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Preclinical Modeling of the Dysregulated Aged Immune System in the Context of Viral Infection and Immunotherapy /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Preclinical Modeling of the Dysregulated Aged Immune System in the Context of Viral Infection and Immunotherapy // Craig P Collins.
作者:	Collins, Craig P.,
面頁冊數:	1 electronic resource (134 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-11, Section: A.
Contained By:	Dissertations Abstracts International86-11A.
標題:	Immunology. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31844025
ISBN:	9798314860458

Preclinical Modeling of the Dysregulated Aged Immune System in the Context of Viral Infection and Immunotherapy /
Collins, Craig P.,

Preclinical Modeling of the Dysregulated Aged Immune System in the Context of Viral Infection and Immunotherapy /Craig P Collins. - 1 electronic resource (134 pages)

Source: Dissertations Abstracts International, Volume: 86-11, Section: A.

The negative impact of age on clinical outcomes is well documented. Elderly individuals are almost universally at a higher risk of developing more severe pathology during immune challenges such as viral infections, and stimulatory immune therapies used to address afflictions that are experienced more by the elderly, such as cancer, have an elevated risk of adverse effects. Preclinical modeling could be highly useful in dissecting the aged immune system and responses, as well as investigating age specific therapeutics to target dysfunctional components, but most studies use young animals and attempt to extrapolate the data to the aged population, despite the well-known immunological differences incurred with aging. While studies have been performed with aged mice to study these phenomena, SPF conditions have led to longer lifespans in mice, and the definition of what constitutes an "aged" mouse, as well as robust immune characterization of mouse age groups as they grow older, has not been sufficiently performed or correlated to aged human data. Contrasting data has been noted in aged mice, with some studies finding that aged mice are protected against certain immune driven pathologies, while others have found the exact opposite. A critical difference in these studies was the age of the mice used, with some using 16 months (the NIA defined minimum for an "aged" mouse), and others using 20+ month old mice. While it is known that age exacerbates most morbidity, the mechanisms of how this occurs is not fully known, and the aged mouse model needs to be advanced to reflect the clinical paradigm. This dissertation begins with a thorough review on the strengths and weaknesses of preclinical models such as mice, non-human primates, and ferrets, particularly in the context of aging and SARS-CoV-2. The second chapter details thymic rebound hyperplasia following stimulatory immunotherapy, a phenomenon in which the thymus acutely involutes and the periphery sees an expansion of memory T cells, with both the involution and memory expansion gradually reversing after the immunotherapy ceases, with the thymus eventually being even larger than at the start, and the naive population being larger than at the start as the memory T cells contract. However, in aged mice, which already have involuted thymuses at a baseline, acute involution and memory expansion occurs and doesn't reverse in the timespan of younger mice, indicating prolonged susceptibility to novel pathogens following immunotherapy. The third chapter details the fundamental immune differences between young, aged, and advance aged mice, with a focus on T and NK cells, and the differentials in immune responses to acute viral infections. The data presented implies that advanced aged mice have impaired antigen specific responses and compensate with non-antigen specific responses, particularly NK cells, which were found to have a significantly larger fold expansion and numbers in key organs effected by the viruses used. While this compensation controlled the virus comparably to younger groups, the advanced aged mice ultimately saw more pathology and mortality, which was likely immune driven due to overcompensation of the innate response. In both chapters, data is correlated to human data, showing translatability between mouse and human models.This data advances our knowledge of the aged mouse model by defining how mice change over time, both at a fundamental level and in the context of immune challenge and immune therapy. This also provides targets for immune modulation / therapy for the aged immune response and addressing multiple levels of dysfunction as mice age. Critically, linking mouse and human data together and showing similar dysfunction at baselines and during immune response strengthens the translatability of the model, while also potentially addressing previous discrepancies of the aged immune response.

English

ISBN: 9798314860458Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Inflammation

Preclinical Modeling of the Dysregulated Aged Immune System in the Context of Viral Infection and Immunotherapy /
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