Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16<i>INK</i>4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A

Furuzawa‐Carballeda, Janette; Lima, Guadalupe; Alberú, Josefina; Palafox, Damián; Uribe‐Uribe, Norma; Morales-Buenrostro, L. E.; Acevedo, Renan; Mondragón, G.; Chevaile, Alejandro; Llórente, Luis

doi:10.1111/j.1365-2249.2011.04504.x

Cited by 17 publications

(19 citation statements)

References 26 publications

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“…Regarding regulatory cells, it is worth mentioning that, in healthy individuals, T regs constitute 5-15% of peripheral and tissue CD4 + T cells. In this study, we also found higher numbers of T regs in biopsies from patients under belatacept treatment (10-12%), but within the values observed in healthy tissues [9] compared with CNI treatment (5-7%). a significant increase in intragraft FoxP3 + T cells was demonstrated in belatacept-treated patients during acute rejection compared to CNI-treated patients, suggesting that this may lead to better resolution of graft rejection episodes [10].…”

Section: Discussionsupporting

confidence: 84%

“…4), as has been demonstrated in previous studies [2,8,9,44]. This effect could have been due to less inflammation and fibrosis and better immunoregulation based on the abundance of T reg , B reg and pDC reg cells.…”

Section: Discussionmentioning

confidence: 53%

“…It is interesting to note that the 12-month intragraft cell infiltration in a similar group of patients from Mexico participating in the BENEFIT study showed a preponderance of regulatory cells (CD25 + /FoxP3 + and CD16 + /indoleamine 2,3-dioxygenase (IDO + ) in the belatacept-treated group and significantly higher amounts of inflammatory cells (CD4 + / IL-17 + ) in the CNI-treated group [9]. The findings of this study make clear that not only did the grafts show significantly less inflammation and chronic damage with belatacept than with CNI, but also the cell infiltrating pattern in the grafts from patients on belatacept showed a significant difference in relative percentage of regulatory cells.…”

Section: Discussionmentioning

confidence: 99%

“…T regs have a key suppressive role in the pathological immune responses after transplantation [9,10], and even though they require IL-2 and CD28-CD80/CD86 co-stimulation as survival factors [11], belatacept does not appear to interfere with T reg homeostasis, i.e. Regarding regulatory cells, it is worth mentioning that, in healthy individuals, T regs constitute 5-15% of peripheral and tissue CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

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Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years

Furuzawa‐Carballeda

Uribe‐Uribe

Arreola-Guerra³

et al. 2019

Clinical and Experimental Immunology

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Previously, we found a substantial number of regulatory T cells (T regs ) and fewer senescent and T helper type 17 (Th17) and a decrease in interstitial fibrosis (IF) in 12-month graft biopsies in belatacept versus cyclosporin (CNI)-treated patients [Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT) study]. Seven years after kidney transplantation (KT), mean estimated glomerular filtration rate (eGFR), patient and graft survival were significantly higher with belatacept versus CNI treatment. The aim of this study was to determine whether the immunophenotypes of inflammatory and regulatory cell subsets infiltrating the grafts contribute to the BENEFIT's clinical findings a decade after KT. Twenty-three adult patients with functionally stable KT treated with belatacept and 10 treated with CNI were enrolled. Biopsies were analyzed by histomorphometry and immunohistochemistry for proliferation, senescence, apoptosis, inflammatory and regulatory cell markers in a blinded manner. Significantly lower percentages of inflammatory/fibrogenic cells [interleukin (IL)-22 + /Th17/Th2/M1 macrophages] were observed in patients treated with belatacept than in patients treated with CNI. By contrast, remarkably higher percentages of regulatory cells [T regs /B regs / plasmacytoid dendritic regulatory cells (pDC regs )/M2] were found in belatacept-treated patients than in CNI-treated patients. Conspicuously lower percentages of apoptosis and senescence and higher proliferation markers were found in belatacept-treated patients than in CNI-treated patients. Consequently, there was significantly more inflammation in the microvascular compartments as well as increased tubular atrophy and IF in CNI-treated patients. These findings strongly suggest that regulatory mechanisms, along with the absence of deleterious effects of CNI, contribute to the long-term graft histology and function stability in patients treated with belatacept.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years

Furuzawa‐Carballeda

Uribe‐Uribe

Arreola-Guerra³

et al. 2019

Clinical and Experimental Immunology

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“…Transplant biopsies from the BENEFIT trial suggest that belatacept confers a substantially different immunologic profile at the tissue level than cyclosporine A, demonstrating increased levels of markers of tolerance [68]. While the induction of transplantation tolerance is still a number of years away, these results are promising for the development of regimens toward that end.…”

Section: Drug Profilementioning

confidence: 95%

Belatacept: a novel immunosuppressive agent for kidney transplant recipients

Charpentier¹

2012

Expert Review of Clinical Immunology

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Long-term graft and patient survival remain the most significant challenges in kidney transplantation, and new therapies are needed to improve long-term outcomes. Belatacept, a first-in-class selective costimulation blocker, has been approved for prophylaxis of organ rejection in kidney transplant recipients who are positive for EBV. In Phase III trials, belatacept demonstrated superior preservation of renal function and comparable patient/graft survival compared with cyclosporine, while avoiding the renal toxicities and other adverse events associated with the use of a calcineurin inhibitor. Patients treated with belatacept had higher rates of acute rejection than cyclosporine-treated patients. However, acute rejection episodes that occurred early and did not recur were generally not associated with donor-specific antibodies, and few belatacept patients had graft loss due to rejection. The improved renal benefit with belatacept may translate into improvements in long-term graft and patient outcomes. Targeting T-cell costimulation is an important new option for maintenance immunosuppression in kidney transplant recipients.

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Belatacept for kidney transplant recipients

Masson

Henderson

Chapman

et al. 2014

Cochrane Database of Systematic Reviews

101

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Cochrane Database of Systematic Reviews Main resultsWe included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better gra function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m , 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m , 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes a er transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.

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Infiltrating cellular pattern in kidney graft biopsies translates into forkhead box protein 3 up-regulation and p16INK4α senescence protein down-regulation in patients treated with belatacept compared to cyclosporin A

Cited by 17 publications

References 26 publications

Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years

Tissue talks: immunophenotype of cells infiltrating the graft explains histological findings and the benefits of belatacept at 10 years

Belatacept: a novel immunosuppressive agent for kidney transplant recipients

Belatacept for kidney transplant recipients

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