Immune therapy for age-related diseases

Weksler, Marc E.; Pawelec, Graham; Franceschi, Claudio

doi:10.1016/j.it.2009.03.011

Cited by 35 publications

(29 citation statements)

References 47 publications

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“…Among these changes, the most noticeable consequence of immunosenescence is the reduced effectiveness of immune responses [5]. Increased vulnerability to infection, reduced efficacy of vaccination, and reactivation of latent viruses are associated with a decline in immune functioning in later life [6][7][8][9][10][11][12]. Clinically, these defects are considered major contributing factors to the increased morbidity and mortality of elderly individuals due to infectious diseases [10,[13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

T cell senescence and cardiovascular diseases

Park

Shin

et al. 2015

Clin Exp Med

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Age-related changes in the immune system, commonly termed "immunosenescence," contribute to deterioration of the immune response and fundamentally impact the health and survival of elderly individuals. Immunosenescence affects both the innate and adaptive immune systems; however, the most notable changes are in T cell immunity and include thymic involution, the collapse of T cell receptor (TCR) diversity, an imbalance in T cell populations, and the clonal expansion of senescent T cells. Senescent T cells have the ability to produce large quantities of proinflammatory cytokines and cytotoxic mediators; thus, they have been implicated in the pathogenesis of many chronic inflammatory diseases. Recently, an increasing body of evidence has suggested that senescent T cells also have pathogenic potential in cardiovascular diseases, such as hypertension, atherosclerosis, and myocardial infarction, underscoring the detrimental roles of these cells in various chronic inflammatory responses. Given that cardiovascular disease is the number one cause of death worldwide, there is great interest in understanding the contribution of age-related immunological changes to its pathogenesis. In this review, we discuss general features of age-related alterations in T cell immunity and the possible roles of senescent T cells in the pathogenesis of cardiovascular disease.

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Section: Introductionmentioning

confidence: 99%

T cell senescence and cardiovascular diseases

Park

Shin

et al. 2015

Clin Exp Med

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“…As stated before, it will be discussed briefl y, but the reader is referred to many excellent recent review articles on this subject (Weksler et al 2005;Arbel and Solomon 2007 ;Boche and Nicoll 2008 ;Popovich and Longbrake 2008;Shah et al 2008 ;Villoslada et al 2008;Brody and Holtzman 2008 ;Foster et al 2009 ;Yamin et al 2008;Weksler et al 2009 ;Morgan 2009;Jicha 2009 ;Tarditi et al 2009;Wisniewski 2009 ;Federoff 2009 ;Neugroschl and Sano 2009;Deane et al 2009 ;Bednar 2009 ;Röskam et al 2010;von Bernhardi 2010 ;Lemere and Masliah 2010;Fu et al 2010 ;Grill and Cummings 2010 ;Citron 2010 ) .…”

Section: Immunotherapy For Alzheimer's Disease?mentioning

confidence: 99%

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

Lanning

Meredith

2011

Non-Fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

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Self-aggregation of proteins and peptides is at the root of many diseases, especially neurodegenerative diseases. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, type-2 diabetes mellitus, and transmissible spongiform encephalopathies, which are associated with self-aggregation of amyloid b -protein (A b ), huntingtin, a -synuclein, islet amyloid polypeptide, and the prion protein, respectively. The list of diseases for which protein/peptide aggregation is the root cause is ever expanding. There does not appear to be a single biochemical mechanism by which proteins and peptides self-associate, or a single pathogenic mechanism to explain all protein-/peptide-aggregation diseases. Nevertheless, inhibition of protein self-aggregation remains a potential target for therapeutic intervention. Beyond therapy, inhibitors of protein self-aggregation can serve as tools to help us understand the mechanisms by which aggregation occurs and harms cells. In this chapter, we examine select examples of inhibitors of protein aggregation. We have divided aggregating proteins/peptides into two types: (1) Proteins that have an unstable tertiary structure, that unfold under cellular stress, or that fail to fold correctly during biosynthesis. This instability leads to persistence of unfolded domains that can act as a nidus for self-association. (2) Peptides or proteins (or protein domains) that cannot fold at all, or fold only in the presence of a bound ligand. Examples of the fi rst group include transthyretin, the mammalian prion protein, and certain point-mutant forms of lysozyme or a 1-antitrypsin. In general, self-aggregation of these proteins results from exposure of normally buried hydrophobic residues to aqueous media. Examples of the second group include A b , islet amyloid polypeptide, and calcitonin. Within the second group, we also include proteins that are "peptide-like" in having domains with no unique, stable

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“…Indeed, accumulation of Aβ in the brain has been suggested to be caused by an impaired capacity to clear the protein in AD patients. 2 Initial phase I and phase II clinical (Elan/Wyeth AN1792) trials were conducted with aggregated Aβ1-42 and the QS-21; a Th1 response-activating adjuvant. 68,69 In the late stages of the phase I trial polysorbate 80, an emulsifying agent, was added to the active vaccine.…”

Section: Development Of Anti-aβ Vaccination In Humansmentioning

confidence: 99%

“…2 These deposits consist of amyloid fibrils in a β-pleated sheet conformation made up of mixed polymers of the 40 and 42 amino acid Aβ peptides. 1,3 The DNA sequence coding for Aβ is a small portion of a larger gene encoding a transmembrane amyloid precursor protein (APP).…”

Section: Introductionmentioning

confidence: 99%

The central role of T-cell memory in Alzheimer’s disease vaccination

Giunta¹,

Ruscin²,

Salemi³

et al. 2010

Ageing Res

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Alzheimer's disease (AD) is the most common progressive neurodegenerative brain disease as well as the most common dementia among the elderly. In the future as the average lifespan continues to extend, the number of AD patients will continue to grow. Amyloidbeta (Aβ) peptides, in both soluble oligomeric, and insoluble forms, are key in the neuropathogenesis of AD and have thus been a therapeutic target for vaccines. Multiple Aβ vaccination strategies in animal models of AD have demonstrated a marked reduction in both amyloid burden and neurocognitive deficits. Due to the success of these studies, initial human clinical trials of an active Aβ vaccine were conducted. These were discontinued due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Studies examining the brains of Aβ-vaccinated patients developing meningoencephalitis implicate Aβ-reactive T-cell subsets as major components of this deleterious response to active Aβ vaccination. To subvert possible meningoencephalitis resulting from Aβ vaccination a second generation of vaccines has been more recently developed. These however have met with little success in humans. To build on these findings, an understanding of the role of T-cells in vaccination against Aβ is presented in this review. Various methods of Aβ immunotherapy are reviewed including studies in both animal models and humans. Recent works suggest that Aβ-derived peptides delivered intranasally or transcutaneously results in effective clearance of Aβ plaques and improvement of cognitive function in animal models of AD. Moreover, undesired T-cell reactivity appeared to be considerably reduced compared with other active immunization strategies. In spite of the past clinical studies, these findings imply that Aβ vaccination may be both efficacious and safe depending route of delivery, adjuvant choice, and Aβ epitope administered.

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Immune therapy for age-related diseases

Cited by 35 publications

References 47 publications

T cell senescence and cardiovascular diseases

T cell senescence and cardiovascular diseases

Strategies for Inhibiting Protein Aggregation: Therapeutic Approaches to Protein-Aggregation Diseases

The central role of T-cell memory in Alzheimer’s disease vaccination

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