The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.

Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable.

Therapeutic HPV Cancer Vaccine Targeted to CD40 Elicits Effective CD8+ T-cell Immunity.

Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.

Water-soluble PDE4 inhibitors for the treatment of dry eye.

PDE4 inhibitors have the potential to alleviate the symptoms and underlying inflammation associated with dry eye. Disclosed herein is the development of a novel series of water-soluble PDE4 inhibitors. Our studies led to the discovery of coumarin 18, which is effective in a rabbit model of dry eye and a tear secretion test in rats.

Duration of action of topical antiallergy drugs in a Guinea pig model of histamine-induced conjunctival vascular permeability.

The topical application of 0.1% olopatadine has been shown to provide significant attenuation of histamine-induced conjunctival vascular permeability (CVP) within 5 min and for as long as 24 h following a topical administration. The duration of the action of olopatadine was compared to that of epinastine, azelastine, and ketotifen.

Keratocyte apoptosis and failure of corneal allografts.

Background: Murine models of high-risk and low-risk corneal transplantation were used to determine the role of keratocyte apoptosis in the failure of orthotopic allogeneic corneal transplants.

Materials And Methods: Normal (low-risk, low-rejecting) and inflamed/vascularized (high-risk, high-rejecting) BALB/c recipient beds received fully mismatched C57BL/6 corneal allografts. Apoptosis was detected in the corneal stroma at various time points using an in situ terminal deoxynucleotide tranferase-mediated dUTP nick-end labeling assay, and ex vivo via Western analysis for active caspase-3.

Role of interferon-gamma in a mouse model of allergic conjunctivitis.

Purpose: To characterize the effect of repeated topical exposure to allergen in a mouse model of allergic conjunctivitis and to determine the role of interferon-gamma (IFN-gamma) in the pathogenesis of allergic conjunctivitis.

Methods: Wild-type BALB/c mice and IFN-gamma knockout (KO) BALB/c mice were sensitized in the footpad with short ragweed (SRW) allergen and challenged topically for seven consecutive days with SRW allergen. The number of splenic CD4(+) Th2 cells was determined by flow cytometry, and the cytokine profile of CD4(+) T cells from SRW-sensitized mice was evaluated by ELISA.

Cutting edge: atopy promotes Th2 responses to alloantigens and increases the incidence and tempo of corneal allograft rejection.

A large body of evidence suggests that corneal allograft rejection is mediated by a type 1 Th cell response and that deviation toward type 2 immunity favors graft survival. However, clinical observations indicate that patients with severe ocular allergies have increased risk of corneal allograft rejection. We used a mouse model of atopic conjunctivitis to evaluate the effects of Th2 immune deviation on corneal allograft survival and possible mechanisms of graft rejection.

CD4(+) T-cell-mediated mechanisms of corneal allograft rejection: role of Fas-induced apoptosis.

Background: The role of CD4(+) T cells as effector cells in corneal allograft rejection is poorly understood. We investigated the role of CD4(+) T cells as helper cells in the generation of allospecific effector macrophages in corneal graft rejection and the role of CD4(+) T cells as apoptosis-inducing effector cells.

Methods: Corneal allografts were transplanted to CD4 knockout, FasL-deficient, and macrophage-depleted hosts.

Down regulation of interleukin-1beta-induced nitric oxide production in lacrimal gland acinar cells by sex steroids.

Purpose: Because the ocular surface is constantly exposed to allergens and irritants, it was reasoned that one cause of dry eye might be damage from inflammatory responses normally regulated by sex steroids. To test this hypothesis, we determined if sex steroids could down regulate nitric oxide (NO) production induced by interleukin-1beta (IL-1beta) in cultured rabbit lacrimal gland acinar cells.

Methods: Cultured rabbit lacrimal gland acinar cells were exposed to IL-1beta to stimulate NO production.

Peroxisome proliferator-activated receptor agonists inhibit interleukin-1beta-mediated nitric oxide production in cultured lacrimal gland acinar cells.

Development of dry eye disease often occurs in individuals with autoimmune disorders such as Sjögren's syndrome. The cause of dry eye in these patients is thought to be due, at least in part, to lymphocytic infiltration of the lacrimal glands, with subsequent loss of secretion of the aqueous component of tear film. How this lymphocytic infiltration leads to loss of secretion is not fully understood.

Induction of nitric oxide synthase and over-production of nitric oxide by interleukin-1beta in cultured lacrimal gland acinar cells.

Purpose: Inflammation of the lacrimal gland is one of the major causative factors in aqueous tear-deficient dry eye syndrome. Pro-inflammatory cytokine production is upregulated in lacrimal gland autoimmune disease (i.e.

Nitric oxide and cyclic GMP-mediated protein secretion from cultured lacrimal gland acinar cells.

Purpose: Nitric oxide (NO) donors and NO synthase (NOS) substrates were tested for their use to stimulate protein secretion from cultured lacrimal gland acinar cells, through activation of guanylate cyclase.

Method: Rabbit lacrimal gland epithelial cells (RLG cells) were incubated with NO donors and/or NOS substrates and the protein released into culture medium was determined with bicinchoninic acid assay. Guanylate cyclase activation by NO precursors was determined by measurement of c-GMP produced.