Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation

Badell, I. Raul; Karadkhele, Geeta; Vasanth, Payaswini; Farris, Alton B.; Rosenstein, Jennifer; Larsen, Christian

doi:10.1111/ajt.15319

Cited by 24 publications

(22 citation statements)

References 28 publications

(44 reference statements)

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“…The CTLA-4 Ig fusion protein abatacept, which inhibits CD28-mediated costimulatory signals by binding to CD80/CD86 on the surface of APCs, effectively suppresses T cell activation and cytokine production, which are associated with the development of rheumatoid arthritis ( 98 – 100 ). In the field of transplantation, the function of the transplanted graft persists, and no obvious immunological consequences are observed through the conversion from treatment of a CNI early after transplantation ( 100 ).…”

Section: Development In Amr Controlmentioning

confidence: 99%

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Matsuda¹,

Watanabe²,

Li³

2021

Front. Immunol.

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Both acute and chronic antibody-mediated allograft rejection (AMR), which are directly mediated by B cells, remain difficult to treat. Long-lived plasma cells (LLPCs) in bone marrow (BM) play a crucial role in the production of the antibodies that induce AMR. However, LLPCs survive through a T cell-independent mechanism and resist conventional immunosuppressive therapy. Desensitization therapy is therefore performed, although it is accompanied by severe side effects and the pathological condition may be at an irreversible stage when these antibodies, which induce AMR development, are detected in the serum. In other words, AMR control requires the development of a diagnostic method that predicts its onset before LLPC differentiation and enables therapeutic intervention and the establishment of humoral immune monitoring methods providing more detailed information, including individual differences in the susceptibility to immunosuppressive agents and the pathological conditions. In this study, we reviewed recent studies related to the direct or indirect involvement of immunocompetent cells in the differentiation of naïve-B cells into LLPCs, the limitations of conventional methods, and the possible development of novel control methods in the context of AMR. This information will significantly contribute to the development of clinical applications for AMR and improve the prognosis of patients who undergo organ transplantation.

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Section: Development In Amr Controlmentioning

confidence: 99%

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Matsuda¹,

Watanabe²,

Li³

2021

Front. Immunol.

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“…Our findings also indicate that the strategy of increasing A20 243 expression in the graft will synergise with other clinically tested as well as emerging graft 244 tolerance-inducing approaches. These would include rapamycin and abatacept (4,6,56), as 245 well as islet expression of the regulatory T cell attractant CCL22 (57), or graft expression of 246 CTLA4-Ig that prevents T-cell activation (58), and local expression of the anti-inflammatory 247 agent alpha-1-antitrypsin (59).…”

Section: Discussion 208mentioning

confidence: 99%

A20 is an immune tolerance factor that can determine islet transplant outcomes

Zammit

Walters

Seeberger

et al. 2019

Preprint

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1Islet transplantation can restore lost glycemic control in type 1 diabetes subjects, but is 2 restricted in its clinical application by limiting supplies of islets and the need for heavy 3 immune suppression to prevent rejection. TNFAIP3, encoding the ubiquitin editing enzyme 4 A20, regulates the activation of immune cells by raising NF-κB signalling thresholds. Here 5 we show that increasing A20 expression in allogeneic islet grafts resulted in permanent 6 survival for ~45 % of recipients, and >80% survival when combined with subtherapeutic 7 rapamycin. Allograft survival was dependent upon regulatory T cells, was antigen-specific 8 and grafts showed reduced expression of inflammatory factors, but increased TGFb and IL-9 10. By analysing islets expressing an A20 coding mutation (I325N) that cripples A20's OTU 10 ubiquitin editing domain, we found that A20 regulates intra-graft RIPK1 levels to modulate 11 NF-κB signalling. Transplantation of I325N islets resulted in increased NF-κB signalling, 12 graft hyper-inflammation and acute allograft rejection. Neonatal porcine islets (NPI) 13 represent a clinical alternative islet source but are readily rejected. However, forced A20 14 expression reduced NPI inflammation and increased their function after transplantation. 15

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“…AJT blockade methods (e.g., subcutaneous abatacept) perceived as less mechanistically potent but potentially more accessible for longterm maintenance therapy. 22 While gaining a better understanding of long-term outcomes and immunologic risk of a q2m belatacept maintenance strategy will require larger, multicenter studies, reducing belatacept dosing to enhance its long-term use promises to help continue to improve long-term outcomes in kidney transplantation.…”

Section: Ack N Owled G M Entsmentioning

confidence: 99%

Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial

Badell

Parsons

Karadkhele

et al. 2021

American Journal of Transplantation

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Belatacept results in improved kidney transplant outcomes, but utilization has been limited by logistical barriers related to monthly (q1m) intravenous infusions. Every 2month (q2m) belatacept has potential to increase utilization, therefore we conducted a randomized noninferiority trial in low immunologic risk renal transplant recipients greater than 1-year posttransplant. Patients on belatacept were randomly assigned to q1m or q2m therapy. The primary objective was a noninferiority comparison of renal function (eGFR) at 12 months with a noninferiority margin (NIM) of 6.0 ml/ min/1.73 m 2 . One hundred and sixty-six participants were randomized to q1m (n = 82) or q2m (n = 84) belatacept, 163 patients received treatment, and 76 q1m and 77 q2m subjects completed the 12-month study period. Every 2-month belatacept was noninferior to q1m, as the difference in mean eGFR adjusted for baseline renal function did not exceed the NIM. Two-month dosing was safe and well tolerated, with no patient deaths or graft losses. Four rejection episodes and three cases of donor-specific antibodies (DSAs) occurred among q2m subjects; however, only one rejection and one instance of DSA were observed in subjects adherent to the study protocol. Every 2month belatacept therapy may facilitate long-term utilization of costimulation blockade, but future multicenter studies with long-term follow-up will further elucidate immunologic risk. (ClinicalTrials.gov NCT02560558).

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Abatacept as rescue immunosuppression after calcineurin inhibitor treatment failure in renal transplantation

Cited by 24 publications

References 28 publications

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

Approaches for Controlling Antibody-Mediated Allograft Rejection Through Targeting B Cells

A20 is an immune tolerance factor that can determine islet transplant outcomes

Every 2-month belatacept maintenance therapy in kidney transplant recipients greater than 1-year posttransplant: A randomized, noninferiority trial

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