Evidence for immune activation in pathogenesis of the HLA class II associated disease, podoconiosis.

Available evidences suggest that podoconiosis is triggered by long term exposure of bare feet to volcanic red clay soil particles. Previous genome-wide studies in Ethiopia showed association between the HLA class II region and disease susceptibility. However, functional relationships between the soil trigger, immunogenetic risk factors and the immunological basis of the disease are uncharted. Therefore, we aimed to characterise the immune profile and gene expression of podoconiosis patients relative to endemic healthy controls. Peripheral blood immunophenotyping of T cells indicated podoconiosis patients had significantly higher CD4 and CD8 T cell surface HLA-DR expression compared to healthy controls while CD62L expression was significantly lower. The levels of the activation markers CD40 and CD86 were significantly higher on monocytes and dendritic cell subsets in patients compared to the controls. RNA sequencing gene expression data indicated higher transcript levels for activation, scavenger receptors, and apoptosis markers while levels were lower for histones, T cell receptors, variable, and constant immunoglobulin chain in podoconiosis patients compared to healthy controls. Our finding provides evidence that podoconiosis is associated with high levels of immune activation and inflammation with over-expression of genes within the pro-inflammatory axis. This offers further support to a working hypothesis of podoconiosis as soil particle-driven, HLA-associated disease of immunopathogenic aetiology.

Neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 and wild-type virus in patients with inflammatory bowel disease following three doses of COVID-19 vaccine (VIP): a prospective, multicentre, cohort study.

Background: Patients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant. Methods: In this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664). Findings: Both heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in patients with IBD on infliximab (Geometric Mean Ratio (GMR) 0.19 [0.10, 0.36], p < 0.0001), infliximab and thiopurine combination (GMR 0.25 [0.13, 0.49], p < 0.0001) or tofacitinib (GMR 0.43 [0.20, 0.91], p = 0.028), but not in patients on thiopurine monotherapy, ustekinumab, or vedolizumab. Breakthrough infection was associated with lower neutralising antibodies against wild-type (p = 0.037) and BA.4/5 (p = 0.045). Interpretation: A third dose of a COVID-19 mRNA vaccine based on the wild-type spike glycoprotein significantly boosts neutralising antibody titres in patients with IBD. However, responses are lower against the Omicron variant BA.4/5, particularly in patients taking anti-TNF and JAK-inhibitor therapy. Breakthrough infections are associated with lower neutralising antibodies and immunosuppressed patients with IBD may receive additional benefit from bivalent vaccine boosters which target Omicron variants. Funding: Pfizer.

The immunology of long COVID.

Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing-remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein-Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.

Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.

BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p<0·0001), BA.1 (107·3 [86·40-133·2] vs 648·9 [523·5-804·5]; p<0·0001), and BA.4/5 (40·63 [31·99-51·60] vs 223·0 [183·1-271·4]; p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5-16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8-10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08-2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79-0·95]; p=0·0028). INTERPRETATION: Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies. FUNDING: Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos.

Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic.

OBJECTIVE: Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD. DESIGN: Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study. RESULTS: Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups. CONCLUSIONS: Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Serum biomarkers associated with SARS-CoV-2 severity.

Immunity with SARS-CoV-2 infection during the acute phase is not sufficiently well understood to differentiate mild from severe cases and identify prognostic markers. We evaluated the immune response profile using a total of 71 biomarkers in sera from patients with SARS-CoV-2 infection, confirmed by RT-PCR and controls. We correlated biological marker levels with negative control (C) asymptomatic (A), nonhospitalized (mild cases-M), and hospitalized (severe cases-S) groups. Among angiogenesis markers, we identified biomarkers that were more frequently elevated in severe cases when compared to the other groups (C, A, and M). Among cardiovascular diseases, there were biomarkers with differences between the groups, with D-dimer, GDF-15, and sICAM-1 higher in the S group. The levels of the biomarkers Myoglobin and P-Selectin were lower among patients in group M compared to those in groups S and A. Important differences in cytokines and chemokines according to the clinical course were identified. Severe cases presented altered levels when compared to group C. This study helps to characterize biological markers related to angiogenesis, growth factors, heart disease, and cytokine/chemokine production in individuals infected with SARS-CoV-2, offering prognostic signatures and a basis for understanding the biological factors in disease severity.

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

BACKGROUND: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose. METHODS: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data. FINDINGS: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11-0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31-0·87]; p=0·012), and thiopurine (0·69 [0·51-0·95]; p=0·021), but not with ustekinumab (0·64 [0·39-1·06]; p=0·083), or vedolizumab (0·84 [0·54-1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22-2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80-0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021). INTERPRETATION: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors. FUNDING: Pfizer.

Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study.

BACKGROUND: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs. METHODS: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing. FINDINGS: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08-0·17; p<0·0001) and tofacitinib (0·43, 0·23-0·81; p=0·0095), but not with ustekinumab (0·69, 0·41-1·19; p=0·18), thiopurines (0·89, 0·64-1·24; p=0·50), or vedolizumab (1·16, 0·74-1·83; p=0·51). mRNA vaccines (3·68, 2·80-4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72-0·87; p<0·0001) with lower antibody concentrations. INTERPRETATION: For patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised. FUNDING: Pfizer.

Trans-arterial chemoembolization as a loco-regional inducer of immunogenic cell death in hepatocellular carcinoma: implications for immunotherapy.

BACKGROUND: Modulation of adaptive immunity may underscore the efficacy of trans-arterial chemoembolization (TACE). We evaluated the influence of TACE on T-cell function by phenotypic lymphocyte characterization in samples of patients undergoing surgery with (T+) or without (T-) prior-TACE treatment. METHODS: We profiled intratumoral (IT), peritumoral (PT) and non-tumoral (NT) background tissue to evaluate regulatory CD4+/FOXP3+ (T-reg) and immune-exhausted CD8+/PD-1+ T-cells across T+ (n=58) and T- (n=61). We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples (n=24) evaluated in relationship with the expression of actionable drivers of anti-cancer immunity including PD-L1, indoleamine 2,3 dehydrogenase (IDO-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), Lag-3, Tim-3 and CD163. RESULTS: We analyzed 119 patients resected (n=25, 21%) or transplanted (n=94, 79%) for Child-Pugh A (n=65, 55%) and Barcelona Clinic Liver Cancer stage A (n=92, 77%) hepatocellular carcinoma. T+ samples displayed lower IT CD4+/FOXP3+ (p=0.006), CD8+ (p=0.002) and CD8+/PD-1+ and NT CD8+/PD-1+ (p<0.001) compared with T-. Lower IT (p=0.005) and NT CD4+/FOXP3+ (p=0.03) predicted for improved recurrence-free survival. In a subset of samples (n=24), transcriptomic analysis revealed upregulation of a pro-inflammatory response in T+. T+ samples were enriched for IRF2 expression (p=0.01), an interferon-regulated transcription factor implicated in cancer immune-evasion. T-cell clonality and expression of PD-L1, IDO-1, CTLA-4, Lag-3, Tim-3 and CD163 was similar in T+ versus T-. CONCLUSIONS: TACE is associated with lower IT density of immune-exhausted effector cytotoxic and T-regs, with significant upregulation of pro-inflammatory pathways. This highlights the pleiotropic effects of TACE in modulating the tumor microenvironment and strengthens the rationale for developing immunotherapy alongside TACE.

Third generation autologous chondrocyte implantation is a good treatment option for athletic persons.

PURPOSE: Autologous chondrocyte implantation is an established method for the treatment of joint cartilage damage. However, to date it has not been established that autologous chondrocyte implantation is an appropriate procedure for cartilage defects therapy in athletic persons. The aim of this study is to analyze if third-generation autologous chondrocyte implantation is an appropriate treatment for athletic persons with full cartilage defect of the knee joints. METHODS: A total of 84 patients were treated with third-generation autologous chondrocyte implantation (NOVOCART® 3D). The mean follow-up time was 8 years (5-14). Sports activity was measured via UCLA Activity Score and Tegner Activity Scale before the onset of knee pain and postoperatively in an annual clinical evaluation. 41 athletic persons and 43 non-athletic persons (UCLA-Cut-off: 7; Tegner Activity Scale-Cut-off: 4) were analyzed. Patient reported outcomes were captured using IKDC subjective, KOOS, Lysholm score and VAS score on movement. RESULTS: Patient reported outcomes (IKDC, VAS at rest, VAS on movement) showed significant improvement (p < 0.001) postoperatively. Athletic persons demonstrated significantly better results than non-athletic persons in the analyzed outcome scores (IKDC: p < 0.01, KOOS: p < 0.01, Lysholm score: p < 0.01). 96.4% of the patients were able to return to sport and over 50% returned or surpassed their preinjury sports level. The remaining patients were downgraded by a median of two points on the UCLA- and 2.5 on the Tegner Activity Scale. A shift from high-impact sports to active events and moderate or mild activities was found. Furthermore, it was shown that preoperative UCLA score and Tegner Activity Scale correlated significantly with the patient reported outcome postoperatively. CONCLUSION: Autologous chondrocyte implantation is a suitable treatment option for athletic persons with full-thickness cartilage defects in the knee. The return to sports activity is possible, but includes a shift from high-impact sports to less strenuous activities.

Patient-Reported and Magnetic Resonance Imaging Outcomes of Third-Generation Autologous Chondrocyte Implantation After 10 Years.

PURPOSE: To evaluate the long-term clinical and radiologic outcomes of third-generation autologous chondrocyte implantation (ACI) for the treatment of focal cartilage defects of the knee. METHODS: Data capture was carried out between 2004 and 2018. Included were patients with cartilage defects of the knee joint with an International Cartilage Repair Society grade of III or higher treated with third-generation ACI who had a minimum follow-up period of 10 years. International Knee Documentation Committee scores and assessment of pain at rest and on movement using visual analog scale scores were captured preoperatively and at 6 months postoperatively, as well as annually thereafter. In addition, we performed magnetic resonance imaging examinations in 13 cases after 10 years. The MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score was used to evaluate the ACI cartilage. RESULTS: A total of 54 patients met the inclusion criteria. Of these, 30 reached the 10-year follow-up point and were included in this assessment. At 10 years postoperatively, all clinical outcome parameters showed a statistically significant improvement compared with the preoperative situation, with a responder rate of 70%. The average MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) score after 10 years was 59.2 points (range, 20-100 points), and over 60% of the evaluated patients showed good integration of the implant at 10 years postoperatively. CONCLUSIONS: The clinical and radiologic findings of this study show that third-generation ACI is a suitable and effective option in the treatment of full-thickness cartilage defects of the knee. At 10 years after surgery, third-generation ACI shows stable results and leads to significant improvement in all clinical outcome parameters. Despite these results, revision surgery after third-generation ACI is common and was needed in 23% of patients in this study. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Antibiotic therapy and outcome from immune-checkpoint inhibitors.

Sensitivity to immune checkpoint inhibitor (ICPI) therapy is governed by a complex interplay of tumor and host-related determinants. Epidemiological studies have highlighted that exposure to antibiotic therapy influences the probability of response to ICPI and predict for shorter patient survival across malignancies. Whilst a number of studies have reproducibly documented the detrimental effect of broad-spectrum antibiotics, the immune-biologic mechanisms underlying the association with outcome are poorly understood. Perturbation of the gut microbiota, an increasingly well-characterized factor capable of influencing ICPI-mediated immune reconstitution, has been indicated as a putative mechanism to explain the adverse effects attributed to antibiotic exposure in the context of ICPI therapy. Prospective studies are required to validate antibiotic-mediated gut perturbations as a mechanism of ICPI refractoriness and guide the development of strategies to overcome this barrier to an effective delivery of anti-cancer immunotherapy.

Human NK cell receptor KIR2DS4 detects a conserved bacterial epitope presented by HLA-C.

Natural killer (NK) cells have an important role in immune defense against viruses and cancer. Activation of human NK cell cytotoxicity toward infected or tumor cells is regulated by killer cell immunoglobulin-like receptors (KIRs) that bind to human leukocyte antigen class I (HLA-I). Combinations of KIR with HLA-I are genetically associated with susceptibility to disease. KIR2DS4, an activating member of the KIR family with poorly defined ligands, is a receptor of unknown function. Here, we show that KIR2DS4 has a strong preference for rare peptides carrying a Trp at position 8 (p8) of 9-mer peptides bound to HLA-C*05:01. The complex of a peptide bound to HLA-C*05:01 with a Trp at p8 was sufficient for activation of primary KIR2DS4+ NK cells, independent of activation by other receptors and of prior NK cell licensing. HLA-C*05:01+ cells that expressed the peptide epitope triggered KIR2DS4+ NK cell degranulation. We show an inverse correlation of the worldwide allele frequency of functional KIR2DS4 with that of HLA-C*05:01, indicative of functional interaction and balancing selection. We found a highly conserved peptide sequence motif for HLA-C*05:01-restricted activation of human KIR2DS4+ NK cells in bacterial recombinase A (RecA). KIR2DS4+ NK cells were stimulated by RecA epitopes from multiple human pathogens, including Helicobacter, Chlamydia, Brucella, and Campylobacter. We predict that over 1,000 bacterial species could activate NK cells through KIR2DS4, and propose that human NK cells also contribute to immune defense against bacteria through recognition of a conserved RecA epitope presented by HLA-C*05:01.

The immune regulatory role of neutrophils.

Neutrophils are appreciated to perform a wide range of pro- and anti-inflammatory effector functions in diverse settings. These go far beyond the response to acute infection, encompassing sterile injury, autoimmunity, allergy and tumours. There is growing appreciation of the nuances of their modes of action, especially elucidation of the nature and consequences of NETosis. New work suggests that it is time to give greater consideration to the anti-inflammatory role of neutrophils, such as in the control of cytokine release during sepsis.

Functions of adipose-resident immune subsets and the impact on metabolic syndrome.

There is a growing appreciation of the role in the aetiology of metabolic syndrome that is played by the interplay of diet, microbiota and the interactions of immune cells and adipose cells in visceral adipose tissue. Recent studies have highlighted the programmes, properties and roles of the specialized, resident immune subsets that are abundant in adipose tissue, which may be considered a newly identified lymphoid compartment for immunology research. The findings indicate important roles for resident T effector and regulatory cells, innate lymphoid cells (ILCs), invariant natural killer T (iNKT) cells and macrophages, among others. Immunologists are at the very beginning of trying to narrate a story of complex interactions, with the need to unravel cause from effect. The enterprise will require studies in humans as well as mice, and needs to bring together the collaborative efforts of scientists and clinicians from diverse spheres including metabolic disease, diet and microbiology.

A Nobel Prize-worthy pursuit: cancer immunology and harnessing immunity to tumour neoantigens.

The field of cancer immunology stepped into the limelight this year when James P. Allison and Tasuku Honjo received the Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation. Among many exciting advances contributing to the coming of age of tumour immunology as a viable clinical specialty has been the ability to progress from the initial elucidation of tumour antigens, such as the melanoma antigen, MAGE-1, to high-throughput sequencing facilitating identification of T cell epitopes from diverse tumour neoantigens. This has resulted from the convergence of expertise in tumour biology, next-generation sequencing, T cell and structural immunology, and predictive algorithms. Among many examples, immunotherapy for ovarian cancer has been one of the beneficiaries of these advances, leading to a number of recent and ongoing clinical trials.

Regulatory T-cells: receptors, repertoires and roles in disease.

In the 20-or-so years that immunologists have spent describing the mechanisms and functions of regulatory T-cells, a very great deal has been learnt: a T-cell subset once described for the generic ability to harness autoimmunity in vivo or diminish T-cell proliferation in vitro is now appreciated to act on a plethora of cellular pathways using a diverse array of mechanisms. Recent studies have shed new light on basic and applied aspects of Treg function, including T-cell receptor usage, specialist functions of tissue-resident Tregs, and the therapeutic consequences of tuning Treg function up or down for applications in autoimmunity or cancer, respectively.

New tools for MHC research from machine learning and predictive algorithms to the tumour immunopeptidome.

At a time when immunology seeks to progress ever more rapidly from characterization of a microbial or tumour antigen to the immune correlates that may define protective T-cell immunity, there is a need for robust tools to enable accurate predictions of peptide-major histocompatibility complex (pMHC) and peptide-MHC-T-cell receptor binding. Improvements in the curation of data sets from high throughput pMHC analysis, such as the NIH Immune Epitope Database (IEDB), and the associated developments of predictive tools rooted in machine-learning approaches, are having significant impact. When such approaches are linked to the powerful empirical immunopeptidome data sets from peptide MHC elution and mass spectrometry, there is considerable potential for rapid translation to T-cell therapies and vaccines.