scholarly journals Terminally Differentiated Effector Memory CD8+ T Cells Identify Kidney Transplant Recipients at High Risk of Graft Failure

2020 ◽  
Vol 31 (4) ◽  
pp. 876-891
Author(s):  
Lola Jacquemont ◽  
Gaëlle Tilly ◽  
Michelle Yap ◽  
Tra-My Doan-Ngoc ◽  
Richard Danger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Kidney Transplant ◽  
Graft Failure ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Post Transplant ◽  
Transplant Failure

BackgroundIdentifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation.MethodsWe investigated the frequency and function of CD8+ T cell subsets—including effector memory (EM) and terminally differentiated EM (TEMRA) CD8+ T cells—in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8+ T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants.ResultsIncreased frequency of circulating TEMRA CD8+ T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8+ T cells associated with reduced risk of graft failure. A distinct TEMRA CD8+ T cell subpopulation was identified that was characterized by expression of FcγRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8+ T cells, CD16 engagement resulted in selective activation of TEMRA CD8+ T cells, which mediated antibody-dependent cytotoxicity.ConclusionsAt 1 year post-transplant, the composition of memory CD8+ T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8+ T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8+ T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8+ T cell monitoring for predicting risk of kidney transplant failure.

scholarly journals Early Homeostatic Expansion of Regulatory T Cells with the Predominant Effector/Memory Phenotype May Stabilize Immune Recovery in the First Month after HSCT

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2501-2501
Author(s):  
Takanori Yoshioka ◽  
Yusuke Meguri ◽  
Takeru Asano ◽  
Taro Masunari ◽  
Kumiko Kagawa ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Phase ◽  
Cd4 T Cells ◽  
Chronic Phase ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Ki 67 ◽  
Memory Phenotype ◽  
Post Transplant

Abstract CD4+Foxp3+ regulatory T cells (Treg) play a central role in establishing immune tolerance after allogeneic hematopoietic stem cell transplantation (HSCT). We previously reported that the long-term severe lymphopenia could result in the collapse of Treg homeostasis leading to the onset of chronic GVHD (Matsuoka et al. JCI 2010). However, Treg homeostasis in the very early phase after HSCT has not been well studied. To address this issue, we here examined the early lymphocytes reconstitution in total 34 patients who received HSCT. Peripheral blood samples were obtained at 2, 4, 8 and 12 weeks after transplant and analyzed the reconstitution of CD4+CD25med-highCD127lowFoxp3+ Treg comparing with CD4+CD25neg-lowCD127highFoxp3- conventional T cell (Tcon) and CD8+ T cells. CD4 T cell subsets are further divided into subpopulations by the expression of CD45RA and CD31. The expressions of Helios, Ki-67, Bcl-2 and C-C chemokine receptor type 4 (CCR4) on these subsets were also examined. These patients were transplanted the grafts from various stem cell sources (7 HLA-matched PBSCT, 12 HLA-matched BMT, 6 HLA-mismatched CBT and 9 HLA-haploidentical PBSCT) and this enables us the opportunity to comparatively evaluate the early lymphocyte reconstitution among the different types of HSCT. After transplant, total lymphocyte counts were significantly lower than the counts before the start of conditioning (median lymphocytes 113/ul at 2 weeks and 223/ul at 4 weeks vs 550/ul before conditioning, P<0.01 and P<0.01, respectively). In the severely lymphopenic condition in the first month after HSCT, all T cell subsets were undergoing aggressive proliferation in this acute phase as compared to proliferation in the chronic phase, however, Treg proliferation was significantly higher than in Tcon at 4 weeks (%Ki-67+ cells; median 56.4%, 23.4%, respectively, P<0.02). %Treg of total CD4 T cells elevated and peaked at 4 weeks post-transplant. At this timepoint, %Treg of CD4 T cells showed the clear inverse correlation with %CD45RA+ of Treg (r2=0.40), suggesting the expansion of Treg in this phase appears to be a result from severe lymphopenia-driven proliferation which involves conversion from naive into memory phenotype. Elevation of %Treg was most evident in the patients who received HLA-haploidentical graft after ATG-containing conditioning (median 8.41% in haplo-HSCT, 5.25% in other groups, P<0.05), again indicating the lymphopenia is critical factor to drive Treg proliferatrion. Expanded Treg showed a predominant Helios+CD45RA-CD31- effector/memory phenotype with the lower level of Bcl-2 expression as compared to CD45RA+ naïve Treg. The elevation of Treg did not sustain and %Treg of CD4 T cells got back to the baseline level by 8 weeks. During the first 3 months after HSCT, CD45RA- Treg exhibited high level of CCR4 and the recovery of this subset was critically delayed in Adult T-cell Leukemia (ATL) patients treated with anti-CCR4 antibody in the peri-transplant period, resulting in the development of acute graft-versus-host diseases. In conclusion, our findings suggest that, not only in the chronic phase but also in the acute phase, the homeostasis of Treg is more susceptible to the post-transplant environment as compared to other lymphocyte subsets. Post-transplant lymphopenia drives aggressive Treg proliferation resulting in the increased percentage of this subset in the very acute phase which may contribute to stabilize the immune recovery. The careful monitoring of Treg from the point of view might provide important information to promote immune tolerance. Disclosures No relevant conflicts of interest to declare.

Systemic varicella zoster virus reactive effector memory T-cells impaired in the elderly and in kidney transplant recipients

2012 ◽  
Vol 84 (12) ◽  
pp. 2018-2025 ◽  
Author(s):  
Nicole M. van Besouw ◽  
Georges M.G.M. Verjans ◽  
Joke M. Zuijderwijk ◽  
Nicolle H.R. Litjens ◽  
Albert D.M.E. Osterhaus ◽  
...  
Keyword(s):  
T Cells ◽  
Varicella Zoster Virus ◽  
Kidney Transplant ◽  
Memory T Cells ◽  
The Elderly ◽  
Effector Memory ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Varicella Zoster ◽  
Effector Memory T Cells

scholarly journals Functionally active virus-specific T cells that target CMV, adenovirus, and EBV can be expanded from naive T-cell populations in cord blood and will target a range of viral epitopes

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1958-1967 ◽  
Author(s):  
Patrick J. Hanley ◽  
Conrad Russell Young Cruz ◽  
Barbara Savoldo ◽  
Ann M. Leen ◽  
Maja Stanojevic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Cord Blood Transplantation ◽  
Viral Disease ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Transplant Recipients ◽  
Blood Transplantation ◽  
Related Mortality

The naive phenotype of cord blood (CB) T cells may reduce graft-versus-host disease after umbilical cord blood transplantation, but this naivety and their low absolute numbers also delays immune reconstitution, producing higher infection-related mortality that is predominantly related to CMV, adenovirus (Adv), and EBV. Adoptive immunotherapy with peripheral blood-derived virus-specific cytotoxic T lymphocytes (CTLs) can effectively prevent viral disease after conventional stem cell transplantation, and we now describe the generation of single cultures of CTLs from CB that are specific for multiple viruses. Using EBV-infected B cells transduced with a clinical-grade Ad5f35CMVpp65 adenoviral vector as sources of EBV, Adv, and CMV antigens, we expanded virus-specific T cells even from CB T cells with a naive phenotype. After expansion, each CTL culture contained both CD8+ and CD4+ T-cell subsets, predominantly of effector memory phenotype. Each CTL culture also had HLA-restricted virus-specific cytotoxic effector function against EBV, CMV, and Adv targets. The CB CTLs recognized multiple viral epitopes, including CD4-restricted Adv-hexon epitopes and immunosubdominant CD4- and CD8-restricted CMVpp65 epitopes. Notwithstanding their naive phenotype, it is therefore possible to generate trivirus-specific CTLs in a single culture of CB, which may be of value to prevent or treat viral disease in CB transplant recipients. This study is registered at www.clinicaltrials.gov as NCT00078533.

scholarly journals Antibody and T Cell Response to SARS-CoV-2 Messenger RNA BNT162b2 Vaccine in Kidney Transplant Recipients and Hemodialysis Patients

2021 ◽  
pp. ASN.2021040480
Author(s):  
Dominique Bertrand ◽  
Mouad Hamzaoui ◽  
Veronique Lemée ◽  
Julie Lamulle ◽  
Melanie Hanoy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Kidney Transplant ◽  
Cell Response ◽  
Cellular Response ◽  
Hemodialysis Patients ◽  
T Cell Response ◽  
High Rate ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients

Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high rate of mortality in patients with end stage renal disease and vaccination is hoped to prevent infection. Methods. Between January 18, and February 24, 2021, 225 kidney transplant recipients (KTR) and 45 hemodialysis patients (HDP) received two injections of mRNA BNT162b2 vaccine. The post-vaccinal humoral and cellular response was explored in the first 45 KTR and 10 HDP. Results. After the second dose, 8 HDP (88.9%) and 8 KTR (17.8%) developed anti-spike SARS-CoV-2 antibodies (p<0.0001). Median titer of antibodies in responders was 1052 AU/mL (IQR: 515-2689) in HDP and 671 AU/mL (IQR: 172-1523) in KTR (p=0.4). Nine HDP (100%) and 26 KTR (57.8%) showed a specific T cell response (p=0.06) after the second injection. In responders, median numbers of spike-reactive T cells were 305 SFC/106 CD3+ T cells (IQR: 95-947) in HDP and 212 SFC/106 CD3+ T cells (IQR: 61-330) in KTR (p=0.4). In KTR, the immune response to BNT162b2 seemed influenced by the immunosuppressive regimen, particularly tacrolimus or belatacept. Conclusion. Immunization with BNT162b2 seems more efficient in HDP, indicating that vaccination should be highly recommended in these patients awaiting a transplant. However, the current vaccinal strategy for KTR may not provide effective protection against COVID-19 and will likely need to be improved.

Dynamic prediction models for graft failure in paediatric kidney transplantation

2020 ◽  
Author(s):  
Rémi Kaboré ◽  
Loïc Ferrer ◽  
Cécile Couchoud ◽  
Julien Hogan ◽  
Pierre Cochat ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Kidney Transplant ◽  
Graft Failure ◽  
Cox Model ◽  
Kidney Graft ◽  
Transplant Recipients ◽  
Kidney Transplant Recipients ◽  
Joint Models ◽  
Dynamic Prediction ◽  
Post Transplant

Abstract Background Several models have been proposed to predict kidney graft failure in adult recipients but none in younger recipients. Our objective was to propose a dynamic prediction model for graft failure in young kidney transplant recipients. Methods We included 793 kidney transplant recipients waitlisted before the age of 18 years who received a first kidney transplantation before the age of 21 years in France in 2002–13 and survived &gt;90 days with a functioning graft. We used a Cox model including baseline predictors only (sex, age at transplant, primary kidney disease, dialysis duration, donor type and age, human leucocyte antigen matching, cytomegalovirus serostatus, cold ischaemia time and delayed graft function) and two joint models also accounting for post-transplant estimated glomerular filtration rate (eGFR) trajectory. Predictive performances were evaluated using a cross-validated area under the curve (AUC) and R2 curves. Results When predicting the risk of graft failure from any time within the first 7 years after paediatric kidney transplantation, the predictions for the following 3 or 5 years were accurate and much better with the joint models than with the Cox model (AUC ranged from 0.83 to 0.91 for the joint models versus 0.56 to 0.64 for the Cox model). Conclusion Accounting for post-transplant eGFR trajectory strongly increased the accuracy of graft failure prediction in young kidney transplant recipients.

Sign in / Sign up

Export Citation Format

Share Document