Intracellular signalling pathways: targets to reverse immunosenescence.

Ageing is a very complex process, the result of the dysregulation of multiple systems interacting in many ways. A prominent change occurring with ageing is related to the architecture and functioning of the immune system, viewed commonly as detrimental and termed 'immunosenescence'. However, age-associated changes may also lead to increased function in certain respects, which can be viewed as adaptive. None the less, on balance it is well-recognized that immunosenescence is accompanied by the low-grade inflammation observed commonly in elderly people, which has been dubbed 'inflamm-ageing'. The exact cause and significance of all these changes is not clear, but there is a consensus that they are related to the occurrence of chronic non-infectious age-associated disease, as well as increased susceptibility to infections. Alterations to immune cell signalling may be a prominent cause of malfunctioning immunity. Emerging attempts to reverse immunosenescence have recently targeted the signalling pathways in various different cell types of the immune system. Here, we review and discuss alterations in the signalling pathways of immune cells with ageing and consider current targets and means to modulate altered functions. We discuss the potential dangers as well as the benefits of these interventions, and consider future approaches to this problem.

From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation.

Aging is accompanied by many physiological changes including those in the immune system. These changes are designated as immunosenescence indicating that age induces a decrease in immune functions. However, since many years we know that some aspects are not decreasing but instead are increasing like the pro-inflammatory activity by the innate immune cells, especially by monocytes/macrophages. Recently it became evident that these cells may possess a sort of memory called trained memory sustained by epigenetic changes occurring long after even in the absence of the initiator aggressor. In this review we are reviewing evidences that such changes may occur in aging and describe the relationship between inflamm-aging and immunosenescence as an adaptation/remodelling process leading on one hand to increased inflammation and on the other to decreased immune response (immune-paralysis) mastered by the innate immune system. These changes may collectively induce a state of alertness which assure an immune response even if ultimately resulting in age-related deleterious inflammatory diseases.

Clinical aspects of cytomegalovirus antiviral resistance in solid organ transplant recipients.

Despite advances in the prophylaxis and acute treatment of cytomegalovirus (CMV), it remains an important pathogen affecting the short- and long-term clinical outcome of solid organ transplant. The emergence of CMV resistance in a patient reduces the clinical efficacy of antiviral therapy, complicates therapeutic and clinical management decisions, and in some cases results in loss of the allograft and/or death of the patient. There is increasing use of antiviral prophylaxis after transplant with little expansion in the range of antiviral agents effective in treatment of CMV. Further understanding is needed of the risk factors for development of CMV antiviral resistance and of therapeutic strategies for treating patients infected with resistant viruses. We review the current status of CMV resistance in solid organ transplant recipients, and provide diagnostic and therapeutic suggestions for the clinician in managing antiviral resistance.

Discordant hepatitis C serological testing in Australia and the implications for organ transplant programs.

BACKGROUND: Discordant and equivocal hepatitis C (HCV) serology testing is problematic for making decisions regarding deceased organ donor (DOD) transplant allocation based on allograft infection status. OBJECTIVES: This study aimed to analyse the prevalence and follow-up testing of discordant HCV tested patients from an Australian population at increased risk of HCV infection, with prevalence modelling for the Australian DOD population. STUDY DESIGN: De-identified patient discordant HCV serology results (primary chemiluminescent microparticle immunoassay and secondary Bio-Rad MonoLisa HCV Ag/Ab Ultra assay) were retrospectively identified in a general referral laboratory between May 2008 and August 2011. Prior and follow-up serology testing was reviewed. Discordant result prevalencewas calculated using Bayes' theorem for the DOD population using Australian DOD rates and HCV seroprevalence. RESULTS: The tested population had a 6.6% HCV seroprevalence. The rate of discordant serotesting was 0.54%, with no cases identified as having definite HCV infection at follow-up. Two patients had evidence of definite HCV seropositivity before the index discordant test. Modelling for the Australian DOD population of 337 per year estimated a discordant test prevalence of 1.8 per year. CONCLUSIONS: Discordant HCV serotesting may occur for 1 of 185 patients tested in higher risk populations. The majority of such tests represent falsely reactive tests although a small number may reflect partial seroreversion. Amongst Australian DOD, this represents 1 or 2 discordant cases per year. It is likely that if this discordant sample were from a donor with no blood borne virus risk factors, and was concurrently RNA negative, that HCV infectious risk would be extremely low.