Clinical targeting of the TNF and TNFR superfamilies

Croft, Michael; Benedict, Chris A.; Ware, Carl F.

doi:10.1038/nrd3930

Cited by 395 publications

(391 citation statements)

References 214 publications

(203 reference statements)

Supporting

Mentioning

372

Contrasting

Unclassified

Order By: Relevance

“…Recombinant fusion proteins and mAbs (biologics) that target members of the TNF, TNFR and immunoglobulin superfamily molecules are the central focus of attention for therapy in many immune-mediated diseases. 37,38 An example of this statement is the efficacy of CD40L/CD40 targeting in preclinical and clinical settings of transplantation and autoimmune disease. 39,40 The data presented herein demonstrate that modulation of BTLA/HVEM pathway does not affect Tfh cell expansion, GC reactions or the de novo formation of host antidonor allogeneic antibodies.…”

Section: Discussionmentioning

confidence: 99%

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

et al. 2016

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

et al. 2016

View full text Add to dashboard Cite

“…Targeting TNF and TNF receptor for disease intervention is already established for autoimmune and inflammatory disorders. 39 Earlier clinical studies evaluated the promising use of anti-TNF antibodies in alcoholic steatohepatitis (ASH). 40 However, subsequent clinical trials with higher anti-TNF concentrations failed to have a positive effect in these patients and the studies were terminated.…”

Section: Discussionmentioning

confidence: 99%

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

et al. 2013

View full text Add to dashboard Cite

Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-jB essential modulator in hepatocytes (IKKc/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKKc/Nemo-deleted livers. We crossed hepatocyte-specific IKKc/Nemo knockout mice (Nemo Dhepa ) with constitutive TNFR1 À / À and TRAIL À / À mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF-and not TRAIL signaling determines the progression of IKKc/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.

show abstract

“…7–9 These receptors belong to the TNF receptor superfamily (TNFRSF), which are activated by binding of their cognate ligands of the TNF superfamily (TNFSF). However, efficient activation of the receptors often requires receptor clustering induced by binding of more than one ligand displayed on the cell membrane.…”

Section: Introductionmentioning

confidence: 99%

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

et al. 2018

View full text Add to dashboard Cite

Co-stimulatory signals induced by ligands of the tumor necrosis factor superfamily (TNFSF) play a central role in T cell activation and have emerged as a promising strategy in cancer immunotherapy. Here, we established a novel class of bifunctional co-stimulatory fusion proteins with the aim to boost T cell activation at the level of T cell – antigen-presenting cell (APC) interaction. These novel dual-acting cytokine fusion proteins were created by connecting two different homotrimeric TNFSF ligands to form homotrimeric bifunctional molecules (Duokines) or by connecting single-chain derivatives of two different homotrimeric TNFSF with a single, flexible linker (single-chain Duokines, scDuokines). By linking the TNFSF ligands 4-1BBL, OX40L and CD27L in all possible combinations, cis-acting Duokines were generated that act on the same or adjacent T cells, while combining CD40L with 4-1BBL, OX40L and CD27L resulted in trans-acting Duokines acting simultaneously on APCs and T cells. In vitro, co-stimulation of T cells was seen for cis- and trans-acting Duokines and scDuokines in an antigen-independent as well as antigen-specific setting. Trans-acting molecules furthermore activated B cells, which represent a subclass of APCs. In a pilot experiment using the syngeneic B16-FAP mouse tumor model scDuokines displayed antitumoral activity in vivo in combination with a primary T cell-activating bispecific antibody, evident from reduced number of lung metastasis compared to the antibody-only treated group. Our data show that the bifunctional, co-stimulatory duokines are capable to enhance T cell-mediated anti-tumor immune responses, suggesting that they can serve as a new class of immuno-stimulatory molecules for use in cancer immunotherapy strategies.

show abstract

Clinical targeting of the TNF and TNFR superfamilies

Cited by 395 publications

References 214 publications

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

T follicular helper expansion and humoral-mediated rejection are independent of the HVEM/BTLA pathway

TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model

Duokines: a novel class of dual-acting co-stimulatory molecules acting in cis or trans

Contact Info

Product

Resources

About