Defense Date

1994

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Pharmacology & Toxicology

First Advisor

Bruce A. Fuchs

Abstract

The immune system is critical for the maintenance of homeostasis. Due to the fact that a coordinated effort between organ systems is required for internal stability, it has been postulated that the immune system interacts with the neuroendocrine system. Clinical, anatomical, and receptor studies have provided evidence for a bi-directional communication between the nervous and immune systems. The goal of the present studies was to determine the potential influence of the sympathetic nervous system (SNS) on the primary antibody forming cell (AFC) response.

The adrenergic neurotoxin, 6-hydroxydopamine (6-OHDA), has been utilized extensively by researchers to explore the possible relationship between SNS and the antibody response. However, the literature describing the humoral effects observed following 6-OHDA treatment is irresolute. In an attempt to provide insight into these apparent discrepancies, studies were conducted comparing the effects of 6-OHDA and its non-neurotoxic congener, 5-hydroxydopamine (5-OHDA). Both chemicals, when added directly into cultures containing naive splenocytes, suppressed the in vitro AFC response. Analysis following in vivo treatment with 6-OHDA or 5-OHDA revealed that while both chemical treatments resulted in suppression of the AFC response following in viva sensitization, only the splenocytes from 6-OHDA treated mice were suppressed when subsequently sensitized in vitro. Pretreatment with desmethylimipramine (DMI) blocked the observed 6-OHDA- and 5-OHDA-induced immunosuppression displayed in vivo, indicating that the uptake of the chemicals into adrenergic neurons was required. As an alternative method for removing the sympathetic influence in the spleen, studies were conducted with chlorisondamine, a non-competitive ganglionic blocker. While direct addition of chlorisondamine was without effect in the in vitro-in vitro AFC response, the in viva AFC response following chlorisondamine treatment was significantly suppressed.

In addition to the suppression of the primary AFC response, 6-OHDA and chlorisondamine treatment resulted in a time dependent increase in the level of DNA fragmentation in the thymus. Analysis of serum corticosterone levels in 6-OHDA- and chlorisondamine-treated mice revealed that both treatments elevated levels of serum corticosterone. Given the potential role of corticosterone in the 6-OHDA- and chlorisondamine-induced immunosuppression, studies were conducted to determine if the glucocorticoid receptor antagonist, RU-486, was able to block the DNA fragmentation in the thymus and the suppression of the AFC response demonstrated after 6-OHDA or chlorisondamine treatment. While RU-486 was effective at blocking the 6-OHDA- and chlorisondamine-induced thymic effects, it was unable to block the suppression of the primary AFC response. Collectively, these studies reveal that removal of the peripheral SNS by either sympathectomy with 6-OHDA or ganglionic blockade with chlorisondamine can result in 1) thymic alterations which are mediated by increased levels of corticosterone and 2) suppression of the primary AFC response which is independent of the elevated corticosterone levels. Importantly, these results provide evidence for positive modulation of the humoral immune response by the sympathetic nervous system.

Comments

Scanned, with permission from the author, from the original print version, which resides in University Archives.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

6-18-2018

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