Role of the Immune Modulator Programmed Cell Death-1 during Development and Apoptosis of Mouse Retinal Ganglion Cells

Background: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. Methods: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. Results: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signaling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and MicroRNAs, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in immune escape of cervical cancer through inhibition of host immune response. creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PD-L1/PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. Conclusion: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body’s immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

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The role of B7 family molecules in hematologic malignancy

Blood ◽

10.1182/blood-2012-10-385591 ◽

2013 ◽

Vol 121 (5) ◽

pp. 734-744 ◽

Cited By ~ 98

Author(s):

Paul Greaves ◽

John G. Gribben

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Immune Responses ◽

Hematologic Malignancy ◽

Surface Proteins ◽

Cell Responses ◽

Inducible Costimulator ◽

Programmed Cell Death 1 ◽

B7 Family

AbstractThe B7 family consists of structurally related, cell-surface proteins that regulate immune responses by delivering costimulatory or coinhibitory signals through their ligands. Eight family members have been identified to date including CD80 (B7-1), CD86 (B7-2), CD274 (programmed cell death-1 ligand [PD-L1]), CD273 (programmed cell death-2 ligand [PD-L2]), CD275 (inducible costimulator ligand [ICOS-L]), CD276 (B7-H3), B7-H4, and B7-H6. B7 ligands are expressed on both lymphoid and nonlymphoid tissues. The importance of the B7 family in regulating immune responses is clear from their demonstrated role in the development of immunodeficiency and autoimmune diseases. Manipulation of the signals delivered by B7 ligands shows great potential in the treatment of cancers including leukemias and lymphomas and in regulating allogeneic T-cell responses after stem cell transplantation.

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Excess of Serotonin (5-HT) Alters the Segregation of Ispilateral and Contralateral Retinal Projections in Monoamine Oxidase A Knock-Out Mice: Possible Role of 5-HT Uptake in Retinal Ganglion Cells During Development

Journal of Neuroscience ◽

10.1523/jneurosci.19-16-07007.1999 ◽

1999 ◽

Vol 19 (16) ◽

pp. 7007-7024 ◽

Cited By ~ 121

Author(s):

A. L. Upton ◽

N. Salichon ◽

C. Lebrand ◽

A. Ravary ◽

R. Blakely ◽

...

Keyword(s):

Monoamine Oxidase ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Monoamine Oxidase A ◽

Retinal Ganglion ◽

Knock Out ◽

Retinal Projections ◽

5 Ht Uptake ◽

Knock Out Mice

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Role of tumor necrosis factor receptor-1 in the death of retinal ganglion cells following optic nerve crush injury in mice

Brain Research ◽

10.1016/j.brainres.2003.10.029 ◽

2004 ◽

Vol 996 (2) ◽

pp. 202-212 ◽

Cited By ~ 120

Author(s):

Gülgün Tezel ◽

Xiangjun Yang ◽

Junjie Yang ◽

Martin B. Wax

Keyword(s):

Retinal Ganglion Cells ◽

Tumor Necrosis ◽

Ganglion Cells ◽

Tumor Necrosis Factor Receptor ◽

Optic Nerve Crush ◽

Retinal Ganglion ◽

Nerve Crush ◽

Necrosis Factor ◽

Nerve Crush Injury

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The Role of N-Methyl-D-Aspartate Receptor Activation in Homocysteine-Induced Death of Retinal Ganglion Cells

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.10-6870 ◽

2011 ◽

Vol 52 (8) ◽

pp. 5515 ◽

Cited By ~ 52

Author(s):

Preethi S. Ganapathy ◽

Richard E. White ◽

Yonju Ha ◽

B. Renee Bozard ◽

Paul L. McNeil ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Receptor Activation ◽

Retinal Ganglion ◽

Aspartate Receptor

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Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis

Journal of Neuroinflammation ◽

10.1186/s12974-019-1622-1 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 5

Author(s):

Barakat Alrashdi ◽

Bassel Dawod ◽

Andrea Schampel ◽

Sabine Tacke ◽

Stefanie Kuerten ◽

...

Keyword(s):

Multiple Sclerosis ◽

Retinal Ganglion Cells ◽

Axonal Degeneration ◽

Ganglion Cells ◽

Neuronal Degeneration ◽

Retinal Ganglion ◽

Autoimmune Encephalomyelitis ◽

Aav Vector ◽

Α Subunit

Abstract Background In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na+/Ca2+ exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. The persistent influx of sodium through Nav1.6 is believed to reverse the function of NCX, resulting in an increased influx of damaging Ca2+ ions. However, direct evidence for the role of Nav1.6 in axonal degeneration is lacking. Methods In mice floxed for Scn8a, the gene that encodes the α subunit of Nav1.6, subjected to EAE we examined the effect of eliminating Nav1.6 from retinal ganglion cells (RGC) in one eye using an AAV vector harboring Cre and GFP, while using the contralateral either injected with AAV vector harboring GFP alone or non-targeted eye as control. Results In retinas, the expression of Rbpms, a marker for retinal ganglion cells, was found to be inversely correlated to the expression of Scn8a. Furthermore, the gene expression of the pro-inflammatory cytokines Il6 (IL-6) and Ifng (IFN-γ), and of the reactive gliosis marker Gfap (GFAP) were found to be reduced in targeted retinas. Optic nerves from targeted eyes were shown to have reduced macrophage infiltration and improved axonal health. Conclusion Taken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.

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