Objective Analysis and Clinical Significance of the Spatial Tumor-Infiltrating Lymphocyte Patterns in Non-Small Cell Lung Cancer.

PURPOSE: The spatial arrangement of lymphocytes in the tumor bed (e.g., immune infiltrated, immune excluded, immune desert) is expected to reflect distinct immune evasion mechanisms and to associate with immunotherapy outcomes. However, data supporting these associations are scant and limited by the lack of a clear definition for lymphocyte infiltration patterns and the subjective nature of pathology-based approaches. EXPERIMENTAL DESIGN: We used multiplexed immunofluorescence to study major tumor-infiltrating lymphocyte (TIL) subsets with single-cell resolution in baseline whole-tissue section samples from NSCLC patients treated with immune checkpoint inhibitors (ICI). The spatial TIL patterns were analyzed using a qualitative pathologist-based approach, and an objective analysis of TIL density ratios in tumor/stromal tissues. The association of spatial patterns with outcomes was studied for different TIL markers. RESULTS: The analysis of CD8+ TIL patterns using qualitative assessment identified prominent limitations including the presence of a broad spectrum of phenotypes within most tumors and limited association with outcomes. The utilization of an objective method to classify NSCLCs showed the existence of at least three subgroups with partial overlap with those defined using visual patterns. Using this strategy, a subset of cases with "immune excluded-like" tumors showed prominently worse outcomes, suggesting reduced sensitivity to ICI; however, these results need to be validated. The analysis for other TIL subsets showed different results, underscoring the relevance of the marker selected for spatial TIL pattern evaluation and opportunities for market integration. CONCLUSIONS: Our results identified major challenges associated with the qualitative spatial TIL pattern evaluation. We devised a novel objective strategy to overcome some of these limitations that has strong biomarker potential.

Role of therapeutic contact lenses in management of corneal disease.

PURPOSE OF REVIEW: The current review highlights areas of innovation and research in the use of contact lenses in the treatment of corneal ectasia and ocular surface disease. RECENT FINDINGS: A series of academic reports were published by a committee of experts reviewing evidence-based practice patterns of contact lens use. There continues to be active research in the use of contact lenses in the management of keratoconus, including mini-scleral lenses, custom impression-based scleral lenses and wavefront-guided scleral lenses. Recent reports on contact lenses for ocular surface disease were primarily reviews, retrospective case reports or case series, with publications on contact lens use in corneal epithelial defects, graft-vs.-host disease, limbal stem cell deficiency and neurotrophic keratitis. There are recent publications on advances in drug-eluting contact lenses. SUMMARY: Corneal specialists should be aware of current advances in the field of contact lens expanding their use in corneal ectasia and ocular surface disease.

Open Globe Injury with Intraocular Foreign Body.

PURPOSE: To investigate characteristics of Open Globe Injuries (OGI) that presented with Intra-Ocular Foreign Body (IOFB), along with their long-term visual outcomes, complications and need for subsequent surgeries. METHODS: Retrospective interventional consecutive case series of OGIs with IOFBs that presented to the Eye Trauma service at the Massachusetts Eye and Ear from 2010 to 2015. Data collected included time from injury to OGI repair, location of injury and IOFB, retinal detachment (RD) rate, presenting and final visual acuity (VA) and subsequent surgeries. RESULTS: Fifty-seven consecutive cases of OGIs with IOFBs were included. The majority of patients were male (93%), mean age was 37 years and mean follow-up was 28 +/- 22 months. The median time from injury to OGI repair was 0 days (range: 0-16 days). Overall, 38/57 (66.7%) eyes achieved final vision of 20/40 or better and 43/57 (75.4%) vision of 20/150 or better. Zone I injuries were the most common (86%), followed by Zone II (16%), and Zone III (10%). 33 cases had IOFBs in the anterior segment only and 24 cases had posterior segment involvement. In total, 30% of cases (17/57) were complicated by an RD, 58.3% (14/24) in the posterior versus 9.1% (3/33) in the anterior IOFB group.( p<0.01). There were no cases of endophthalmitis. Posterior IOFB and higher zone of injury were found to be risk factors for RD both at presentation (all p<0.05) and post-primary repair.(all p<0.05) Posterior IOFB was associated with higher vitrectomy rates both at presentation (p<0.0001) and post-primary repair (p=0.002) and worse long-term visual outcome (p = 0.014). CONCLUSION: OGIs with IOFB involving the posterior segment are associated with higher complication and re-operation rates and worse visual prognosis compared to those involving the anterior segment only.

Long-term Outcomes of Punctal Cauterization in the Management of Ocular Surface Diseases.

PURPOSE: To evaluate the long-term outcomes of surgical occlusion of lacrimal puncta using thermal cautery in the management of ocular surface diseases. METHODS: We reviewed medical records of 80 consecutive patients from a single academic center who underwent punctal cauterization. Patient demographics, ocular history, symptoms, and signs of ocular surface diseases pre- and post-cauterization were recorded. RESULTS: A total of 80 patients (171 puncta) were included, with an average age of 59 years and a follow-up duration of 27 months. The most common ocular morbidity was ocular graft-versus-host disease (n = 36), followed by primary keratoconjunctivitis sicca (n = 15). Indications for punctal cauterization included plug loss (n = 51), difficulty in plug fitting (n = 11), plug-related complications (n = 6), recanalization of previous cauterization (n = 7), and severe ocular surface disease requiring permanent punctal closure (n = 4). After punctal cauterization, the percentage of eyes with severe (21%) and moderate (25%) dry eye decreased significantly (8% and 19% at 3 months and 6% and 17% at 12 months, P = 0.0006). Fifty-four percent of patients reported improvement in their symptoms. The rate of recanalization was 21% during the follow-up period. The use of topical corticosteroids was associated with higher recanalization rate. Associated complications were limited to temporary pain and swelling. CONCLUSIONS: Punctal cauterization is an effective modality in treating severe ocular surface diseases in patients who repeatedly lose punctal plugs, and it can be easily performed in a clinic setting without major complications. However, cauterization may need to be repeated in up to a quarter of cases because of recanalization.

Comparison of central topographic maps from a swept-source OCT biometer and a Placido disk-dual Scheimpflug tomographer.

PURPOSE: To compare central topography (CT) from IOLMaster 700 with predicate topographic (PT) maps from a Placido disk-dual Scheimpflug tomographer in detection of irregularities that would influence the decision-making for implanting premium intraocular lenses (IOLs) (toric, multifocal, or extended depth-of-focus). SETTING: Cullen Eye Institute, Baylor College of Medicine, Houston, Texas. DESIGN: Prospective comparative case series. METHODS: Eyes with various corneal conditions were randomly selected: regular/irregular corneas, previous corneal refractive surgery, and keratoconus or pellucid marginal degeneration. Three observers compared the CT and PT maps and answered a questionnaire for each eye. The questionnaire focused on (1) overall shape similarity between CT and PT and (2) decision-making for premium IOL implantation based on CT and PT. Answers to the questionnaire and agreement in answers among observers were evaluated. RESULTS: The study included 105 eyes. Comparing CT and PT, similar shape was observed in 68.6% to 89.5% of cases, and comparable map symmetries were reported in 60.0% to 83.8%; the same decision regarding premium IOL implantation was made in 75.2% to 97.1% of cases. There were significant interobserver agreements among 3 observers for all questions, with Fleiss κ values ranging from 0.141 to 0.450 (all P < .05). Peripheral corneal steeping or flattening was the primary finding that was visible on PT but not on CT. CONCLUSIONS: Compared with the PT, CT provided similar overall shape and comparable symmetries in most cases. The same decision was made whether to recommend a premium IOL based on CT and PT in 75% to 97% of cases.

Wireless Technologies for Implantable Devices.

Wireless technologies are incorporated in implantable devices since at least the 1950s. With remote data collection and control of implantable devices, these wireless technologies help researchers and clinicians to better understand diseases and to improve medical treatments. Today, wireless technologies are still more commonly used for research, with limited applications in a number of clinical implantable devices. Recent development and standardization of wireless technologies present a good opportunity for their wider use in other types of implantable devices, which will significantly improve the outcomes of many diseases or injuries. This review briefly describes some common wireless technologies and modern advancements, as well as their strengths and suitability for use in implantable medical devices. The applications of these wireless technologies in treatments of orthopedic and cardiovascular injuries and disorders are described. This review then concludes with a discussion on the technical challenges and potential solutions of implementing wireless technologies in implantable devices.

Validation of a Comprehensive Clinical Algorithm for the Assessment and Treatment of Microbial Keratitis.

PURPOSE: To validate a comprehensive clinical algorithm for the assessment and treatment of microbial keratitis (MK). DESIGN: Retrospective cohort study. METHODS: The "1, 2, 3 Rule" for the initial management of MK was conceived by Vital and associates in 2007 to inform the decision as to when to perform corneal cultures. The rule is invoked when any 1 of 3 clinical parameters is met: ≥1+ anterior chamber cells, ≥2 mm infiltrate, or infiltrate ≤3 mm distance from the corneal center. When the rule is met, we added the mandatory use of fortified topical antibiotics after cultures are obtained. We compared outcomes of cases presenting to Massachusetts Eye and Ear 2 years before (Group I, n = 665) and after (Group II, n = 767) algorithm implementation. The primary composite outcome was a vision-threatening complication, such as corneal perforation. RESULTS: At a median follow-up of 67.0 and 60.0 days, respectively, 172 patients experienced a vision-threatening complication (Group I, 12.9% vs Group II, 11.2%, P = .51). While the algorithm codified conventional management practice at either end of disease severity, the effect of algorithm-augmented care was best appreciated in patients with lesions satisfying only 1 criterion. In this group, there was an increase in the proportion of patients undergoing culture at presentation (54.6% vs 67.7%, P = .006), fortified antibiotic prescription (29.7% vs 53.9%, P < .001), and reduction in vision-threatening complications (9.7% vs 1.8%, P = .001). The proportion of patients who were not cultured at presentation but later required culturing decreased (13.4% vs 5.1%, P = .001), as did patients who did not meet any criteria but were nonetheless cultured (23.9% vs 8.5%, P < .001). Multiple logistic regression showed that all algorithm parameters were independently associated with outcome: ≥1+ anterior chamber cells (odds ratio [OR] 1.66, 95% confidence interval 1.09-2.52); ≥2 mm infiltrate (OR 4.74, 2.68-8.40); and ≤3 mm from corneal center (OR 2.82, 1.85-4.31), confirmed with comparison to a bootstrapped sample (n = 10,000). CONCLUSIONS: The implementation of this algorithm reduced vision-threatening complications for patients with lesions satisfying only 1 criterion, arguably the most difficult patients in whom to judge disease severity. Implementation also led to a decrease in patients receiving unnecessary care.

Prosthetic Replacement of the Ocular Surface Ecosystem Treatment for Ocular Surface Disease in Pediatric Patients With Stevens-Johnson Syndrome.

PURPOSE: To report the outcomes of prosthetic replacement of the ocular surface ecosystem (PROSE) treatment in pediatric patients with chronic ocular surface disease associated with Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). DESIGN: Retrospective, interventional case series. METHODS: Patients aged 18 years or younger seen in consultation for PROSE treatment at a single center between January 1992 and December 2016 with a history of SJS/TEN were reviewed. Demographics, etiology of SJS/TEN, age at treatment milestones, best-corrected visual acuity (BCVA) at treatment milestones, and treatment failures were recorded. BCVA at the initial presentation visit was compared to BCVA at the time of PROSE device dispense and at the last recorded visit. RESULTS: Twenty-seven female and 22 male patients were reviewed. Reported etiology was antibiotic (n = 19), antiepileptic (n = 9), antipyretic (n = 9), other (n = 3), and unknown (n = 9). The mean age was 6.4 years at disease onset and 9.3 years at time of initial presentation. The mean duration of follow-up was 5.45 years. The median BCVA at the initial presentation was 0.6 logMAR (20/80 Snellen), and was significantly improved to 0.18 logMAR (20/30 Snellen) at the time a PROSE device was dispensed (P < .0001). The median BCVA at the last recorded visit was significantly improved to 0.18 logMAR (20/30 Snellen, P = .0004). There were 15 patients who failed PROSE treatment (30.6%). CONCLUSIONS: PROSE treatment is feasible in over two thirds of pediatric patients with chronic ocular surface disease related to SJS/TEN and results in significant improvement in vision that is durable over a period of many years.

A Lacrimal Gland Choristoma of the Lacrimal Sac.

Choristomatous lacrimal gland tissue has been detected in many different sites of the ocular adnexa, but has never before been convincingly described in the submucosa of the lacrimal sac. A 77-year-old woman with epiphora had a biopsy of the sac wall preformed during a dacryocystorhinostomy that contained such a lacrimal choristoma. Zymogen granules were found in the cytoplasm of the secretory cells with the periodic acid-Schiff reaction. No mucus-producing cells, as found in normal sac submucosal glands, were detected using the Alcian blue, mucicarmine, and Gomori methenamine silver histochemical stains. Gross cystic fluid protein-15 positivity was demonstrated immunohistochemically. The clinical implications of this choristoma are explored.

Dopamine neuron dependent behaviors mediated by glutamate cotransmission.

Dopamine neurons in the ventral tegmental area use glutamate as a cotransmitter. To elucidate the behavioral role of the cotransmission, we targeted the glutamate-recycling enzyme glutaminase (gene Gls1). In mice with a dopamine transporter (Slc6a3)-driven conditional heterozygous (cHET) reduction of Gls1 in their dopamine neurons, dopamine neuron survival and transmission were unaffected, while glutamate cotransmission at phasic firing frequencies was reduced, enabling a selective focus on the cotransmission. The mice showed normal emotional and motor behaviors, and an unaffected response to acute amphetamine. Strikingly, amphetamine sensitization was reduced and latent inhibition potentiated. These behavioral effects, also seen in global GLS1 HETs with a schizophrenia resilience phenotype, were not seen in mice with an Emx1-driven forebrain reduction affecting most brain glutamatergic neurons. Thus, a reduction in dopamine neuron glutamate cotransmission appears to mediate significant components of the GLS1 HET schizophrenia resilience phenotype, and glutamate cotransmission appears to be important in attribution of motivational salience.

Assessing the impact of an emergency trauma course for senior medical students in Kenya.

INTRODUCTION: Ninety percent of all injury-related deaths occur in low- and middle-income countries. The WHO recommends short, resource-specific trauma courses for healthcare providers. Studies show that teaching trauma courses to medical students in developed countries leads to significant increases in knowledge and skill. High costs hinder widespread and sustained teaching of these courses in low-income countries. METHODS: A two-day trauma course was designed for students at Moi College of Health Sciences in Eldoret, Kenya. Participants underwent pre- and post-course written and simulation testing and rated their confidence in 21 clinical scenarios and 15 procedures pre- and post-course using a five point Likert scale. A subset of the students was re-evaluated nine months post-course. Using the paired t-test, mean written, simulation and confidence scores were compared pre-course, immediately post-course and nine months post-course. RESULTS: Twenty-two students were enrolled. Written test score means were 61.5% pre-course and 76.9% post-course, mean difference 15.5% (p < 0.001). Simulation test score means were 36.7% pre-course and 82.2% post-course, mean difference 45.5% (p < 0.001). Aggregate confidence scores were 3.21 pre-course and 4.72 post-course (scale 1-5). Ten out of 22 (45.5%) students were re-evaluated nine months post-course. Results showed written test score mean of 75%, simulation score mean of 61.7%, and aggregate confidence score of 4.59 (scale 1-5). Mean differences between immediate post- and nine months post-course were 1.6% (p = 0.75) and 8.7% (p = 0.10) for the written and simulation tests, respectively. CONCLUSION: Senior Kenyan medical students demonstrated statistically significant increases in knowledge, skills and confidence after participating in a novel student trauma course. Nine months post-course, improvements in knowledge skills and confidence were sustained.

Assessing the impact of an emergency trauma course for senior medical students in Kenya

Introduction:Ninety percent of all injury-related deaths occur in low- and middle-income countries. The WHO recommends short, resource-specific trauma courses for healthcare providers.Studies show that teaching trauma courses to medical students in developed countries leads to significant increases in knowledge and skill. High costs hinder widespread and sustained teaching of these courses in low-income countries.Methods:A two-day trauma course was designed for students at Moi College of Health Sciences in Eldoret,Kenya. Participants underwent pre- and post-course written and simulation testing and rated their confidence in 21 clinical scenarios and 15 procedures pre- and post-course using a five point Likert scale. A subset of the students was re-evaluated nine months post-course. Using the pairedt-test, mean written, simulation and confidence scores were compared pre-course,immediately post-course and nine months post-course.Results:Twenty-two students were enrolled. Written test score means were 61.5% pre-course and 76.9%post-course, mean difference 15.5% (p < 0.001). Simulation test score means were 36.7% pre-course and 82.2% post-course, mean difference 45.5% (p < 0.001). Aggregate confidence scores were 3.21 pre-course and 4.72 post-course (scale 1­5). Ten out of 22 (45.5%) students were re-evaluated nine months post- course. Results showed written test score mean of 75%, simulation score mean of 61.7%, and aggregate confidence score of 4.59 (scale 1­5). Mean differences between immediate post- and nine months post-course were 1.6% (p = 0.75) and 8.7% (p = 0.10) for the written and simulation tests, respectively.Conclusion: Senior Kenyan medical students demonstrated statistically significant increases in knowledge, skills and confidence after participating in a novel student trauma course. Nine months post-course, improvements in knowledge skills and confidence were sustained

Clinical Experience With PROSE Fitting: Significance of Diagnosis and Age.

OBJECTIVE: To compare ease of adoption of the BostonSight Prosthetic Replacement of the Ocular Surface Ecosystem device, a custom-fit scleral lens, by patients in different age and diagnosis groups. METHODS: In this prospective study, patients were categorized by age as younger than 60 or 60 years and older and by diagnosis as corneal irregularity (CI) or ocular surface disease (OSD). Ease of adoption of the scleral device was assessed by (1) number of devices and visits required to complete the fitting process, (2) time needed for device insertion and removal, (3) adaptation to the device, as assessed by daily wear time and by time needed to achieve full-time wear (defined as 8 hours per day), and (4) patients' subjective rating of ease of device insertion and removal. The length of the fitting process was also assessed. RESULTS: There was no significant difference in the number of devices and visits needed between age group younger than 60 and age group of 60 and older or between CI and OSD groups. Patients in all groups achieved full-time wear in less than 2 weeks. Average wear time per week did not differ significantly between age or diagnosis groups. Similarly, the time needed for daily insertion and removal during the fitting period, as well as patients' subjective rating of ease of device insertion and removal, did not differ between age or diagnosis categories. The length of the fitting process was significantly longer in the OSD group compared with the CI group (P<0.001); however, factors not related to ease of adoption of the scleral device may be responsible for this difference. CONCLUSIONS: Patients in both younger and older patient groups adopted the use of a scleral device with equal ease, as did patients in the CI and OSD diagnosis groups.

Dermatomyositis-Related Nonischemic Central Retinal Vein Occlusion.

A 25-year-old woman with dermatomyositis suffered a right central retinal vein occlusion (CRVO) with visual acuity of 20/40. Examination of the right eye showed vitreous cells, suggesting inflammation of the central retinal vein leading to a CRVO as the presumed mechanism. She was admitted to hospital, and extensive evaluation was negative. She was maintained on corticosteroids to manage her dermatomyositis. One month later, she had macular edema and elevated intraocular pressure. Both resolved with dorzolamide, timolol, and intravitreal bevacizumab, and vision returned to 20/20 in the right eye.

Corneal nerve structure and function after long-term wear of fluid-filled scleral lens.

PURPOSE: The aim of this study was to determine whether long-term wear of a fluid-filled scleral lens alters basal tear production, corneal sensation, corneal nerve density, and corneal nerve morphology in 2 disease categories. METHODS: Patients recruited from the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) treatment program at the Weill Cornell Medical College were categorized into 2 groups: distorted corneas (DC) or ocular surface disease (OSD). We measured tear production, central corneal sensation, subbasal nerve density and tortuosity, and stromal nerve thickness before and after long-term wear of the prosthetic device used in PROSE treatment, defined as at least 60 days of wear for a minimum of 8 hours a day. RESULTS: Twenty patients were included in the study. After long-term wear of the prosthetic device, tear production decreased in patients with DC (21.2 ± 8.5 to 10.4 ± 4.6 mm; P < 0.0001) but did not change in patients with OSD (7.5 ± 5.2 to 8.7 ± 7.2 mm; P = 0.71). Corneal sensation increased in the DC group (45.6 ± 9.2 to 55.0 ± 5.6 mm; P < 0.05). There was no significant change in sensation in patients with OSD (45.0 ± 8.7 to 49.1 ± 14.8 mm; P = 0.37). Subbasal nerve density, subbasal nerve tortuosity, and stromal nerve thickness remained unchanged in both DC and OSD groups after long-term wear (P > 0.05). CONCLUSIONS: Patients with DC had significantly reduced basal tear production and increased corneal sensation after long-term wear of the scleral lens, but patients with OSD did not show any changes in tear production or corneal sensation.

Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice.

Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG(ERT2cre∕+) mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reduction in GLS1 allelic abundance and glutaminase mRNA levels in the brain. While GLS1 iHET mice showed some recombination prior to tamoxifen, there was no impact on mRNA levels. We then asked whether induction of GLS heterozygosity would attenuate the locomotor response to propsychotic amphetamine challenge. Before tamoxifen, control and GLS1 iHET mice did not differ in their response to amphetamine. One month after tamoxifen treatment, amphetamine-induced hyperlocomotion was blocked in GLS1 iHET mice. The block was largely maintained after 5 months. Thus, a genetically induced glutaminase reduction-mimicking pharmacological inhibition-strongly attenuated the response to a propsychotic challenge, suggesting that glutaminase may be a novel target for the pharmacotherapy of schizophrenia. These results demonstrate how genetic pharmacotherapy can be implemented to test a CNS target in advance of the development of specific neuroactive inhibitors. We discuss further the advantages, limitations, and feasibility of the wider application of genetic pharmacotherapy for neuropsychiatric drug development.

Characterization of α-galacto-oligosaccharides formed via heterologous expression of α-galactosidases from Lactobacillus reuteri in Lactococcus lactis.

α-Galacto-oligosaccharides (α-GOS) are produced by transgalactosylation reactions of α-galactosidase (α-Gal) or by conversion of raffinose family oligosaccharides by levansucrase. Similarly to ß-GOS, α-GOS have the potential to mimic glycan receptors on eukaryotic cells and act as molecular decoys to prevent bacterial infection; however, data on transgalactosylation reactions of α-Gal remain scarce. The α-Gal gene sequence from Lactobacillus reuteri was cloned into an α-Gal negative strain of Lactococcus lactis. Transgalactosylation reactions were achieved using crude cell extracts with melibiose or raffinose as galactosyl donor and fucose, N-acetylglucosamine or lactose as galactosyl acceptor. The composition, sequence and most linkage types of α-GOS formed with acceptors saccharides were determined by liquid chromatography-tandem mass spectrometry. α-Gal of Lactobacillus reuteri formed (1 → 3)-, (1 → 4)- or (1 → 6)-linked α-GOS but exhibited a preference for formation of (1 → 6)-linkages. Fucose, N-acetylglucosamine and lactose were suitable galactosyl acceptors for α-Gal of L. reuteri, resulting in formation of (1 → 3)-, (1 → 4)- or (1 → 6)-linked hetero-oligosaccharides. By determining the structural specificity of α-Gal and increasing the variation of oligosaccharides produced by introducing alternative acceptor sugars, this work supports further studies to assess α-GOS pathogen adhesion prevention in mammalian hosts.

Kupffer cells potentiate liver sinusoidal endothelial cell injury in sepsis by ligating programmed cell death ligand-1.

PD-1 and PD-L1 have been reported to provide peripheral tolerance by inhibiting TCR-mediated activation. We have reported that PD-L1-/- animals are protected from sepsis-induced mortality and immune suppression. Whereas studies indicate that LSECs normally express PD-L1, which is also thought to maintain local immune liver tolerance by ligating the receptor PD-1 on T lymphocytes, the role of PD-L1 in the septic liver remains unknown. Thus, we hypothesized initially that PD-L1 expression on LSECs protects them from sepsis-induced injury. We noted that the increased vascular permeability and pSTAT3 protein expression in whole liver from septic animals were attenuated in the absence of PD-L1. Isolated LSECs taken from septic animals, which exhibited increased cell death, declining cell numbers, reduced cellular proliferation, and VEGFR2 expression (an angiogenesis marker), also showed improved cell numbers, proliferation, and percent VEGFR2(+) levels in the absence of PD-L1. We also observed that sepsis induced an increase of liver F4/80(+)PD-1(+)-expressing KCs and increased PD-L1 expression on LSECs. Interestingly, PD-L1 expression levels on LSECs decreased when PD-1(+)-expressing KCs were depleted with clodronate liposomes. Contrary to our original hypothesis, we document here that increased interactions between PD-1(+) KCs and PD-L1(+) LSECs appear to lead to the decline of normal endothelial function-essential to sustain vascular integrity and prevent ALF. Importantly, we uncover an underappreciated pathological aspect of PD-1:PD-L1 ligation during inflammation that is independent of its normal, immune-suppressive activity.