Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT
Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2020.593863/full |
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| author | Mahinbanu Mammadli Weishan Huang Weishan Huang Rebecca Harris Aisha Sultana Ying Cheng Wei Tong Jeffery Pu Teresa Gentile Shanti Dsouza Qi Yang Alaji Bah Avery August Mobin Karimi |
| author_facet | Mahinbanu Mammadli Weishan Huang Weishan Huang Rebecca Harris Aisha Sultana Ying Cheng Wei Tong Jeffery Pu Teresa Gentile Shanti Dsouza Qi Yang Alaji Bah Avery August Mobin Karimi |
| author_sort | Mahinbanu Mammadli |
| collection | DOAJ |
| description | Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment. |
| first_indexed | 2024-12-19T14:43:15Z |
| format | Article |
| id | doaj.art-c0a291f10bb64bf48c6e7ee416cf454c |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-19T14:43:15Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c0a291f10bb64bf48c6e7ee416cf454c2022-12-21T20:17:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-11-011110.3389/fimmu.2020.593863593863Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCTMahinbanu Mammadli0Weishan Huang1Weishan Huang2Rebecca Harris3Aisha Sultana4Ying Cheng5Wei Tong6Jeffery Pu7Teresa Gentile8Shanti Dsouza9Qi Yang10Alaji Bah11Avery August12Mobin Karimi13Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, United StatesDepartment of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, United StatesDepartment of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, United StatesDivision of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDivision of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, United StatesDepartment of Hematology, SUNY Upstate Medical University, Syracuse, NY, United StatesDepartment of Hematology, SUNY Upstate Medical University, Syracuse, NY, United StatesDepartment of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United StatesDepartment of Immunology and Microbial Disease, Albany Medical College, Albany, NY, United StatesDepartment of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, United StatesDepartment of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, United StatesDepartment of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY, United StatesAllogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.https://www.frontiersin.org/articles/10.3389/fimmu.2020.593863/fullGVHD after blood transfusionT cellGvLITK deficiencyEomesodermin (EOMES)JAK-STAT signalling pathway |
| spellingShingle | Mahinbanu Mammadli Weishan Huang Weishan Huang Rebecca Harris Aisha Sultana Ying Cheng Wei Tong Jeffery Pu Teresa Gentile Shanti Dsouza Qi Yang Alaji Bah Avery August Mobin Karimi Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT Frontiers in Immunology GVHD after blood transfusion T cell GvL ITK deficiency Eomesodermin (EOMES) JAK-STAT signalling pathway |
| title | Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT |
| title_full | Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT |
| title_fullStr | Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT |
| title_full_unstemmed | Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT |
| title_short | Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT |
| title_sort | targeting interleukin 2 inducible t cell kinase itk differentiates gvl and gvhd in allo hsct |
| topic | GVHD after blood transfusion T cell GvL ITK deficiency Eomesodermin (EOMES) JAK-STAT signalling pathway |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2020.593863/full |
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