the presence of FOXP3 short alleles in the donor and the development of post-SCT complications.</p