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    Heterochronic Parabiosis Studies of the Aging Immune System

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    Author
    Davies, John Stephen
    Issue Date
    2016
    Keywords
    heterochronic
    immunology
    parabiosis
    T cells
    Immunobiology
    aging
    Advisor
    Nikolich-Zugich, Janko
    
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    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Abstract
    Parabiosis is the surgical union of two organisms resulting in the development of a single, shared circulatory system. When animals of different ages are conjoined (i.e. heterochronic parabiosis), blood-borne factors from the parabionts can affect the physiology of the other parabiont. This is manifested sometimes by beneficial, rejuvenating impact upon the older animal's tissues and organs (anti-geronic effect), and sometimes by younger animal's tissues regressing and appearing old-like (pro-geronic effect). These effects, and the ability to identify individual factors that could recapitulate pro- and anti-geronic effects, have made heterochronic parabiosis a very attractive approach to studying biology of aging and rejuvenation.cHowever, heterochronic parabiosis has not been widely used to investigate the aged immune system. An important question to be answered is whether the cellular defects involved in the aged immune system are due to intrinsic defects or if they can be rescued by extrinsic factors. Heterochronic parabiosis is ideal to test cellular migration patterns, interrogate the mechanisms driving migration defects that occur with aging, establish if these defects can be rejuvenated and identify molecules that are targets for intervention. Here, we provide evidence of the importance of reducing differences in the background genetics of different C57BL/6 substrains prior to parabiosis. This improvement allowed us to improve survival and confirm robust lymphocyte equilibration across secondary, but not primary, lymphoid tissues. We found no evidence for rejuvenation of the old immune cells, whereas results suggested that adult peripheral lymph nodes (pLN) lost mass and cellularity, potentially indicating the presence of a pro-geronic factor(s) in the old circulation that affects pLN function. Adult and old immune cells were present in equal frequencies in both adult and old secondary lymphoid tissues, indicating that there was no restriction of cellular migration due to the age of the cell or age of the tissue. The propensity of adult immune cells (i.e. large naïve compartment) to occupy lymph nodes and old immune cells (i.e. large memory compartment) to occupy bone marrow was retained following heterochronic parabiosis. Finally, parabiosis separation experiments illuminated the peripheral survival advantage of old T cells over adult T cells. These results highlight the power of heterochronic parabiosis in studying immune aging and provide hypothesis-generating data for future mechanistic studies of peripheral T cell maintenance with aging.
    Type
    text
    Electronic Dissertation
    Degree Name
    Ph.D.
    Degree Level
    doctoral
    Degree Program
    Graduate College
    Immunobiology
    Degree Grantor
    University of Arizona
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