Relationship between antithymocyte globulin, T cell phenotypes, and clinical outcomes in pediatric kidney transplantation

Shaw, Brian I.; Lee, Hui‐Jie; Chan, Cliburn; Ettenger, Robert B.; Grimm, Paul; Pearl, Meghan; Reed, Elaine F.; Robien, Mark A.; Sarwal, Minnie M.; Stempora, Linda; Warshaw, Barry L.; Zhao, Congwen; Martinez, Olivia M.; Kirk, Allan D.; Chambers, Eileen Tsai

doi:10.1111/ajt.16263

Cited by 6 publications

(11 citation statements)

References 38 publications

(47 reference statements)

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“…Previously, we have shown that ATG induction is associated with broad changes in the pediatric immune system regardless of nutritional status 24 . Some of these changes, including an increase in certain memory and/or senescent T‐cell types in both the CD4 and CD8 compartment, were observed to a greater extent in patients with obesity compared with those with normal nutrition and undernutrition.…”

Section: Discussionmentioning

confidence: 94%

“…In the present study, we do not observe that children with malnu- Previously, we have shown that ATG induction is associated with broad changes in the pediatric immune system regardless of nutritional status. 24 Some of these changes, including an increase in certain memory and/or senescent T-cell types in both the CD4 and CD8 compartment, were observed to a greater extent in patients with obesity compared with those with normal nutrition and undernutrition. These findings point to the potential for an interaction between obesity and induction that may ) and no differences between nutritional status groups observed for CD8 Tem (p = .736).…”

Section: Discussionmentioning

confidence: 99%

“…The primary clinical outcome was the first clinical event after kidney transplantation, defined as experiencing either the alloimmune or infectious outcomes, as previously described 11,24 . Patients were followed from the time of transplantation until the alloimmune or infectious outcomes, or 1‐year post‐transplantation, whichever occurred first.…”

Section: Methodsmentioning

confidence: 99%

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Malnutrition and immune cell subsets in children undergoing kidney transplantation

Shaw

Lee

Ettenger

et al. 2022

Pediatric Transplantation

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Background Malnutrition, including obesity and undernutrition, among children is increasing in prevalence and is common among children on renal replacement therapy. The effect of malnutrition on the pre‐transplant immune system and how the pediatric immune system responds to the insult of both immunosuppression and allotransplantation is unknown. We examined the relationship of nutritional status with post‐transplant outcomes and characterized the peripheral immune cell phenotypes of children from the Immune Development of Pediatric Transplant (IMPACT) study. Methods Ninety‐eight patients from the IMPACT study were classified as having obesity, undernutrition, or normal nutrition‐based pre‐transplant measurements. Incidence of infectious and alloimmune outcomes at 1‐year post‐transplantation was compared between nutritional groups using Gray's test and Fine‐Gray subdistribution hazards model. Event‐free survival was estimated by Kaplan–Meier method and compared between groups. Differences in immune cell subsets between nutritional groups over time were determined using generalized estimating equations accounting for the correlation between repeated measurements. Results We did not observe that nutritional status was associated with infectious or alloimmune events or event‐free survival post‐transplant. We demonstrated that children with obesity had distinct T‐and B‐cell signatures relative to those with undernutrition and normal nutrition, even when controlling for immunosuppression. Children with obesity had a lower frequency of CD8 Tnaive cells 9‐month post‐transplant (p < .001), a higher frequency of CD4 CD57 + PD1‐ T cells, and lower frequencies of CD57‐PD1+ CD8 and CD57‐PD1‐ CD8 T cells at 12‐month transplant (p < .05 for all). Conclusions Children with obesity have distinct immunophenotypes that may influence the tailoring of immunosuppression.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Malnutrition and immune cell subsets in children undergoing kidney transplantation

Shaw

Lee

Ettenger

et al. 2022

Pediatric Transplantation

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“…54 In paediatric KT patients, ATG induction is also associated with an increase in CD4 + effector memory and senescent CD57 + T cells that are associated with early event-free survival, suggesting its short-term clinical benefits. 55 In addition, it has been demonstrated that T-cell exhaustion correlates with improved outcomes in KT recipients. 56 Since ATG treatment causes increased accumulation of CD28 À CD8 + EMRA T cells (Figures 2c and d), we sought to scrutinise the effect of ATG on immunosenescent changes of T cells.…”

Section: Discussionmentioning

confidence: 99%

“…CKD and related immunosuppressive therapies in paediatric patients accelerate immune senescence, including causing increases in CD57 + or CD28 − CD8 + T cells 54 . In paediatric KT patients, ATG induction is also associated with an increase in CD4 + effector memory and senescent CD57 + T cells that are associated with early event‐free survival, suggesting its short‐term clinical benefits 55 . In addition, it has been demonstrated that T‐cell exhaustion correlates with improved outcomes in KT recipients 56 .…”

Section: Discussionmentioning

confidence: 99%

Anti‐thymocyte globulin‐mediated immunosenescent alterations of T cells in kidney transplant patients

Lee

Jang

et al. 2022

Clin & Trans Imm

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Objectives Kidney transplant (KT) is the most effective treatment for end‐stage renal disease. The immunosuppressant anti‐thymocyte globulin (ATG) has been applied for induction therapy to reduce the risk of acute transplant rejection for patients at high immunological risk. Despite its putative role in replicative stress during immune reconstitution, the effects of ATG on T‐cell immunosenescent changes remain to be understood. Methods Phenotypic and functional features of senescent T cells were examined by flow cytometry in 116 healthy controls (HC) and 95 KT patients for comparative analysis according to ATG treatment and CMV reactivation. The TCR repertoire was analysed in peripheral blood mononuclear cells (PBMCs) of KT patients. Results T cells of KT patients treated with ATG (ATG+) show typical immunosenescent features, accumulation of CD28−, CD85j+ or CD57+ T cells, and imbalance of functional T‐cell subsets, compared with untreated KT patients (ATG−). Plasma IL‐15 and CMV‐IgG levels were higher in KT patients than in HCs, and the IL‐15 level positively correlated with the frequency of CD28− T cells in KT patients. ATG+ patients had a higher prevalence of CMV reactivation, which is associated with an increased frequency of CD28− T cells. As a result, ATG+ patients had expanded CMV‐specific T cells and decreased TCR diversity. However, proliferation, cytokine‐producing capacity and polyfunctionality of T cells were preserved in ATG+ patients. Conclusion Our findings suggest that ATG treatment contributes to the accumulation of senescent T cells, which may have lifelong clinical implications in KT patients. Thus, these patients require long‐term and comprehensive immune monitoring.

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A novel flow-cytometric based method to assess post-HSCT donor chimerism exploiting RNA hybridization

Nucera,

Sindoni,

Bugarin

et al. 2023

Bone Marrow Transplant

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Analysis of donor-recipient chimerism after hematopoietic stem cell transplantation (HSCT) is of pivotal importance for patient’s clinical management, especially in the context of mixed chimerism. Patients are routinely monitored for chimerism in sorted subsets of peripheral blood cells. However, measurement of chimerism in sorted immune cell subsets is technically challenging and time consuming. We here propose a novel, flow cytometry-based approach to detect donor cell chimerism in sex-mismatched HSCT. We exploit RNA PrimeFlow™ system, based on RNA hybridization, to detect mRNA from a lysine demethylase encoded by Y chromosome, KDM5D. This approach allows to distinguish male and female derived cells with around 1% sensitivity. The procedure can be coupled with multiparametric immunophenotyping to assess chimerism in specific immune cell subsets without the need for prior FACS-sorting. We apply this method to a cohort of HSCT patients (n = 10) and we show that it is consistent with standard PCR-based method. We also show that different T lymphocyte subsets display variable degrees of donor chimerism, especially in CD8+ T cell compartment where we observe an enrichment for recipient chimerism in central memory T cells. This method can be exploited to advance current knowledge on immune reconstitution focusing on specific subsets avoiding prior FACS-sorting.

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Relationship between antithymocyte globulin, T cell phenotypes, and clinical outcomes in pediatric kidney transplantation

Cited by 6 publications

References 38 publications

Malnutrition and immune cell subsets in children undergoing kidney transplantation

Malnutrition and immune cell subsets in children undergoing kidney transplantation

Anti‐thymocyte globulin‐mediated immunosenescent alterations of T cells in kidney transplant patients

A novel flow-cytometric based method to assess post-HSCT donor chimerism exploiting RNA hybridization

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