Explore the vast range of titles available.

Multiple sclerosis (MS) is the most common human demyelinating disease of the central nervous system. The IL-12 family of cytokines has four members, which are IL-12 (p40:p35), IL-23 (p40:p19), the p40 monomer (p40), and the p40 homodimer (p40₂). Since all four members contain p40 in different forms, it is important to use a specific monoclonal antibody (mAb) to characterize these molecules. Here, by using such mAbs, we describe selective loss of p40 in serum of MS patients as compared to healthy controls. Similarly, we also observed decrease in p40 and increase in IL-12, IL-23, and p40₂ in serum of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, as compared to control mice. Interestingly, weekly supplementation of mouse and human recombinant p40 ameliorated clinical symptoms and disease progression of EAE. On the other hand, IL-12, IL-23, and p40₂ did not exhibit such inhibitory effect. In addition to EAE, p40 also suppressed collagen-induced arthritis in mice. Using IL-12Rβ1−/−, IL-12Rβ2−/−, and IL-12Rβ1+/−/IL-12Rβ2−/− mice, we observed that p40 required IL-12Rβ1, but not IL-12Rβ2, to suppress EAE. Interestingly, p40 arrested IL-12–, IL-23–, or p402-mediated internalization of IL-12Rβ1, but neither IL-12Rβ2 nor IL-23R, protected regulatory T cells, and suppressed Th1 and Th17 biasness. These studies identify p40 as an anti-autoimmune cytokine with a biological role different from IL-12, IL-23, and p40₂ in which it attenuates autoimmune signaling via suppression of IL-12Rβ1 internalization, which may be beneficial in patients with MS and other autoimmune disorders.

Interleukins 12 and 23 have important roles in the pathophysiology of psoriasis. We assessed ustekinumab, a human monoclonal antibody directed against these cytokines, for the treatment of psoriasis. In this phase III, parallel, double-blind, placebo-controlled study, 766 patients with moderate-to-severe psoriasis were randomly assigned to receive ustekinumab 45 mg (n=255) or 90 mg (n=256) at weeks 0 and 4 and then every 12 weeks; or placebo (n=255) at weeks 0 and 4, with subsequent crossover to ustekinumab at week 12. Patients who were initially randomised to receive ustekinumab at week 0 who achieved long-term response (at least 75% improvement in psoriasis area and severity index [PASI 75] at weeks 28 and 40) were re-randomised at week 40 to maintenance ustekinumab or withdrawal from treatment until loss of response. Both randomisations were done with a minimisation method via a centralised interactive voice response system. The primary endpoint was the proportion of patients achieving PASI 75 at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00267969. All randomised patients were included in the efficacy analysis. 171 (67·1%) patients receiving ustekinumab 45 mg, 170 (66·4%) receiving ustekinumab 90 mg, and eight (3·1%) receiving placebo achieved PASI 75 at week 12 (difference in response rate vs placebo 63·9%, 95% CI 57·8–70·1, p<0·0001 for 45 mg and 63·3%, 57·1–69·4, p<0·0001 for 90 mg). At week 40, long-term response had been achieved by 150 patients in the 45 mg group and 172 patients in the 90 mg group. Of these, 162 patients were randomly assigned to maintenance ustekinumab and 160 to withdrawal. PASI 75 response was better maintained to at least 1 year in those receiving maintenance ustekinumab than in those withdrawn from treatment at week 40 (p<0·0001 by log-rank test). During the placebo-controlled phase, adverse events occurred in 278 (54·5%) of the 510 patients receiving ustekinumab and 123 (48·2%) of the 255 receiving placebo. Serious adverse events occurred in six (1·2%) of 510 patients receiving ustekinumab and in two (0·8%) of 255 receiving placebo in this phase. The pattern of adverse events was much the same in the placebo crossover and randomised withdrawal phases as it was in the placebo-controlled phase. Ustekinumab seems to be efficacious for the treatment of moderate-to-severe psoriasis; dosing every 12 weeks maintains efficacy for at least a year in most patients. Centocor Inc.

Ustekinumab, a human monoclonal antibody against interleukins 12 and 23, has shown therapeutic potential for psoriasis. This study assessed the efficacy and safety of ustekinumab in psoriasis patients and assessed dosing intensification in partial responders. In this multicentre, phase III, double-blind, placebo-controlled study, 1230 patients with moderate-to-severe psoriasis (defined by a psoriasis area and severity index [PASI] score ≥12, and at least 10% total body surface area involvement) were randomly assigned to receive ustekinumab 45 mg (n=409) or 90 mg (n=411) at weeks 0 and 4, then every 12 weeks, or placebo (n=410). Partial responders (ie, patients achieving ≥50% but <75% improvement from baseline in PASI) were re-randomised at week 28 to continue dosing every 12 weeks or escalate to dosing every 8 weeks. Both randomisations were done with a minimisation method via a centralised interactive voice response. The primary endpoint was the proportion of patients achieving at least 75% improvement in PASI (PASI 75) at week 12. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00307437. All randomised patients were included in the efficacy analysis. 273 (66·7%) patients receiving ustekinumab 45 mg, 311 (75·7%) receiving ustekinumab 90 mg, and 15 (3·7%) receiving placebo achieved the primary endpoint (difference in response rate 63·1%, 95% CI 58·2–68·0, p<0·0001 for the 45 mg group vs placebo and 72·0%, 67·5–76·5, p<0·0001 for the 90 mg group vs placebo). More partial responders at week 28 who received ustekinumab 90 mg every 8 weeks achieved PASI 75 at week 52 than did those who continued to receive the same dose every 12 weeks (22 [68·8%] vs 11 [33·3%]; difference in response rate 35·4%, 95% CI 12·7–58·1, p=0·004). There was no such response to changes in dosing intensity in partial responders treated with ustekinumab 45 mg. During the placebo-controlled phase, 217 (53·1%) patients in the 45 mg group, 197 (47·9%) in the 90 mg group, and 204 (49·8%) in the placebo group experienced adverse events; serious adverse events were seen in eight (2·0%) patients in the 45 mg group, five (1·2%) in the 90 mg group, and eight (2·0%) in the placebo group. Although treatment with ustekinumab every 12 weeks is effective for most patients with moderate-to-severe psoriasis, intensification of dosing to once every 8 weeks with ustekinumab 90 mg might be necessary to elicit a full response in patients who only partially respond to the initial regimen. Centocor Inc.

Repeated subcutaneous injections of a monoclonal antibody against the p40 subunit of interleukins 12 and 23, ustekinumab, were used to treat patients with relapsing-remitting multiple sclerosis (RRMS) to assess the drug's safety, efficacy, and pharmacokinetics. In this phase II, multicentre, randomised, double-blind, placebo-controlled study, 249 patients with RRMS, aged 18–65 years, were eligible to be assigned equally (by a central randomisation procedure based on study site and presence or absence of gadolinium-enhancing T1-weighted lesions at baseline) to one of five groups that received placebo or four different ustekinumab dosages at weeks 0, 1, 2, 3, 7, 11, 15, and 19. Ustekinumab doses were 27 mg, 90 mg q8w, 90 mg, or 180 mg; the 90 mg q8w dosage group received placebo substitute at weeks 7 and 15. The primary endpoint was the cumulative number of new gadolinium-enhancing T1-weighted lesions on serial cranial MRI through week 23. Patients were followed up through week 37. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00207727. From August, 2004, to December, 2006, 249 patients underwent randomisation (49 for placebo; 50 for each ustekinumab group). Ustekinumab treatment did not show a significant reduction in the primary endpoint for any dosage groups versus placebo. At week 37, adverse events occurred in 38 (78%) placebo-treated patients and 170 (85%) ustekinumab-treated patients, with infections most commonly reported. Serious adverse events occurred in one (2%) placebo-treated patient and six (3%) ustekinumab-treated patients. Malignant diseases were reported in two patients shortly after the initiation of ustekinumab treatment; both patients were withdrawn from the trial and given appropriate treatment, which resulted in complete remission. No serious infections, cardiovascular events, or exacerbation of demyelinating events occurred. A dose-dependent increase in serum concentrations of ustekinumab was recorded. Ustekinumab is generally well tolerated but does not show efficacy in reducing the cumulative number of gadolinium-enhancing T1-weighted lesions in multiple sclerosis. Centocor Research & Development.

Premenstrual syndrome (PMS) is a common disorder in the reproductive age that negatively significant impacts on women’s quality of life. This randomized clinical trial study was undertaken to investigate the effect of vitamin D supplementation on inflammatory and antioxidant markers in 44 vitamin D deficient (25(OH)D < 20 ng/mL) students with PMS. Participants received either 50,000 IU vitamin D3 or a placebo pearl fortnightly for 4 months. At the baseline and in the last 2 months of intervention, participants were asked to complete the PMS Daily Symptoms Rating form along with taking the pearls and their blood samples were collected to assess serum levels of 25(OH)D 3 , Interleukin 10 and 12 (IL-10, IL-12) and total antioxidant capacity (TAC). In vitamin D group, serum levels of IL-10 and IL-12 significantly decreased while TAC significantly increased post-intervention. There were significant differences regarding serum IL-12 and TAC levels between the two groups. Mean score of the total PMS symptoms showed significant improvement in 25(OH)D . Vitamin D supplementation seems to be an effective strategy to improve inflammation and antioxidant markers in vitamin D deficient women with PMS. This clinical trial was registered at Iranian Registry of Clinical Trials on 20/06/2018 (IRCT20180525039822N1).

Type 1 cytokines are overexpressed in psoriatic plaques. This trial evaluated a monoclonal antibody against interleukin-12 and interleukin-23 in patients with psoriasis. Response rates at 12 weeks were significantly higher in patients treated with interleukin-12/23 monoclonal antibody than in those treated with placebo. Four percent of patients who received interleukin-12/23 monoclonal antibody and 1% of those who received placebo had serious adverse events. Larger studies of longer duration are needed to assess the effectiveness and safety of interleukin-12/23 monoclonal antibody for psoriasis. In patients with psoriasis, response rates at 12 weeks were significantly higher in those treated with interleukin-12/23 monoclonal antibody than in those treated with placebo. Psoriasis is a chronic inflammatory skin disorder affecting 2 to 3% of the world's population. 1 , 2 Psoriasis affects the physical and emotional well-being of patients, and its effect on quality of life is similar to that seen with other major medical diseases. 3 Significant unmet need remains for safe, highly effective, and convenient treatments. Aberrant type 1 immune responses have been linked to the pathogenesis of psoriasis, 4 – 7 and cytokines that elicit these immune responses (e.g., interleukin-12 and interleukin-23) may represent appropriate therapeutic targets. 8 Interleukin-12 p40 is overexpressed in psoriasis plaques, 9 and preclinical studies implicate this cytokine in the pathogenesis of . . .

Proinflammatory cytokine expression increases as a result of amyloid deposition in Alzheimer's disease. Frank L. Heppner and colleagues show that genetic and pharmacological inhibition of IL-12 and IL-23 signaling reduces plaque load and improves cognitive deficits in mouse models of Alzheimer's disease. As the concentration of p40 is also increased in the cerebrospinal fluid of individuals with Alzheimer's disease, this suggests that this pathway may be targeted therapeutically in patients. The pathology of Alzheimer's disease has an inflammatory component that is characterized by upregulation of proinflammatory cytokines, particularly in response to amyloid-β (Aβ). Using the APPPS1 Alzheimer's disease mouse model, we found increased production of the common interleukin-12 (IL-12) and IL-23 subunit p40 by microglia. Genetic ablation of the IL-12/IL-23 signaling molecules p40, p35 or p19, in which deficiency of p40 or its receptor complex had the strongest effect, resulted in decreased cerebral amyloid load. Although deletion of IL-12/IL-23 signaling from the radiation-resistant glial compartment of the brain was most efficient in mitigating cerebral amyloidosis, peripheral administration of a neutralizing p40-specific antibody likewise resulted in a reduction of cerebral amyloid load in APPPS1 mice. Furthermore, intracerebroventricular delivery of antibodies to p40 significantly reduced the concentration of soluble Aβ species and reversed cognitive deficits in aged APPPS1 mice. The concentration of p40 was also increased in the cerebrospinal fluid of subjects with Alzheimer's disease, which suggests that inhibition of the IL-12/IL-23 pathway may attenuate Alzheimer's disease pathology and cognitive deficits.

The cytokine interleukin-12 has been implicated in the intestinal inflammation of Crohn's disease. In this phase 2 trial, the rates of adverse events were similar among patients who received a monoclonal antibody against interleukin-12 and patients who received placebo, with the exception of local reactions at injection sites, which were more common in the former group. The rates of clinical response and remission were higher among patients treated with antibody but not significantly so in most cases. This study suggests that a monoclonal antibody targeted to interleukin-12 p40 may have biologic activity against Crohn's disease. Interleukin-12 is a key cytokine that drives the inflammatory response mediated by type 1 helper T (Th1) cells. 1 , 2 As such, it underlies both normal host responses to a variety of intracellular bacterial, fungal, and protozoal pathogens and the abnormal inflammatory responses that accompany many autoimmune diseases, such as Crohn's disease. Crohn's disease is characterized by increased production of interleukin-12 by antigen-presenting cells in intestinal tissue and interferon-γ and tumor necrosis factor α (TNF-α) by intestinal lymphocytes and macrophages. 3 – 7 These inflammatory cytokines induce and sustain the granulomatous inflammation and bowel-wall thickening that are hallmarks of Crohn's disease. Targeting interleukin-12 . . .

DNA vaccines are a promising approach to vaccination since they circumvent the problem of vector-induced immunity. DNA plasmid cytokine adjuvants have been shown to augment immune responses in small animals and in macaques. We performed two first in human HIV vaccine trials in the US, Brazil and Thailand of an RNA-optimized truncated HIV-1 gag gene (p37) DNA derived from strain HXB2 administered either alone or in combination with dose-escalation of IL-12 or IL-15 plasmid cytokine adjuvants. Vaccinations with both the HIV immunogen and cytokine adjuvant were generally well-tolerated and no significant vaccine-related adverse events were identified. A small number of subjects developed asymptomatic low titer antibodies to IL-12 or IL-15. Cellular immunogenicity following 3 and 4 vaccinations was poor, with response rates to gag of 4.9%/8.7% among vaccinees receiving gag DNA alone, 0%/11.5% among those receiving gag DNA+IL-15, and no responders among those receiving DNA+high dose (1500 ug) IL-12 DNA. However, after three doses, 44.4% (4/9) of vaccinees receiving gag DNA and intermediate dose (500 ug) of IL-12 DNA demonstrated a detectable cellular immune response. This combination of HIV gag DNA with plasmid cytokine adjuvants was well tolerated. There were minimal responses to HIV gag DNA alone, and no apparent augmentation with either IL-12 or IL-15 plasmid cytokine adjuvants. Despite the promise of DNA vaccines, newer formulations or methods of delivery will be required to increase their immunogenicity. Clinicaltrials.gov NCT00115960 NCT00111605.

IL-12 and IL-23 cytokines respectively drive Th1 and Th17 type responses. Yet, little is known regarding the biology of these receptors. As the IL-12 and IL-23 receptors share a common subunit, it has been assumed that these receptors are co-expressed. Surprisingly, we find that the expression of each of these receptors is restricted to specific cell types, in both mouse and human. Indeed, although IL-12Rβ2 is expressed by NK cells and a subset of γδ T cells, the expression of IL-23R is restricted to specific T cell subsets, a small number of B cells and innate lymphoid cells. By exploiting an IL-12- and IL-23-dependent mouse model of innate inflammation, we demonstrate an intricate interplay between IL-12Rβ2 NK cells and IL-23R innate lymphoid cells with respectively dominant roles in the regulation of systemic versus local inflammatory responses. Together, these findings support an unforeseen lineage-specific dichotomy in the in vivo role of both the IL-12 and IL-23 pathways in pathological inflammatory states, which may allow more accurate dissection of the roles of these receptors in chronic inflammatory diseases in humans.