T cell depletion increases humoral response by favoring T follicular helper cells expansion

Gassen, Rodrigo Benedetti; Borges, Thiago J.; Pérez‐Sáez, María José; Zhang, Hengcheng; Jurdi, Ayman Al; Llinàs‐Mallol, Laura; Aoyama, Bruno T.; Lima, Maurício; Arias-Cabrales, Carlos; Sage, Peter T.; Murakami, Naoka; Riella, Leonardo V.

doi:10.1111/ajt.17038

Cited by 8 publications

(8 citation statements)

References 43 publications

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“…In contrast, from a clinical perspective, whether this subtle immune activation of follicular cells is preventable, either by optimization of the current immunosuppression ( 48 ) or by new agents targeting the Tfh activation pathway, remains unanswered. First, we found no signal for a different level of immunosuppression between those who increased their circulating Tfh levels and the controls.…”

Section: Discussionmentioning

confidence: 99%

T follicular helper cells expansion in transplant recipients correlates with graft infiltration and adverse outcomes

Désy,

Béland,

Thivierge

et al. 2024

Front. Immunol.

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IntroductionThe process of immunization following vaccination in humans bears similarities to that of immunization with allografts. Whereas vaccination aims to elicit a rapid response, in the transplant recipient, immunosuppressants slow the immunization to alloantigens. The induction of CD4+CXCR5+ T follicular helper (Tfh) cells has been shown to correlate with the success of vaccine immunization.MethodWe studied a cohort of 65 transplant recipients who underwent histological evaluation concurrent with PBMC isolation and follow-up sampling to investigate the phenotypic profiles in the blood and allotissue and analyze their association with clinical events.ResultsThe proportion of circulating Tfh cells was heterogeneous over time. Patients in whom this compartment increased had lower CCR7-PD1+CD4+CXCR5+ T cells during follow-up. These patients exhibited more alloreactive CD4+ T cells using HLA-DR-specific tetramers and a greater proportion of detectable circulating plasmablasts than the controls. Examination of baseline biopsies revealed that expansion of the circulating Tfh compartment did not follow prior intragraft leukocyte infiltration. However, multicolor immunofluorescence microscopy of the grafts showed a greater proportion of CXCR5+ T cells than in the controls. CD4+CXCR5+ cells were predominantly PD1+ and were in close contact with B cells in situ. Despite clinical stability at baseline, circulating Tfh expansion was associated with a higher risk of a composite of anti-HLA donor-specific antibodies, rejection, lower graft function, or graft loss.ConclusionIn otherwise stable patients post-transplant, circulating Tfh expansion can identify ongoing alloreactivity, detectable before allograft injury. Tfh expansion is relevant clinically because it predicts poor graft prognosis. These findings have implications for immune surveillance.

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Section: Discussionmentioning

confidence: 99%

T follicular helper cells expansion in transplant recipients correlates with graft infiltration and adverse outcomes

Désy,

Béland,

Thivierge

et al. 2024

Front. Immunol.

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“…In a mouse model of kidney transplant, ATG was effective in depleting T cells, but favored the expansion of T follicular helper cells following depletion. Treatment with ATG also increased germinal center B cells and lead to higher titers of antigen-specific antibodies compared to controls (40). Though a small percentage of those who receive a de novo simultaneous kidney-pancreas transplant is sensitized (20%), pre-transplant work up is based only on humoral response (anti-HLA antibodies), and no functional cellular analysis was performed to determine the presence of donor-specific memory T cells at time of transplantation.…”

Section: Discussionmentioning

confidence: 99%

Immune Profiling of Peripheral Blood Mononuclear Cells at Pancreas Acute Rejection Episodes in Kidney-Pancreas Transplant Recipients

Rovira¹,

Ramírez-Bajo²,

Bañón-Maneus³

et al. 2022

Transpl Int

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Profiling of circulating immune cells provides valuable insight to the pathophysiology of acute rejection in organ transplantation. Herein we characterized the peripheral blood mononuclear cells in simultaneous kidney-pancreas transplant recipients. We conducted a retrospective analysis in a biopsy-matched cohort (n = 67) and compared patients with biopsy proven acute rejection (BPAR; 41%) to those without rejection (No-AR). We observed that CD3+ T cells, both CD8+ and CD4+, as well as CD19+ B cells were increased in patients with BPAR, particularly in biopsies performed in the early post-transplant period (<3 months). During this period immune subsets presented a good discriminative ability (CD4+ AUC 0.79; CD8+ AUC 0.80; B cells AUC 0.86; p < 0.05) and outperformed lipase (AUC 0.62; p = 0.12) for the diagnosis of acute rejection. We further evaluated whether this could be explained by differences in frequencies prior to transplantation. Patients presenting with early post-transplant rejection (<3 months) had a significant increase in T-cell frequencies pre-transplant, both CD4+ T cells and CD8+ T cells (p < 0.01), which were associated with a significant inferior rejection-free graft survival. T cell frequencies in peripheral blood correlated with pancreas acute rejection episodes, and variations prior to transplantation were associated with pancreas early acute rejection.

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“…However, the rate of dnDSA was more than 40% within first-year posttransplant, leading to the early termination of the study [19]. Although T-cell depletion has a potent effect in lowering acute TCMR rates in high immunological risk patients, it can favour preferential expansion of T follicular helper (Tfh) cells and be associated with a higher risk of DSA generation [20 ▪ ]. Therefore, delaying initiation, dose minimization or withdrawal of CNI may favour the development of an antibody-mediated alloimmune response [21,22].…”

Section: What Is the Best Strategy To Prevent The Development Of De-n...mentioning

confidence: 99%

Antibody-mediated rejection: prevention, monitoring and treatment dilemmas

Rodríguez-Ramírez

Jurdi

Konvalinka

et al. 2022

Current Opinion in Organ Transplantation

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Purpose of reviewAntibody-mediated rejection (AMR) has emerged as the leading cause of late graft loss in kidney transplant recipients. Donor-specific antibodies are an independent risk factor for AMR and graft loss. However, not all donor-specific antibodies are pathogenic. AMR treatment is heterogeneous due to the lack of robust trials to support clinical decisions. This review provides an overview and comments on practical but relevant dilemmas physicians experience in managing kidney transplant recipients with AMR. Recent findingsActive AMR with donor-specific antibodies may be treated with plasmapheresis, intravenous immunoglobulin and corticosteroids with additional therapies considered on a case-by-case basis. On the contrary, no treatment has been shown to be effective against chronic active AMR. Various biomarkers and prediction models to assess the individual risk of graft failure and response to rejection treatment show promise.

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T cell depletion increases humoral response by favoring T follicular helper cells expansion

Cited by 8 publications

References 43 publications

T follicular helper cells expansion in transplant recipients correlates with graft infiltration and adverse outcomes

T follicular helper cells expansion in transplant recipients correlates with graft infiltration and adverse outcomes

Immune Profiling of Peripheral Blood Mononuclear Cells at Pancreas Acute Rejection Episodes in Kidney-Pancreas Transplant Recipients

Antibody-mediated rejection: prevention, monitoring and treatment dilemmas

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