CD5 + Gamma Delta T-Cell Lymphoproliferative Disorder/Lymphoma Without Cytotoxic Granules in the Skin.

ABSTRACT: We report a case of an unusual and aggressive gamma delta T-cell lymphoproliferative disorder/lymphoma presenting in the skin that lacked the expected cytotoxic markers and had increased expression of CD5, CD20, CD79a, CD30, and PD-1 without CD56. Monoclonal TCR-γ gene rearrangement was identified. A computed tomography scan of the chest, abdomen, and pelvis revealed a 7.7-cm soft-tissue inguinal mass and prominent retroperitoneal and pelvic lymphadenopathy, without hepatosplenomegaly. Flow cytometry finding on peripheral blood was normal. The clinical, morphologic, and immunophenotypic features of this case defy the current World Health Organization and European Organization for Research and Treatment of Cancer classifications, and a similar case has not been reported previously.

T cells mediate cell non-autonomous arterial ageing in mice.

KEY POINTS: Increased large artery stiffness and impaired endothelium-dependent dilatation occur with advanced age. We sought to determine whether T cells mechanistically contribute to age-related arterial dysfunction. We found that old mice exhibited greater proinflammatory T cell accumulation around both the aorta and mesenteric arteries. Pharmacologic depletion or genetic deletion of T cells in old mice resulted in ameliorated large artery stiffness and greater endothelium-dependent dilatation compared with mice with T cells intact. ABSTRACT: Ageing of the arteries is characterized by increased large artery stiffness and impaired endothelium-dependent dilatation. T cells contribute to hypertension in acute rodent models but whether they contribute to chronic age-related arterial dysfunction is unknown. To determine whether T cells directly mediate age-related arterial dysfunction, we examined large elastic artery and resistance artery function in young (4-6 months) and old (22-24 months) wild-type mice treated with anti-CD3 F(ab'2) fragments to deplete T cells (150 µg, i.p. every 7 days for 28 days) or isotype control fragments. Old mice exhibited greater numbers of T cells in both aorta and mesenteric vasculature when compared with young mice. Old mice treated with anti-CD3 fragments exhibited depletion of T cells in blood, spleen, aorta and mesenteric vasculature. Old mice also exhibited greater numbers of aortic and mesenteric IFN-γ and TNF-α-producing T cells when compared with young mice. Old control mice exhibited greater large artery stiffness and impaired resistance artery endothelium-dependent dilatation in comparison with young mice. In old mice, large artery stiffness was ameliorated with anti-CD3 treatment. Anti-CD3-treated old mice also exhibited greater endothelium-dependent dilatation than age-matched controls. We also examined arterial function in young and old Rag-1-/- mice, which lack lymphocytes. Rag-1-/- mice exhibited blunted increases in large artery stiffness with age compared with wild-type mice. Old Rag-1-/- mice also exhibited greater endothelium-dependent dilatation compared with old wild-type mice. Collectively, these results demonstrate that T cells play an important role in age-related arterial dysfunction.

Structure-Activity Relationship Analysis of Benzotriazine Analogues as HIV-1 Latency-Reversing Agents.

"Shock and kill" therapeutic strategies toward HIV eradication are based on the transcriptional activation of latent HIV with a latency-reversing agent (LRA) and the consequent killing of the reactivated cell by either the cytopathic effect of HIV or an arm of the immune system. We have recently found several benzotriazole and benzotriazine analogues that have the ability to reactivate latent HIV by inhibiting signal transducer and activator of transcription 5 (STAT5) SUMOylation and promoting STAT5 binding to the HIV long terminal repeat and increasing its transcriptional activity. To understand the essential structural groups required for biological activity of these molecules, we performed a systematic analysis of >40 analogues. First, we characterized the essential motifs within these molecules that are required for their biological activity. Second, we identified three benzotriazine analogues with similar activity. We demonstrated that these three compounds are able to increase STAT5 phosphorylation and transcriptional activity. All active analogues reactivate latent HIV in a primary cell model of latency and enhance the ability of interleukin-15 to reactivate latent HIV in cells isolated from aviremic participants. Third, this family of compounds also promote immune effector functions in vitro in the absence of toxicity or global immune activation. Finally, initial studies in mice suggest lack of acute toxicity in vivo A better understanding of the biological activity of these compounds will help in the design of improved LRAs that work via inhibition of STAT5 SUMOylation.

Update in Soft-Tissue Filler-Associated Blindness.

BACKGROUND: Soft-tissue filler administration is an increasingly popular minimally invasive cosmetic procedure. Simultaneously, there have been a greater number of adverse events reported, including the devastating complication of blindness. OBJECTIVE: To report cases of filler-related blindness published since 2015. MATERIALS AND METHODS: The Ovid MEDLINE database was searched from January 1, 2015, to August 1, 2018, using a previously described Boolean string. RESULTS: Sixty new cases of filler blindness were identified. The most common type of filler reported was hyaluronic acid (HA) (N = 42, 70.0%), followed by autologous fat (N = 7, 11.7%), and calcium hydroxyapatite (CaHA) (N = 7, 11.7%). The most common injection locations were the nose (N = 33, 55.0%), glabella (N = 21, 35.0%), and forehead (N = 11, 18.3%). Ten cases reported vision restoration (16.7%). Four of the successful cases involved hyaluronidase administration, including 1 retrobulbar hyaluronidase injection. CONCLUSION: Since 2015, there have been 60 newly reported cases of soft-tissue filler blindness. Most recent cases have occurred with HA, which is a shift from previous reports. In HA cases, hyaluronidase injection may be successful in restoring vision if administered promptly. It is imperative for providers to be familiar with strategies for managing soft-tissue filler blindness.

Lower Socioeconomic Status is Associated With Decreased Therapeutic Response to the Biologic Agents in Psoriasis Patients.

BACKGROUND: Lower socioeconomic status is associated with poorer overall health outcomes. However, few studies have examined the impact of socioeconomic status on psoriasis. OBJECTIVE: To examine the impact of individual socioeconomic status on systemic therapeutic outcomes amongst psoriasis patients. METHODS: The study analyzed 156 psoriasis patients treated at the Tufts Medical Center Department of Dermatology from 2008-2014. Individual socioeconomic status was inferred from neighborhood income, defined as the percentage of households with income below the federal poverty line (% below FPL) in the patient's census tract. The following outcomes were compared between socioeconomic groups: improvement in simple measure for assessing psoriasis activity (S-MAPA) score at 12 weeks, primary and secondary drug failure rates, and incidence of documented medication non-adherence. RESULTS: Those patients living in relatively poorer neighborhoods (% below FPL ≤ 10%) experienced a significantly decreased improvement in S-MAPA score at 12 weeks of biologic treatment when compared to those in relatively richer neighborhoods (% below FPL >10%), 23.2% vs. 45.5%, P=0.021. Patients living in poorer neighborhoods also had a significantly higher rate of primary drug failure when treated with biologics (34.7% vs. 18.4%, P=0.039) and were significantly more likely to have ≥ 1 documented instance of medication non-adherence when treated with biologics (45.5% vs. 8.8%, P < 0.001). LIMITATIONS: Retrospective design, small sample size CONCLUSIONS: Our study offers preliminary data that suggests lower socioeconomic status may be associated with decreased clinical response to the biologic agents, presumably through decreased medication adherence.

Cosmetic complications: rare and serious events following botulinum toxin and soft tissue filler administration.

BACKGROUND: Botulinum toxin (BTX) and soft tissue fillers continue to gain in popularity due to their safety, affordability, quick effects, and short recovery times. With the excellent safety profile of BTX and soft tissue fillers, patients may develop a nonchalant attitude towards treatment with injectables. However, it is important for both patient and physician to be familiar with all the possible complications, both common and uncommon. OBJECTIVE: This article aims to review the rare but serious complications associated with the injectables used in cosmetic dermatology, and the pathogenesis, diagnosis, and management of each. METHODS AND MATERIALS: A literature review for case reports pertaining to rare adverse events following botulinum toxin or soft tissue fillers was performed using the MEDLINE database. RESULTS: Complications of BTX included dry eye syndrome, strabismus and diplopia, superficial temporal artery pseudoaneurysm, neck weakness, hoarseness, and dysphagia. Complications associated with soft tissue fillers included tissue necrosis, inflammatory nodules, hypersensitivity reaction, and blindness and cerebral ischemia. CONCLUSION: The injector should be comfortable in diagnosing and managing the above complications, and the patient should be counseled about these potentially harmful adverse events prior to injection.

Biologic and Conventional Systemic Therapies Show Similar Safety and Efficacy in Elderly and Adult Patients With Moderate to Severe Psoriasis.

BACKGROUND/OBJECTIVE: Despite the aging population, few studies have documented the treatment of geriatric psoriasis. The purpose of this study is to compare the efficacy, safety, and prescribing patterns of biologics and conventional systemic medications in elderly versus adult psoriasis. METHODS: All patient visits coded for psoriasis or psoriatic arthritis (ICD-9 696.1 or 696.0) at the Tufts Medical Center General Dermatology Clinic from January 1, 2008, to March 1, 2015 were included in this retrospective cohort study. The outcome measure used was the validated simple-measure for assessing psoriasis activity (S-MAPA), the product of the physician's global assessment and the body surface area. RESULTS: 194 patients who underwent 278 treatment courses were included in the study. 48 patients were included in the elderly cohort (≥ 65 years old) and 146 in the adult cohort (18-64 years old). There was no significant difference in S-MAPA improvement at 12 weeks between the two cohorts when treated with biologics (42.92% improvement in adults, 48.77% in elderly; P=0.498) or conventional systemics (43.96% and 51.82%, respectively; P=0.448). Within the elderly cohort, there was no significant difference in efficacy of biologics versus conventional systemics at any time point. Topical prescription rates were significantly higher in the elderly cohort ( P=0.004) while biologic prescription rates were significantly lower ( P=0.014) despite the same baseline S-MAPA in both age groups. For both biologics and conventional systemics, there was no statistically significant intergroup difference in the rate of adverse events ( P=0.322 for biologics; P=0.581 for conventional systemics) or infection ( P=0.753 for biologics; P=0.828 for conventional systemics). Within the elderly cohort, there was a higher rate of adverse events with conventional systemic treatment than with biologic treatment ( P=0.033). CONCLUSIONS: This study provides preliminary evidence to suggest that biologic and conventional systemic therapies are similarly safe and effective in the elderly and non-elderly cohorts. Within the elderly population, biologics may be a safer option than conventional systemic agents.

Systemic Treatment of Recalcitrant Pediatric Psoriasis: A Case Series and Literature Review.

BACKGROUND/PURPOSE: No systemic drugs are approved by the Food and Drug Administration to treat pediatric psoriasis due to a lack of supporting data. The purpose of this study is to present cases demonstrating the use of systemic drugs in pediatric psoriasis. METHODS: In this case series, data were collected on patients ≤ 18 years old with moderate-to-severe psoriasis treated with systemic medications (traditional systemic drugs or biologics) from 2008 through 2014. Efficacy was measured using the validated simple measure for assessing psoriasis activity (S-MAPA), and the product of the body surface area and Physician Global Assessment. RESULTS: Twenty-seven patients aged 5 to 18 years were eligible, and 56 treatment courses were analyzed. Methotrexate (MTX) was the most frequently prescribed systemic (70%), followed by etanercept (59%). Clearance rates were highest on biologic medications (67% for etanercept and adalimumab, 33% for ustekinumab). Phototherapy, cyclosporine, and MTX were less effective in clearing psoriasis, although they were successful in improving S-MAPA ≥ 50% from baseline 100%, 67%, and 36% of the time, respectively. The most common adverse events were sunburn for patients on narrowband ultraviolet B phototherapy (14%), gastrointestinal intolerance and minor infections for patients on MTX (16% each), and minor infections for patients on etanercept (25%) and adalimumab (33%). The most common reasons for discontinuation were secondary failure (38% for etanercept, 33% for adalimumab) or lack of response (37% for MTX, 33% for cyclosporine). CONCLUSION: Although phototherapy, MTX, and cyclosporine are effective for controlling resistant pediatric psoriasis, concerns about long-term safety or inconvenience have led people to consider biologics in their place. However, there is a lack of literature on the use of biologics in pediatric psoriasis. These cases attest to the safety and efficacy of etanercept, adalimumab, and ustekinumab in pediatric psoriasis, expanding the treatment repertoire and guiding dermatologists in better managing recalcitrant pediatric psoriasis.

Tumor Necrosis Factor Inhibitor Primary Failure Predicts Decreased Ustekinumab Efficacy in Psoriasis Patients.

BACKGROUND: Additional studies are needed to examine the efficacy of ustekinumab in psoriasis patients who have previously been exposed to tumor necrosis factor inhibitors (TNFi). OBJECTIVE: To examine the predictive effect of TNFi primary failure and the number of TNFi exposures on the efficacy of ustekinumab in psoriasis treatment. METHODS: This retrospective study examined 44 psoriasis patients treated at the Tufts Medical Center Department of Dermatology between January 2008 and July 2014. Patients were selected if they were treated with ustekinumab and had ≥ 1 previous TNFi exposure. The following subgroups were compared: patients with vs without a previous TNFi primary failure, and patients with one vs multiple previous TNFi exposures. The efficacy measure used was the previously validated Simple Measure for Assessing Psoriasis Activity (S-MAPA), which is calculated by the product of the body surface area and physician global assessment. The primary outcome was the percentage improvement S-MAPA from course baseline at week 12 of ustekinumab treatment. Secondary outcomes were the psoriasis clearance, primary failure, and secondary failure rates with ustekinumab treatment. RESULTS: Patients with a previous TNFi primary failure had a significantly lower percentage improvement in S-MAPA score at week 12 of ustekinumab treatment compared with patients without TNFi primary failure (36.2% vs 61.1%, P=.027). Multivariate analysis demonstrated that this relationship was independent of patient demographics and medical comorbidities. Patients with multiple TNFi exposures had a non-statistically significant lower percentage S-MAPA improvement at week 12 (40.5% vs 52.9%, P=.294) of ustekinumab treatment compared with patients with a single TNFi exposure. CONCLUSIONS: Among psoriasis patients previously exposed to TNFi, a history of a previous TNFi primary failure predicts a decreased response to ustekinumab independent of patient demographics and medical comorbidities.

The in vitro pharmacology of GS-5759, a novel bifunctional phosphodiesterase 4 inhibitor and long acting ß2-adrenoceptor agonist.

Inhaled long-acting ß(2)-adrenoceptor agonists (LABA) that act as bronchodilators and the oral anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor roflumilast are both approved therapies for chronic obstructive pulmonary disease (COPD). Here we describe the activity of a novel, inhaled, bifunctional, small molecule (R)-6-[(3-{[4-(5-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}pent-1-yn-1-yl)phenyl]carbamoyl}phenyl)sulfonyl]-4-[(3-methoxyphenyl)amino]-8-methylquinoline-3-carboxamide (GS-5759), which has specific ß(2) agonist and PDE4 inhibitory activity. GS-5759 demonstrated potent and full agonist activity at ß(2) adrenoceptors (EC(50) = 8 ± 4 nM) and is a potent inhibitor of the PDE4 enzyme (IC(50) = 5 ± 3 nM). In cell assays, GS-5759 inhibited lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNFα) production in human peripheral mononuclear cells (PBMC) with an IC(50) = 0.3 nM [confidence interval (CI) 0.1-0.6] and in human neutrophils formyl-methionyl-leucyl-phenylalanine (fMLP)-induced super oxide anion production with an IC(50) = 3 nM (CI 0.8-8). The addition of the ß(2) antagonist ICI 118551 shifted the IC(50) in these cell assays to 4 and 38 nM, respectively, demonstrating the contribution of both ß(2) agonist and PDE4 inhibitory activity to GS-5759. GS-5759 was also a potent inhibitor of profibrotic and proinflammatory mediator release from human lung fibroblasts. GS-5759 relaxed guinea pig airway smooth muscle strips precontracted with carbachol in a concentration-dependent manner with an EC(50) = 0.5 µM (CI 0.2-2) and had slow dissociation kinetics with an Off T(1/2) > 720 minutes at an EC(80) concentration of 3 µM. GS-5759 is a novel bifunctional molecule with both potent ß(2) agonist and PDE4 inhibitor activity that could provide inhaled bronchodilator and anti-inflammatory therapy for COPD.

Filtration markers may have prognostic value independent of glomerular filtration rate.

Serum levels of creatinine, cystatin C, or ß trace protein allow estimation of GFR, but whether these markers contribute additional prognostic information beyond that reflected in GFR is unknown. Here, we analyzed data from the Modification of Diet in Renal Disease study, which provided baseline levels of these markers for 816 participants with a median follow-up of 16.6 years. We examined associations between the reciprocals of these filtration markers and (125)I iothalamate GFR, expressed per SD, with kidney failure and mortality. In univariate analysis, lower GFR and higher levels of each filtration marker associated with a higher risk for all outcomes. After adjustment for GFR in a Cox proportional hazards model, higher creatinine associated with a higher risk for kidney failure but a lower risk for all-cause mortality. Higher cystatin C and ß trace protein associated with a higher risk for both kidney failure and all-cause mortality. In models including either cystatin C or ß trace protein, the association of GFR with all-cause mortality was no longer significant after the addition of the filtration marker, suggesting the possibility of multicollinearity. In summary, after adjustment for GFR, levels of creatinine, cystatin C, and ß trace protein, each remained directly associated with kidney failure but differed with respect to their associations with mortality. These differences may be a result of non-GFR-related associations of filtration markers, residual confounding by GFR, or collinearity between the filtration markers and GFR. ß trace protein and cystatin C seem to provide more consistent prognostic information than creatinine.

The kidney disease quality of life cognitive function subscale and cognitive performance in maintenance hemodialysis patients.

BACKGROUND: Cognitive impairment is common but often undiagnosed in patients with end-stage renal disease, in part reflecting limited validated and easily administered tools to assess cognitive function in dialysis patients. Accordingly, we assessed the utility of the Kidney Disease Quality of Life Cognitive Function (KDQOL-CF) scale in comparison to an extensive neuropsychological battery, building on a prior assessment of this potential cognitive screen. STUDY DESIGN: Cross-sectional cohort. SETTING & PARTICIPANTS: Maintenance hemodialysis patients at 6 Boston area dialysis units were administered an extensive neurocognitive battery and the KDQOL-CF at the beginning of a hemodialysis session. PREDICTORS: KDQOL-CF score, depression symptom burden, and demographic and clinical characteristics. OUTCOMES: Neurocognitive performance classified into executive function and memory domains, determined using principal components analysis. MEASUREMENTS: Univariate and multivariable linear regression models adjusting for age, sex, race, and end-stage renal disease cause were used to evaluate the association between KDQOL-CF score and cognitive performance, and test metrics were determined for a KDQOL-CF cutoff score of 60 or less from a maximum score of 100. RESULTS: For 168 prevalent hemodialysis patients, KDQOL-CF score was 76 ± 19 and 40 (24%) had scores of 60 or less, consistent with self-identified worse cognitive performance. There was no significant correlation between KDQOL-CF score and either memory (P = 0.2 and P = 0.3) or executive function (P = 0.1 and P = 0.4) in univariate and multivariable models, respectively. There was a strong correlation between higher KDQOL-CF score and fewer depression symptoms (P < 0.001). Sensitivity of the KDQOL-CF was poor (range, 0.28-0.36), with modest specificity (range, 0.77-0.81) for identifying worse executive function and memory. LIMITATIONS: Cross-sectional study, modest population size, and abbreviated gold-standard cognitive battery. CONCLUSIONS: The KDQOL-CF is a poor determinant of neurocognitive performance in hemodialysis patients, with limited sensitivity. To assess cognitive impairment in hemodialysis patients, better screening tests are essential.

Additive anti-inflammatory effects of beta 2 adrenoceptor agonists or glucocorticosteroid with roflumilast in human peripheral blood mononuclear cells.

The phosphodiesterase 4 inhibitor (PDE4i) roflumilast has been approved in the US and EU for treatment of GOLD stage 3 and 4 chronic obstructive pulmonary disease (COPD). Inhaled ß2 adrenoceptor agonist bronchodilators and anti-inflammatory glucocorticosteroids are also used as standard of care in COPD. We investigated the anti-inflammatory interaction of roflumilast in combination with long-acting ß2 agonists (LABA), salmeterol or formoterol, or a glucocorticosteroid, dexamethasone, on cytokine production from LPS-stimulated human primary peripheral blood mononuclear cells (PBMC). Salmeterol or formoterol caused a concentration-dependent inhibition of tumor necrosis factor-α (TNFα) secretion with an IC50 of 0.33 pM (C.I. 0.006-19) and 34 pM (C.I. 13-87), respectively. When roflumilast was evaluated, the addition of salmeterol (1 nM) to roflumilast caused the IC50 for roflumilast to shift from 1.8 nM (C.I. 0.8-4) to 4.1 pM (C.I.0.3-69) (p < 0.01), and maximal inhibition increased from 72.5 ± 3.2% to 90.9 ± 3.1%. Addition of formoterol to roflumilast also produced an increased TNFα inhibition more than either drug alone (p < 0.05). The inhibition of TNFα production with salmeterol was both ß2 adrenoceptor- and protein kinase A-dependent. Addition of roflumilast (10 nM) in the presence of dexamethasone increased the inhibition of LPS-induced TNFα and CCL3. Roflumilast in combination with salmeterol, formoterol, or dexamethasone increased the inhibition of LPS-induced TNFα from human PBMC, in an additive manner. Addition of roflumilast to either a ß2 adrenoceptor agonist or a glucocorticosteroid may provide superior anti-inflammatory activity and greater efficacy in COPD patients and be dose sparing.

Cardiovascular disease and cognitive function in maintenance hemodialysis patients.

BACKGROUND: Cardiovascular disease (CVD) and cognitive impairment are common in dialysis patients. Given the proposed role of microvascular disease on cognitive function, particularly cognitive domains that incorporate executive functions, we hypothesized that prevalent systemic CVD would be associated with worse cognitive performance in hemodialysis patients. DESIGN: Cross-sectional cohort. SETTING & PARTICIPANTS: 200 maintenance hemodialysis patients without prior stroke from 5 Boston-area hemodialysis units. PREDICTOR: CVD, defined as history of coronary disease or peripheral vascular disease. OUTCOME: Performance on a detailed neurocognitive battery. Primary analyses quantified cognitive performance using principal components analysis to reduce cognitive tests to a processing speed/executive function domain and a memory domain. Multivariable linear regression models adjusted for age, sex, education, race, and other clinical and demographic characteristics. RESULTS: Mean age of participants was 62 ± 18 (standard deviation) years and 75 (38%) had CVD. Individuals with CVD were older and more likely to be men, have diabetes, and be current or former smokers. In adjusted models, individuals with CVD performed 0.50 standard deviation worse (P < 0.001) on tests assessing processing speed/executive function, whereas there was no difference in performance on tests of memory. Similar results were seen assessing individual tests, with performance on the Block Design, Digit Symbol Coding, and Trail Making Tests A and B significantly associated with CVD in age-, sex-, education-, and race-adjusted analyses and approaching significance in fully adjusted models. LIMITATIONS: CVD ascertainment dependent on patient recall and dialysis unit documentation. No brain imaging. CONCLUSIONS: The presence of CVD is associated with worse cognitive performance on tests of processing speed and executive functioning in hemodialysis patients and identifies a high-risk population for greater difficulty with complex tasks.

Cognitive function and dialysis adequacy: no clear relationship.

BACKGROUND/AIMS: Cognitive impairment is common in hemodialysis patients and may be impacted by multiple patient and treatment characteristics. The impact of dialysis dose on cognitive function remains uncertain, particularly in the current era of increased dialysis dose and flux. METHODS: We explored the cross-sectional relationship between dialysis adequacy and cognitive function in a cohort of maintenance hemodialysis patients. Adequacy was defined as the average of the 3 most proximate single pool Kt/V assessments. A detailed neurocognitive battery was administered during the 1st hour of dialysis. Multivariable linear regression models were adjusted for age, sex, education, race and other clinical and demographic characteristics. RESULTS: Among 273 patients who underwent cognitive testing, the mean (SD) age was 63 (17) years and the median dialysis duration was 13 months, 47% were woman, 22% were African American, and 48% had diabetes. The mean (SD) Kt/V was 1.51 (0.24). In univariate, parsimonious and multivariable models, there were no significant relationships between decreased cognitive function and lower Kt/V. CONCLUSION: In contrast to several older studies, there is no association between lower Kt/V and worse cognitive performance in the current era of increased dialysis dose. Future studies should address the longitudinal relationship between adequacy of dialysis and cognitive function to confirm these findings.

T lymphocyte depletion ameliorates age-related metabolic impairments in mice.

Both glucose tolerance and adaptive immune function exhibit significant age-related alterations. The influence of the immune system on obesity-associated glucose intolerance is well characterized; however, whether the immune system contributes to age-related glucose intolerance is not as well understood. Here, we report that advancing age results in an increase in T cell infiltration in the epididymal white adipose tissue (eWAT), liver, and skeletal muscle. Subtype analyses show that both CD4+, CD8+ T cells are greater with advancing age in each of these tissues and that aging results in a blunted CD4 to CD8 ratio. Anti-CD3 F(ab')2 fragments depleted CD4+ and CD8+ cells in eWAT, CD4+ cells only in the liver, and did not deplete quadriceps T cells. In old mice, T cells producing both interferon-γ and tumor necrosis factor-α are accumulated in the eWAT and liver, and a greater proportion of skeletal muscle T cells produced interferon-γ. Aging resulted in increased proportion and numbers of T regulatory cells in eWAT, but not in the liver or muscle. Aging also resulted in greater numbers of eWAT and quadriceps CD206- macrophages and eWAT, liver and quadriceps B cells; neither cell type was altered by anti-CD3 treatment. Anti-CD3 treatment improved glucose tolerance in old mice and was accompanied by improved signaling related to liver and skeletal muscle insulin utilization and decreased gluconeogenesis-related gene expression in the liver. Our findings indicate a critical role of the adaptive immune system in the age-related metabolic dysfunction.