Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist

Fife, Brian T.; Griffin, Matthew D.; Abbas, Abul K.; Locksley, Richard M.; Bluestone, Jeffrey A.

doi:10.1172/jci27856

Cited by 66 publications

(57 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Less attention has been paid to targeting the CTLA-4/B7 interaction, though induction of indoleamine 2,3-dioxygenase in DC, following ligation of surface B7 by CTLA-4, may be of relevance -in some models at least -to the development of tolerance [20]. Similarly, no agonistic anti-CTLA-4 mAb are yet described, although transgenic NOD mice expressing a single-chain, membrane-bound anti-CTLA-4 antibody on B cells show protection against development of autoimmune diabetes [21]. By contrast, agonist mAb to PD-1 and fusion proteins, such as PD-L1.Ig, have proven effective in disease models by increasing inhibitory signals within activated T cells [12,22].…”

Section: Discussionmentioning

confidence: 99%

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

2007

View full text Add to dashboard Cite

Programmed cell death-1 (PD-1, CD279) and its widely expressed, inducible ligand, PD-L1 (CD274), together dampen T cell activation, but whether they are essential for allograft tolerance is unknown. We show, using gene-deficient mice and blocking mAbs in wild-type mice, that costimulation blockade is ineffectual in PD-1 -/-or PD-L1 -/-allograft recipients, or in wild-type allograft recipients treated with anti-PD-1 or anti-PD-L1 mAb. Alloreactive PD-1 -/-CD4 and CD8 T cells had enhanced proliferation and cytokine production compared to wild-type controls, and anergy could not be induced in PD-1-deficient CD4 T cells. We conclude that without inhibitory signals from PD-1 ligation, alloantigen-induced T cell proliferation and expansion cannot be regulated by costimulation blockade, and peripheral tolerance induction cannot occur.

show abstract

Section: Discussionmentioning

confidence: 99%

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

2007

View full text Add to dashboard Cite

show abstract

“…Thus, a key role for B cells is most likely that of Ag presentation (39,40), which requires an organized lymphoid setting to promote T-B cell interactions. Recent studies have also shown that B cells can be engineered to down-regulate T cells via cell to cell contact, offering protection against diabetes (41). Thus, knowledge of the characteristics of B cells populating tertiary vs secondary lymphoid tissues may provide critical clues for disrupting the autoimmune process at the site of attack.…”

mentioning

confidence: 99%

Tertiary Lymphoid Structures in the Pancreas Promote Selection of B Lymphocytes in Autoimmune Diabetes

Kendall¹,

Yu²,

Woodward

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

Autoimmune diabetes occurs when invading lymphocytes destroy insulin-producing β cells in pancreatic islets. The role of lymphocytic aggregates at this inflammatory site is not understood. We find that B and T lymphocytes attacking islets in NOD mice organize into lymphoid structures with germinal centers. Analysis of BCR L chain genes was used to investigate selection of B lymphocytes in these tertiary lymphoid structures and in draining pancreatic lymph nodes. The pancreatic repertoire as a whole was found to be highly diverse, with the profile of L chain genes isolated from whole pancreas differing from that observed in regional lymph nodes. A Vκ14 L chain predominated within the complex pancreatic repertoire of NOD mice. Skewing toward Vκ4 genes was observed in the pancreas when the repertoire of NOD mice was restricted using a fixed Ig H chain transgene. Nucleotide sequencing of expressed Vκs identified shared mutations in some sequences consistent with Ag-driven selection and clonal expansion at the site of inflammation. Isolated islets contained oligoclonal B lymphocytes enriched for the germinal center marker GL7 and for sequences containing multiple mutations within CDRs, suggesting local T-B interactions. Together, these findings identify a process that selects B lymphocyte specificities within the pancreas, with further evolution of the selected repertoire at the inflamed site. This interpretation is reinforced by Ag-binding studies showing a large population of insulin-binding B lymphocytes in the pancreas compared with draining lymph nodes.

show abstract

“…In this issue of the JCI, Fife et al describe a novel approach for targeting CTLA-4 on activated T cells in order to inhibit autoimmune responses in the NOD mouse (24). They accomplished this by selectively expressing a single-chain, membranebound anti-CTLA-4 antibody (scFv) on B cells.…”

Section: A New Designer Approach For Targeting Ctla-4mentioning

confidence: 99%

“…A fourth approach would be to utilize gene therapy to target expression of the construct described by Fife et al (24) or ligands of other inhibitory receptors, such as PD-1, on APCs, including macrophages, dendritic cells, and B cells. This approach could perhaps even be extended to parenchymal tissue, for example, the islets, in the context of islet transplantation for autoimmune diabetes.…”

Section: Challenges To Targeting Negative Costimulatory Pathwaysmentioning

confidence: 99%

Costimulation couture: a designer approach to regulating autoimmunity

Ansari

Sayegh

2006

Journal of Clinical Investigation

View full text Add to dashboard Cite

Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist

Cited by 66 publications

References 42 publications

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

Programmed cell death 1 (PD‐1) and its ligand PD‐L1 are required for allograft tolerance

Tertiary Lymphoid Structures in the Pancreas Promote Selection of B Lymphocytes in Autoimmune Diabetes

Costimulation couture: a designer approach to regulating autoimmunity

Contact Info

Product

Resources

About