Extensive studies from our laboratories have shown the presence of noradrenergic (NA) and substance P (SP) innervation of lymphoid organs. Numerous studies have reported that these neuro-transmitters can modulate immune functions. Conversely, Besedovsky and coworkers have shown that an immune response can alter neurotransmitter levels in reacting target lymphoid organs. We, and others, have evidence to support a role for NA and SP innervation of lymphoid organs in age-related immuno-suppression, and a variety of autoimmune disease models, such as experimental adjuvant- induced arthritis (EA). Both clinical studies of rheumatoid arthritis (RA) and experimental evidence of EA indicate involvement of NA and SP innervation in the pathophysiology of this disease. Clinical findings which are consistent with nervous system involvement in RA include: (1) a symmetric distribution of synovitis; (2) hemiplegic patients who later develop RA are spared the inflammatory process in joints on the paretic side; and (3) onset and exacerbation of the disease are often preceded by psychological trauma. It is well documented that NE and SP can modulate chronic inflammatory response and degree of destruction in the joints associated with RA and EA. Many experimental studies have employed systemic methods of denervation to demonstrate a role for these neurotransmitter systems, which would denervate several potential sites of action for these transmitters, including the joint, primary and secondary lymphoid organs, and central outflow to autonomic ganglia. Recently our laboratory has revealed that SP innervation of draining lymph nodes (LNs) is necessary for full expression of EA. This proposal further investigates the influence of NA and SP innervation of draining LNs in development and severity of EA in Lewis rats. Specifically, we propose to examine: (1) the effect of regional denervation of SP or NA innervation of popliteal and inguinal LNs on the expression of EA using chemical denervation, neurochemical analysis of SP and NE and assessing the time of onset, progression, and severity of EA in Lewis rats; and (2) the effect of EA and local inflammatory responses on NA and SP innervation of draining LNs, and subsequent immune responses in LNs, using double-label immunocytochemistry, neurochemical analysis of SP and NE, and beta-adrenoceptor and SP receptor binding assays. Functional studies will examine immuno-responsiveness of EA rats for correlation with neurochemical and anatomical measures of SP and NA innervation. These studies will provide a better understanding of the feedback circuitry involved in the development of EA, the functional consequences of EA in secondary lymphoid organs, and the role of SP and NA innervation during this disease processes. The ultimate significance of such studies lies in use of in vivo pharmacologic manipulation of neurotransmitters or neuromodulators that innervate lymphoid tissue, as a means of altering immune function and host defense, and the possible implications for development of therapeutive approaches for intervention of autoimmune diseases, such as RA.
