PubMed · 16557658
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Larry Moreland, Guy Bate, Peter Kirkpatrick. 2006. Abatacept.. https://doi.org/10.1038/nrd1989
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T cells are central mediators of adaptive immunity. As such, they are involved in both normal immune responses (e.g., rejection of a transplanted organ) and abnormal ones (e.g., rheumatoid arthritis). T cells require both antigen-specific and costimulatory signals for their full activation. Advances in protein engineering and an increased understanding of the immune response have culminated in the evolution and creation of protein therapeutics that target specific costimulatory molecules. The selective costimulation modulator abatacept (CTLA-4Ig) binds to CD80 and CD86, blocking interaction with CD28, and is approved for the treatment of moderate to severe rheumatoid arthritis. Belatacept, currently enrolling phase III trials in renal transplantation, was rationally designed from abatacept to bind with more avidity to CD86, providing the more potent immunosuppressive properties required for immunosuppression in transplantation. This review describes the relevant immunology and summarizes recent clinical findings on these two molecules. Although both inhibit the CD28 costimulatory pathway, they are tailored for specific disease states--abatacept for autoimmune diseases and belatacept for transplantation.
PURPOSE: The pharmacology, pharmacokinetics, indications, clinical efficacy, adverse effects, drug interactions, dosing, and administration of abatacept are discussed. SUMMARY: Abatacept is the first drug in a new class of agents known as selective costimulator modulators. Abatacept has been shown to decrease tumor necrosis factor (TNF)-alpha, which is important to the inflammatory response. Abatacept inhibits T-cell function but does not deplete T cells. Activated T cells are important in the inflammatory cascade, ultimately leading to joint inflammation and irreversible structural damage. In patients with rheumatoid arthritis, there is chronic inflammation of the synovial tissue lining the joint capsule. Abatacept is indicated for reducing the signs and symptoms of moderate to severe rheumatoid arthritis in adult patients who have had an inadequate response to at least one disease-modifying antirheumatic drug. Studies in adult patients with rheumatoid arthritis have evaluated abatacept in patients with an inadequate response to either methotrexate or TNF-alpha blocking agents. One trial showed that abatacept produced a favorable six-month clinical response in patients who had previously failed to respond to anti-TNF-alpha therapy. In a study of concurrent abatacept and methotrexate therapy, the addition of abatacept produced favorable outcomes in patients who were not adequately responding to methotrexate alone. CONCLUSION: Abatacept, a newly approved agent for the treatment of rheumatoid arthritis, has shown promising results in patients who have had an inadequate response to other treatment modalities. Abatacept therapy should be reserved for patients who have failed other time-tested treatment modalities, including TNF-alpha antagonists. Results from ongoing postmarketing studies will help determine abatacept's place in therapy.
In this study, we propagated myeloid dendritic cells (DC) from BALB/c (H2(d)) mouse bone marrow progenitors in IL-10 and TGF-beta, then stimulated the cells with LPS. These "alternatively activated" (AA) DC expressed lower TLR4 transcripts than LPS-stimulated control DC and were resistant to maturation. They expressed comparatively low levels of surface MHC class II, CD40, CD80, CD86, and programmed death-ligand 2 (B7-DC; CD273), whereas programmed death-ligand 1 (B7-H1; CD274) and inducible costimulatory ligand expression were unaffected. AADC secreted much higher levels of IL-10, but lower levels of IL-12p70 compared with activated control DC. Their poor allogeneic (C57BL/10; B10) T cell stimulatory activity and ability to induce alloantigen-specific, hyporesponsive T cell proliferation was not associated with enhanced T cell apoptosis. Increased IL-10 production was induced in the alloreactive T cell population, wherein CD4+Foxp3+ cells were expanded. The AADC-expanded allogeneic CD4+CD25+ T cells showed enhanced suppressive activity for T cell proliferative responses compared with freshly isolated T regulatory cells. In vivo migration of AADC to secondary lymphoid tissue was not impaired. A single infusion of BALB/c AADC to quiescent B10 recipients induced alloantigen-specific hyporesponsive T cell proliferation and prolonged subsequent heart graft survival. This effect was potentiated markedly by CTLA4-Ig, administered 1 day after the AADC. Transfer of CD4+ T cells from recipients of long-surviving grafts (>100 days) that were infiltrated with CD4+Foxp3+ cells, prolonged the survival of donor-strain hearts in naive recipients. These data enhance insight into the regulatory properties of AADC and demonstrate their therapeutic potential in vascularized organ transplantation.