Antroquinonol differentially modulates T cell activity and reduces interleukin-18 production, but enhances Nrf2 activation, in murine accelerated severe lupus nephritis

AbstractRecombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

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T cell–specific STAT3 deficiency abrogates lupus nephritis

Lupus ◽

10.1177/0961203319877242 ◽

2019 ◽

Vol 28 (12) ◽

pp. 1468-1472 ◽

Cited By ~ 2

Author(s):

N Yoshida ◽

F He ◽

V C Kyttaris

Keyword(s):

T Cells ◽

T Cell ◽

Lupus Nephritis ◽

Lupus Erythematosus ◽

Cell Responses ◽

Cytokines And Chemokines ◽

Novel Approach ◽

Cell Tissue ◽

External Stimuli

Signal transducer and activator of transcription (STAT) 3 is a regulator of T-cell responses to external stimuli, such as pro-inflammatory cytokines and chemokines. We have previously shown that STAT3 is activated (phosphorylated) at high levels in systemic lupus erythematosus (SLE) T cells and mediates chemokine-induced migration and T:B cell interactions. Stattic, a small molecular STAT3 inhibitor, can partially ameliorate lupus nephritis in mice. To understand the role of STAT3 better in T-cell pathophysiology in lupus nephritis and its potential as a treatment target, we silenced its expression in T cells using a cd4-driven CRE-Flox model. We found that lupus-prone mice that do not express STAT3 in T cells did not develop lymphadenopathy, splenomegaly, or glomerulonephritis. Moreover, the production of anti-dsDNA antibodies was decreased in these mice compared to controls. To dissect the mechanism, we also used a nephrotoxic serum model of nephritis. In this model, T cell–specific silencing of STAT3 resulted in amelioration of nephrotoxic serum-induced kidney damage. Taken together, our results suggest that in mouse models of autoimmune nephritis, T cell–specific silencing of STAT3 can hamper their ability to help B cells to produce autoantibodies and induce cell tissue infiltration. We propose that STAT3 inhibition in T cells represents a novel approach in the treatment of SLE and lupus nephritis in particular.

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SAT0210 FACTORS ASSOCIATED WITH TIME TO SEVERE LUPUS NEPHRITIS IN A COHORT OF COLOMBIAN PATIENTS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.6282 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1048.2-1048

Author(s):

S. Herrera ◽

J. C. Diaz-Coronado ◽

D. Rojas-Gualdrón ◽

L. Betancur-Vasquez ◽

D. Gonzalez-Hurtado ◽

...

Keyword(s):

Lupus Nephritis ◽

Renal Involvement ◽

Classification Criteria ◽

P Value ◽

Systemic Lupus ◽

P Values ◽

Interval Censored ◽

Severe Lupus Nephritis ◽

Age And Sex

Background:Systemic lupus erythematosus (SLE) clinical manifestations, and their severity, vary according to age, ethnicity and socioeconomic status. Both Hispanic and Afro-Americans have a higher incidence and more sever presentation when compared to Caucasian patients with SLEObjectives:To analyze clinical and immunological characteristics associated with time to severe renal involvement in patients with Systemic Lupus Erythematous in a Colombian cohort followed for one year, between January 2015 and December 2018Methods:Retrospective follow-up study based in clinical records. Patients with SLE diagnosis that fulfilled either 1987 American College of Rheumatology Classification Criteria for SLE or 2011 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE. We included patients with diagnosis of lupus nephritis according to Wallace and Dubois criteria. Patients who did not have at least two follow-up measurements or had a cause of nephritis other than lupus were excluded. The main outcome was defined as time from diagnosis to sever renal involvement defined as creatinine clearance ≤50 ml/min, 24-hour proteinuria ≥3.5 grams o end stage renal disease.We analyzed clinical and immunological characteristics. Descriptive statistical analyses of participant data during the first evaluation are reported as frequencies and percentages for categorical variables, and as medians and interquartile ranges (IQR) for quantitative variables. Age and sex adjusted survival functions and Hazard ratios (HR) with 95% confidence intervals and p-values were estimated using parametric Weibull models por interval-censored data. P values < 0.05 were considered statistically significantResults:548 patients were analyzed: 67 were left-censored as they presented renal involvement at entry, 6 were interval censored as outcome occurred between study visits, and 475 were right-censored as involvement was not registered during follow-up. 529 (96.5%) patients were female, median age at entry was 46 (IQR = 23) and median age to diagnosis was 29.5 (IQR = 20.6). 67% were mestizo, 13% Caucasian and 0.3% Afro-Colombian. Age and sex adjusted variables associated with time to severe lupus nephritis were high blood pressure HR = 3.5 (95%CI 2.2-5.6; p-value <0.001) and Anti-RO (per unit increase) HR = 1.002 (95%CI 1.001-1.004; p-value = 0.04). Figure 1 shows age and sex adjusted survival function.Conclusion:In our cohort the appearance of severe lupus nephritis occurs in less than 15% of patients at 10 years. Both high blood pressure and elevated anti-Ro titers were associated with a higher rate of onset in the presentation of severe lupus nephritis, as seen in some polymorphs of anti Ro.References:Disclosure of Interests:Sebastian Herrera Speakers bureau: academic conference, Juan camilo Diaz-Coronado: None declared, Diego Rojas-Gualdrón: None declared, Laura Betancur-Vasquez: None declared, Daniel Gonzalez-Hurtado: None declared, Juanita Gonzalez-Arango: None declared, laura Uribe-Arango: None declared, Maria Fernanda Saavedra Chacón: None declared, Jorge Lacouture-Fierro: None declared, Santiago Monsalve: None declared, Sebastian Guerra-Zarama: None declared, Juan david Lopez: None declared, Juan david Serna: None declared, Julian Barbosa: None declared, Ana Sierra: None declared, Deicy Hernandez-Parra: None declared, Ricardo Pineda.Tamayo: None declared

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