BTLA targeting modulates lymphocyte phenotype, function, and numbers and attenuates disease in nonobese diabetic mice.
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.
Truong
Wayne
W
Surgical Medical Research Institute, Department of Surgery, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Hancock
Wayne W
WW
Plester
Jennifer C
JC
Merani
Shaheed
S
Rayner
David C
DC
Thangavelu
Govindarajan
G
Murphy
Kenneth M
KM
Anderson
Colin C
CC
Shapiro
A M James
AM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000943:Antigens, Differentiation / Q000276:immunology; D001402:B-Lymphocytes / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D004347:Drug Interactions; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects*; D051379:Mice; D016688:Mice, Inbred NOD; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; C488868:BTLA protein, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D016753:Interleukin-10; D018664:Interleukin-12