Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates
IntroductionSensitization to donor human leukocyte antigen (HLA) molecules prior to transplantation is a significant risk factor for delayed access to transplantation and to long-term outcomes. Memory T cells and their cytokines play a pivotal role in shaping immune responses, thereby increasing the...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-04-01
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| Series: | Frontiers in Transplantation |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/frtra.2024.1336563/full |
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| author | Sarita Negi Sarita Negi Alissa K. Rutman Chee Loong Saw Steven Paraskevas Steven Paraskevas Steven Paraskevas Steven Paraskevas Jean Tchervenkov Jean Tchervenkov Jean Tchervenkov |
| author_facet | Sarita Negi Sarita Negi Alissa K. Rutman Chee Loong Saw Steven Paraskevas Steven Paraskevas Steven Paraskevas Steven Paraskevas Jean Tchervenkov Jean Tchervenkov Jean Tchervenkov |
| author_sort | Sarita Negi |
| collection | DOAJ |
| description | IntroductionSensitization to donor human leukocyte antigen (HLA) molecules prior to transplantation is a significant risk factor for delayed access to transplantation and to long-term outcomes. Memory T cells and their cytokines play a pivotal role in shaping immune responses, thereby increasing the risk of allograft rejection among highly sensitized patients. This study aims to elucidate the precise contribution of different CD4+ memory T cell subsets to alloreactivity in highly sensitized (HS) kidney transplant recipients.Methods and resultsStimulation of peripheral blood mononuclear cells (PBMC) with various polyclonal stimulating agents to assess non-specific immune responses revealed that HS patients exhibit elevated immune reactivity even before kidney transplantation, compared to non-sensitized (NS) patients. HS patients' PBMC displayed higher frequencies of CD4+ T cells expressing IFNγ, IL4, IL6, IL17A, and TNFα and secreted relatively higher levels of IL17A and IL21 upon stimulation with PMA/ionomycin. Additionally, PBMC from HS patients stimulated with T cell stimulating agent phytohemagglutinin (PHA) exhibited elevated expression levels of IFNγ, IL4 and, IL21. On the other hand, stimulation with a combination of resiquimod (R848) and IL2 for the activation of memory B cells demonstrated higher expression of IL17A, TNFα and IL21, as determined by quantitative real-time PCR. A mixed leukocyte reaction (MLR) assay, employing third-party donor antigen presenting cells (APCs), was implemented to evaluate the direct alloreactive response. HS patients demonstrated notably higher frequencies of CD4+ T cells expressing IL4, IL6 and IL17A. Interestingly, APCs expressing recall HLA antigens triggered a stronger Th17 response compared to APCs lacking recall HLA antigens in sensitized patients. Furthermore, donor APCs induced higher activation of effector memory T cells in HS patients as compared to NS patients.ConclusionThese results provide an assessment of pretransplant alloreactive T cell subsets in highly sensitized patients and emphasize the significance of Th17 cells in alloimmune responses. These findings hold promise for the development of treatment strategies tailored to sensitized kidney transplant recipients, with potential clinical implications. |
| first_indexed | 2024-04-24T12:03:02Z |
| format | Article |
| id | doaj.art-7babce58abef47af8c0054d145c0edbc |
| institution | Directory Open Access Journal |
| issn | 2813-2440 |
| language | English |
| last_indexed | 2024-04-24T12:03:02Z |
| publishDate | 2024-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Transplantation |
| spelling | doaj.art-7babce58abef47af8c0054d145c0edbc2024-04-08T14:13:19ZengFrontiers Media S.A.Frontiers in Transplantation2813-24402024-04-01310.3389/frtra.2024.13365631336563Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidatesSarita Negi0Sarita Negi1Alissa K. Rutman2Chee Loong Saw3Steven Paraskevas4Steven Paraskevas5Steven Paraskevas6Steven Paraskevas7Jean Tchervenkov8Jean Tchervenkov9Jean Tchervenkov10Infectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, CanadaHuman Islet Transplantation Laboratory, McGill University Health Centre, Montréal, QC, CanadaDepartment of Medicine, McGill University, Montréal, QC, CanadaHLA Laboratory, Division of Hematology, McGill University Health Centre, Montréal, QC, CanadaInfectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, CanadaHuman Islet Transplantation Laboratory, McGill University Health Centre, Montréal, QC, CanadaDepartment of Surgery, McGill University, Montréal, QC, CanadaDivision of General Surgery and Multi-Organ Transplant Program, Department of Surgery, McGill University Health Centre, Montréal, QC, CanadaInfectious Diseases and Immunity in Global Health Program, Research Institute of the McGill University Health Centre, Montréal, QC, CanadaDepartment of Surgery, McGill University, Montréal, QC, CanadaDivision of General Surgery and Multi-Organ Transplant Program, Department of Surgery, McGill University Health Centre, Montréal, QC, CanadaIntroductionSensitization to donor human leukocyte antigen (HLA) molecules prior to transplantation is a significant risk factor for delayed access to transplantation and to long-term outcomes. Memory T cells and their cytokines play a pivotal role in shaping immune responses, thereby increasing the risk of allograft rejection among highly sensitized patients. This study aims to elucidate the precise contribution of different CD4+ memory T cell subsets to alloreactivity in highly sensitized (HS) kidney transplant recipients.Methods and resultsStimulation of peripheral blood mononuclear cells (PBMC) with various polyclonal stimulating agents to assess non-specific immune responses revealed that HS patients exhibit elevated immune reactivity even before kidney transplantation, compared to non-sensitized (NS) patients. HS patients' PBMC displayed higher frequencies of CD4+ T cells expressing IFNγ, IL4, IL6, IL17A, and TNFα and secreted relatively higher levels of IL17A and IL21 upon stimulation with PMA/ionomycin. Additionally, PBMC from HS patients stimulated with T cell stimulating agent phytohemagglutinin (PHA) exhibited elevated expression levels of IFNγ, IL4 and, IL21. On the other hand, stimulation with a combination of resiquimod (R848) and IL2 for the activation of memory B cells demonstrated higher expression of IL17A, TNFα and IL21, as determined by quantitative real-time PCR. A mixed leukocyte reaction (MLR) assay, employing third-party donor antigen presenting cells (APCs), was implemented to evaluate the direct alloreactive response. HS patients demonstrated notably higher frequencies of CD4+ T cells expressing IL4, IL6 and IL17A. Interestingly, APCs expressing recall HLA antigens triggered a stronger Th17 response compared to APCs lacking recall HLA antigens in sensitized patients. Furthermore, donor APCs induced higher activation of effector memory T cells in HS patients as compared to NS patients.ConclusionThese results provide an assessment of pretransplant alloreactive T cell subsets in highly sensitized patients and emphasize the significance of Th17 cells in alloimmune responses. These findings hold promise for the development of treatment strategies tailored to sensitized kidney transplant recipients, with potential clinical implications.https://www.frontiersin.org/articles/10.3389/frtra.2024.1336563/fulltransplantationhighly sensitizedsensitizationTh17 cellsalloreactivitymixed leukocyte reaction |
| spellingShingle | Sarita Negi Sarita Negi Alissa K. Rutman Chee Loong Saw Steven Paraskevas Steven Paraskevas Steven Paraskevas Steven Paraskevas Jean Tchervenkov Jean Tchervenkov Jean Tchervenkov Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates Frontiers in Transplantation transplantation highly sensitized sensitization Th17 cells alloreactivity mixed leukocyte reaction |
| title | Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates |
| title_full | Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates |
| title_fullStr | Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates |
| title_full_unstemmed | Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates |
| title_short | Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates |
| title_sort | pretransplant th17 dominant alloreactivity in highly sensitized kidney transplant candidates |
| topic | transplantation highly sensitized sensitization Th17 cells alloreactivity mixed leukocyte reaction |
| url | https://www.frontiersin.org/articles/10.3389/frtra.2024.1336563/full |
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