BTLA targeting modulates lymphocyte phenotype, function, and numbers and attenuates disease in nonobese diabetic mice

Abstract

The novel coinhibitory receptor BTLA may have a regulatory role in maintaining peripheral tolerance; however, its role in autoimmune diabetes is unknown. In this study, we show that anti-BTLA mAb 6F7 selectively depleted pathogenic B and CD4+ T(H) cells; enhanced the proportion of cells with the forkhead box p3+ PD-1+CD4+ regulatory T phenotype; and increased the production of potentially protective (IL-10) and detrimental (IL-2, IFN-gamma) cytokines in NOD mice. As interactions between BTLA and PD-1 coinhibitory pathways have been described in the cardiac allograft model, we also investigated if these pathways may have significant interaction in autoimmune diabetes. Anti-BTLA inhibited anti-PD-1-potentiated total IL-12 (p40+p70) production, suggesting the possibility that anti-BTLA may have a greater effect in the setting of anti-PD-1-triggered diabetes. To test this, NOD mice at 4 and 10 weeks of age were treated with anti-BTLA mAb, anti-PD-1 mAb, both mAb, or isotype control and were monitored for diabetes development. Although anti-BTLA mAb delayed diabetes onset significantly in 10- but not 4-week-old NOD mice, anti-BTLA mAb attenuated anti-PD-1-induced diabetes in both age groups. Hence, strategies targeting BTLA+ lymphocytes or therapies enhancing the BTLA-negative cosignal may prove valuable in treating autoimmune diabetes.

B and T Lymphocyte Attenuator Restricts the Protective Immune Response against Experimental Malaria

“…Triggering BTLA or deleting BTLA highly positive T cells also might have therapeutic significance. In a model of cerebral malaria, we have shown that an agonistic Ab can prevent experimental cerebral malaria (14) and others have shown that anti-BTLA can induce delayed onset of diabetes (15), decreased T cell-induced colitis (6), and prolonged allograft survival (15,16).…”

Defining the Role of BTLA in Breast Cancer Immunosurveillance and Selective Targeting of the BTLA-HVEM-LIGHT Costimulatory System

“…As a positive control, we included a de pleting murine antiBTLA antibody, 6F7 Truong et al, 2009). CFSElabeled donor cells were trans ferred into WT recipients that also received PIP, 6A6, or 6F7 antibody.…”

Editorial: Therapeutic potential of targeting BTLA

“…There are a growing number of inhibitory receptors described, including CTLA-4, PD-1, BTLA, LAG-3, and CD160. In this issue of the Journal of Leukocyte Biology, a paper by Truong et al [1] examines the influence of anti-BTLA and anti-PD-1 antibodies on the disease progression in a model of autoimmune diabetes. This paper emphasizes the complexity involved in developing therapeutic antibody-based regimens to regulate immune responses using in vivo models and highlights the importance of understanding the function of these antibodies.…”