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Complement in immune and inflammatory disorders: therapeutic interventions.

ABSTRACT: With the awareness that immune-inflammatory cross-talk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. Although prevalent conditions such as age-related macular degeneration have attracted the most attention, the diverse array of complement-mediated pathologies, with distinct underlying mechanisms, demands a multifaceted arsenal of therapeutic strategies. Fortunately, efforts in recent years have not only introduced the first complement inhibitors to the clinic but also filled the pipelines with promising candidates. With a focus on immunomodulatory strategies, in this review we discuss complement-directed therapeutic concepts and highlight promising candidate molecules.

SUBMITTER: Ricklin D

PROVIDER: S-EPMC3623010 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Complement in immune and inflammatory disorders: therapeutic interventions.

Ricklin Daniel D Lambris John D JD

Journal of immunology (Baltimore, Md. : 1950) 20130401 8

With the awareness that immune-inflammatory cross-talk is at the heart of many disorders, the desire for novel immunomodulatory strategies in the therapy of such diseases has grown dramatically. As a prime initiator and important modulator of immunological and inflammatory processes, the complement system has emerged as an attractive target for early and upstream intervention in inflammatory diseases and has moved into the spotlight of drug discovery. Although prevalent conditions such as age-re ...[more]

PMID: 23564578

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Project description:BackgroundIn patients with immune-mediated inflammatory disorders, poor adherence to medication is associated with increased healthcare costs, decreased patient satisfaction, reduced quality of life and unfavorable treatment outcomes.ObjectiveTo determine the impact of different interventions on medication adherence in patients with immune-mediated inflammatory disorders.DesignSystematic review.Data sourcesMEDLINE, EMBASE and Cochrane Library.Study eligibility criteria for selecting studiesIncluded studies were clinical trials and observational studies in adult outpatients treated for psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, spondyloarthritis, psoriatic arthritis or multiple sclerosis.Study appraisal and synthesis methodsIntervention approaches were classified into four categories: educational, behavioral, cognitive behavioral, and multicomponent interventions. The risk of bias/study limitations of each study was assessed using the GRADE system.ResultsFifteen studies (14 clinical trials and one observational study) met eligibility criteria and enrolled a total of 1958 patients. Forty percent of the studies (6/15) was conducted in patients with inflammatory bowel disease, half (7/15) in rheumatoid arthritis patients, one in psoriasis patients and one in multiple sclerosis patients. Seven out of 15 interventions were classified as multicomponent, four as educational, two as behavioral and two as cognitive behavioral. Nine studies, of which five were multicomponent interventions, had no serious limitations according to GRADE criteria. Nine out of 15 interventions showed an improvement of adherence: three multicomponent interventions in inflammatory bowel disease; one intervention of each category in rheumatoid arthritis; one multicomponent in psoriasis and one multicomponent in multiple sclerosis.ConclusionThe assessment of interventions designed for increasing medication adherence in IMID is rare in the literature and their methodological quality may be improved in upcoming studies. Nonetheless, multicomponent interventions showed the strongest evidence for promoting adherence in patients with IMID.

Project description:Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a wide range of tumor-induced alterations, which affect both the innate and adaptive arms of the immune response, and accumulate during disease progression. In recent years, the development of targeted therapies, such as the B-cell receptor signaling inhibitors and the Bcl-2 protein inhibitor venetoclax, has dramatically changed the treatment landscape of CLL. Despite their remarkable anti-tumor activity, targeted agents have some limitations, which include the development of drug resistance mechanisms and the inferior efficacy observed in high-risk patients. Therefore, additional treatments are necessary to obtain deeper responses and overcome drug resistance. Allogeneic hematopoietic stem cell transplantation (HSCT), which exploits immune-mediated graft-versus-leukemia effect to eradicate tumor cells, currently represents the only potentially curative therapeutic option for CLL patients. However, due to its potential toxicities, HSCT can be offered only to a restricted number of younger and fit patients. The growing understanding of the complex interplay between tumor cells and the immune system, which is responsible for immune escape mechanisms and tumor progression, has paved the way for the development of novel immune-based strategies. Despite promising preclinical observations, results from pilot clinical studies exploring the safety and efficacy of novel immune-based therapies have been sometimes suboptimal in terms of long-term tumor control. Therefore, further advances to improve their efficacy are needed. In this context, possible approaches include an earlier timing of immunotherapy within the treatment sequencing, as well as the possibility to improve the efficacy of immunotherapeutic agents by administering them in combination with other anti-tumor drugs. In this review, we will provide a comprehensive overview of main immune defects affecting patients with CLL, also describing the complex networks leading to immune evasion and tumor progression. From the therapeutic standpoint, we will go through the evolution of immune-based therapeutic approaches over time, including i) agents with broad immunomodulatory effects, such as immunomodulatory drugs, ii) currently approved and next-generation monoclonal antibodies, and iii) immunotherapeutic strategies aiming at activating or administering immune effector cells specifically targeting leukemic cells (e.g. bi-or tri-specific antibodies, tumor vaccines, chimeric antigen receptor T cells, and checkpoint inhibitors).

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Complement in immune and inflammatory disorders: therapeutic interventions.

Publications

Complement in immune and inflammatory disorders: therapeutic interventions.

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