Impact of Induction Therapy on Circulating T Follicular Helper Cells and Subsequent Donor-Specific Antibody Formation After Kidney Transplant

Macedo, Camila; Hadi, Kevin; Walters, John; Elinoff, Beth; Marrari, Marilyn; Zeevi, Adriana; Ramaswami, Bala; Chalasani, Geetha; Landsittel, Douglas; Alloway, Rita R.; Lakkis, Fadi G.; Woodle, E. Steve; Metes, Diana

doi:10.1016/j.ekir.2018.11.020

Cited by 25 publications

(31 citation statements)

References 53 publications

(63 reference statements)

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“…This is in opposition to Macedo et al. ( 104 ), who demonstrated lower Tfh. Similarly, a longitudinal study by Cano-Romero et al.…”

Section: Role Of Tfr In Human Diseasescontrasting

confidence: 83%

“…In an ATG treated group of renal transplant patients, Macedo et al. ( 104 ) found that the absolute numbers of circulating Tfh (CD45RO + CXCR5 + CD4 + CD3 + ) were significantly decreased at all time points up to 360 days post induction. The percentage of Tregs was overall decreased in the ATG group, although they did not evaluate the Tfr numbers.…”

Section: Role Of Tfr In Human Diseasesmentioning

confidence: 99%

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Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

et al. 2021

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Regulatory T cells (Tregs) constitute a small proportion of circulating CD4+ T cells that function to maintain homeostasis and prevent autoimmunity. In light of their powerful immunosuppressive and tolerance-promoting properties, Tregs have become an interesting potential candidate for therapeutic use in conditions such as solid organ transplant or to treat autoimmune and inflammatory conditions. Clinical studies have demonstrated the safety of polyclonally expanded Tregs in graft-versus-host disease, type 1 diabetes, and more recently in renal and liver transplantation. However, Tregs are heterogenous. Recent insights indicate that only a small proportion of Tregs, called T follicular regulatory cells (Tfr) regulate interactions between B cells and T follicular helper (Tfh) cells within the germinal center. Tfr have been mainly described in mouse models due to the challenges of sampling secondary lymphoid organs in humans. However, emerging human studies, characterize Tfr as being CD4+CD25+FOXP3+CXCR5+ cells with different levels of PD-1 and ICOS expression depending on their localization, in the blood or the germinal center. The exact role they play in transplantation remains to be elucidated. However, given the potential ability of these cells to modulate antibody responses to allo-antigens, there is great interest in exploring translational applications in situations where B cell responses need to be regulated. Here, we review the current knowledge of Tfr and the role they play focusing on human diseases and transplantation. We also discuss the potential future applications of Tfr therapy in transplantation and examine the evidence for a role of Tfr in antibody production, acute and chronic rejection and tertiary lymphoid organs. Furthermore, the potential impact of immunosuppression on Tfr will be explored. Based on preclinical research, we will analyse the rationale of Tfr therapy in solid organ transplantation and summarize the different challenges to be overcome before Tfr therapy can be implemented into clinical practice.

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“…This is in opposition to Macedo et al. ( 104 ), who demonstrated lower Tfh. Similarly, a longitudinal study by Cano-Romero et al.…”

Section: Role Of Tfr In Human Diseasescontrasting

confidence: 83%

Section: Role Of Tfr In Human Diseasesmentioning

confidence: 99%

Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

et al. 2021

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Section: Introductionmentioning

confidence: 99%

“…To produce high affinity antibodies against pathogens, B cell requires the assistance from T FH to complete its maturation and class switch recombination inside the GC. Work related to T FH in the kidneys has largely focused on kidney transplantations, and upregulated T FH has been implicated in less favorable outcomes especially due to increased humoral rejections ( 13 ). On the other hand, T FH are also linked to atherosclerosis, autoimmune diseases and some lymphoid tumors, suggesting their potential pathogenic role in promoting chronic inflammation ( 12 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Kidney Failure Associates With T Cell Exhaustion and Imbalanced Follicular Helper T Cells

et al. 2020

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Individuals with kidney failure are at increased risk of cardiovascular events, as well as infections and malignancies, but the associated immunological abnormalities are unclear. We hypothesized that the uremic milieu triggers a chronic inflammatory state that, while accelerating atherosclerosis, promotes T cell exhaustion, impairing effective clearance of pathogens and tumor cells. Clinical and demographic data were collected from 78 patients with chronic kidney disease (CKD) (n = 42) or end-stage kidney disease (ESKD) (n = 36) and from 18 healthy controls (HC). Serum cytokines were analyzed by Luminex. Immunophenotype of T cells was performed by flow cytometry on peripheral blood mononuclear cells. ESKD patients had significantly higher serum levels of IFN-γ, TNF-α, sCD40L, GM-CSF, IL-4, IL-8, MCP-1, and MIP-1β than CKD and HC. After mitogen stimulation, both CD4 + and CD8 + T cells in ESKD group demonstrated a pro-inflammatory phenotype with increased IFN-γ and TNF-α, whereas both CKD and ESKD patients had higher IL-2 levels. CKD and ESKD were associated with increased frequency of exhausted CD4 + T cells (CD4 + KLRG1 + PD1 + CD57 −) and CD8 + T cells (CD8 + KLRG1 + PD1 + CD57 −), as well as anergic CD4 + T cells (CD4 + KLRG1 − PD1 + CD57 −) and CD8 + T cells (CD8 + KLRG1 − PD1 + CD57 −). Although total percentage of follicular helper T cell (T FH) was similar amongst groups, ESKD had reduced frequency of T FH1 (CCR6 − CXCR3 + CXCR5 + PD1 + CD4 + CD8 −), but increased T FH2 (CCR6 − CXCR3 − CXCR5 + PD1 + CD4 + CD8 −), and plasmablasts (CD3 − CD56 − CD19 + CD27 high CD38 high CD138 −). In conclusion, kidney failure is associated with pro-inflammatory markers, exhausted T cell phenotype, and upregulated T FH2 , especially in ESKD. These immunological changes may account, at least in part, for the increased cardiovascular risk in these patients and their susceptibility to infections and malignancies.

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“…We also found that patients with anti-HLA antibodies or DSA at 5–7 years post-transplant had similar cTfr and cTfh cell numbers as patients without antibodies. This is somewhat unexpected as other studies have shown elevated numbers of cTfh in patients with anti-HLA antibodies or DSA ( 45 , 51 ). In this study, 13 of the 34 patients with anti-HLA antibodies had a history of rejection and anti-rejection therapy.…”

Section: Discussionmentioning

confidence: 63%

Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients

et al. 2020

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Background: FoxP3 + follicular regulatory T cells (Tfr) have been identified as the cell population controlling T follicular helper (Tfh) cells and B cells which, are both involved in effector immune responses against transplanted tissue. Methods: To understand the biology of Tfr cells in kidney transplant patients treated with tacrolimus and mycophenolate mofetil (MMF) combination immunosuppression, we measured circulating (c)Tfh and cTfr cells in peripheral blood by flow cytometry in n = 211 kidney transplant recipients. At the time of measurement patients were 5–7 years after transplantation. Of this cohort of patients, 23.2% (49/211) had been previously treated for rejection. Median time after anti-rejection therapy was 4.9 years (range 0.4–7 years). Age and gender matched healthy individuals served as controls. Results: While the absolute numbers of cTfh cells were comparable between kidney transplant recipients and healthy controls, the numbers of cTfr cells were 46% lower in immunosuppressed recipients ( p < 0.001). More importantly, in transplanted patients, the ratio of cTfr to cTfh was decreased (median; 0.10 vs. 0.06), indicating a disruption of the balance between cTfr and cTfh cells. This shifted balance was observed for both non-rejectors and rejectors. Previous pulse methylprednisolone or combined pulse methylprednisolone + intravenous immunoglobulin anti-rejection therapy led to a non-significant 30.6% (median) and 51.2% (median) drop in cTfr cells, respectively when compared to cTfr cell numbers in transplant patients who did not receive anti-rejection therapy. A history of alemtuzumab therapy did lead to a significant decrease in cTfr cells of 85.8% (median) compared with patients not treated with anti-rejection therapy ( p < 0.0001). No association with tacrolimus or MMF pre-dose concentrations was found. Conclusion: This cross-sectional study reveals that anti-rejection therapy with alemtuzumab significantly lowers the number of cTfr cells in kidney transplant recipients. The observed profound effects by these agents might dysregulate cTfr functions.

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Impact of Induction Therapy on Circulating T Follicular Helper Cells and Subsequent Donor-Specific Antibody Formation After Kidney Transplant

Cited by 25 publications

References 53 publications

Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

Potential Application of T-Follicular Regulatory Cell Therapy in Transplantation

Kidney Failure Associates With T Cell Exhaustion and Imbalanced Follicular Helper T Cells

Immunosuppression Has Long-Lasting Effects on Circulating Follicular Regulatory T Cells in Kidney Transplant Recipients

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