Alan J. Husband

Central nervous system influences on lymphocyte migration

The immune response network is only one of many physiologic adaptive responses to environmental change and there is now substantial evidence that adaptive responses involving the central nervous system have an impact on immune outcome. Effective immune function depends upon a highly mobile population of precursor and effector cells of the lymphoid system. In this review it is proposed that many of the alterations in immunity resulting from CNS activity may be explained in terms of changes in lymphocyte migration patterns in response to endocrine signals, neural signals via neurotransmitter release, or direct contacts between nerves and cells of the immune system.

Pavlovian conditioning of nasal tryptase release in human subjects with allergic rhinitis.

The role of Pavlovian conditioning in humans with perennial allergic rhinitis was investigated using release of tryptase from sensitised mast cells as an indicator of allergic responsiveness. Challenge with house dust mite allergen (unconditioned stimulus) was paired with a drink of novel taste and appearance (conditioned stimulus) in a single conditioning trial. Upon reexposure to the conditioned stimulus alone, levels of mast cell tryptase released in subjects who had received both the novel drink and allergen challenge on the conditioning trial was significantly greater than subjects who had received either the drink or the allergen alone. The results support the involvement of the central nervous system in mast cell degranulation in allergic rhinitis in humans.

Behavioral conditioning prolongs heart allograft survival in rats

Conditioned immunosuppression using a taste aversion paradigm has been demonstrated in a number of laboratory models but few reports have demonstrated changes in immunity sufficient to be of clinical relevance. The experiments reported here demonstrate that the survival of heart allografts in rats can be prolonged by behaviorally conditioned immunosuppression using cyclosporin A (CsA) as an unconditioned stimulus in taste aversion conditioning. Conditioned animals received saccharin as the conditioned stimulus paired with an injection of CsA at 10 and 6 days prior to transplantation. They were reexposed to saccharin alone 1 day prior to and 3 days after transplantation. On these occasions the conditioned group displayed taste aversion behavior when offered saccharin and a significant prolongation of heart graft survival was observed compared to the conditioned and nonconditioned control groups. These experiments suggest that behaviorally conditioned immunosuppression may have important clinical implications as an adjunct to drug treatments in transplantation medicine.

In vivo effects of β-endorphin on lymphocyte proliferation and interleukin 2 production

Abstract Experiments were undertaken in rats to investigate the effects of in vivo infusion of β-endorphin (BEP) on subsequent Con A-induced proliferation and interleukin 2 (IL-2) production by spleen cells in vitro . BEP administration induced a dose-dependent enhancement of the proliferative response to Con A. Infusion of the opiate antagonist naloxone (NAL) inhibited the Con A response and infusion of NAL prior to BEP resulted in even further inhibition. None of these treatments resulted in detectable alterations in IL-2 production after 48 h in culture. To demonstrate a direct interaction between BEP and lymphocytes, spleen cells were incubated in vitro with varying concentrations of BEP and/or NAL. Enhanced Con A-induced proliferation was observed following incubation with BEP in the range 10 −12 to 10 −9 M (levels comparable to the effective in vivo doses) and this effect was abrogated by NAL pretreatment (10 −6 M ). These data indicate a role for BEP in enhancing lymphocyte reactivity which is to some extent dependent on opiate receptors on the cell surface. This report extends the evidence obtained from in vitro experiments implicating endogenous opioids in modulation of host immunity by demonstrating that these effects can be obtained in vivo .

Interleukin-1 β and muramyl dipeptide can prevent decreased antibody response associated with sleep deprivation

A single, brief (8 h) period of sleep deprivation (DEP) was found to suppress secondary antibody response to sheep red blood cells in rats. This decrease could be totally prevented if either interleukin-1 beta (IL-1) or muramyl dipeptide (MDP) was administered at the beginning of the DEP vigil. Twenty-five units of IL-1 or 250 micrograms/kg MDP was found to be immunosuppressive in sleeping rats but, paradoxically, the combination of such doses with DEP alleviated this effect. Increased colonic temperatures associated with antigen and/or adjuvant administration were not related to the differences in antibody levels between sleeping and DEP animals. Activation of hypothalamic dopamine in IL-1-treated rats following DEP suggests that this monoamine transmitter system may participate in the observed protective activity of IL-1. The present findings extend the immune adjuvant effects of both IL-1 and MDP to protection of the host against behaviorally induced immunosuppression.

Modulation of body temperature through taste aversion conditioning

Injection of rats with bacterial lipopolysaccharide (LPS) results in an initial fall in body temperature followed by a fever. Lithium chloride (LiCl) injection induces a fall in body temperature without subsequent fever production. When these substances were incorporated as unconditioned stimuli in a taste aversion conditioning paradigm, using saccharin flavour as the conditioning stimulus, these differential effects on body temperature were reenlisted on reexposure to saccharin alone 7 days after conditioning. The changes in body temperature on reexposure were similar in direction and kinetics as on the conditioning day although reduced in magnitude. The finding of a true conditioned effect in these studies is in contrast to the paradoxical or compensatory conditioned body temperature responses described elsewhere using different conditioning models. This apparent conflict may be explained on the basis of different unconditioned stimuli acting on efferent versus afferent arms of a negative feedback system. Since body temperature changes often occur in association with immune responses, these findings may have implications to behavioural conditioning of immunity, the outcome of which may reflect the indirect effects on immunity of inadvertent conditioning of thermoregulatory changes.

Behaviourally conditioned modification of T cell subset ratios in rats

Levamisole injection resulted in an elevation in the T helper:T suppressor (H:S) subset ratio in rats at 24 h after injection due to a selective depression in the cytotoxic/suppressor subset. This response was shown to be conditionable and could be reenlisted 14 days later by re-exposure to the conditioned stimulus. Rats were conditioned using a taste aversion paradigm by pairing levamisole injection with the novel taste of saccharin. Fourteen days later, after a second exposure to saccharin without levamisole injection, H:S ratios were elevated in the blood of these rats compared to control rats injected with levamisole but fed normal water or rats fed saccharin without levamisole injection.

Localization of immunoglobulin-containing cells in the abomasum of sheep following infection with Haemonchus contortus

Abomasal cannulation followed by serial collection of biopsies was used to study the kinetics of appearance of IgA-, IgG1-, IgG2- and IgM-containing cells in the abomasum of sheep following infection with Haemonchus contortus. Very few immunoglobulin-containing cells (ICC) were found in the abomasum of sheep before infection. Following H. contortus infection, there were increased numbers of ICC in the submucosa of the abomasum. Seven days after infection, the numbers of IgA-, IgG1- and IgM-containing cells were six times greater than for uninfected control animals. The numbers of ICC continued to rise as the infection progressed, and the peak response was observed between 21 and 28 days after infection. IgA-containing cells (68-84%) were the most frequent cell types at all the observation times, followed by IgG1 and IgM. IgG2-containing cells were minimal throughout the experiment. As there were no significant changes in the numbers of ICC in the abomasum of uninfected controls it is concluded that H. contortus stimulated a local immune response in the abomasum of parasitized sheep.

Modulation of mitogen-induced spleen cell proliferation and the antibody-forming cell response by beta-endorphin in vivo

Experiments were conducted which compared the in vivo effects of beta-endorphin (BEP), gamma-endorphin (gamma EP), methionine-enkephalin (Met-ENK), and acetylated BEP(1-27) on the in vitro proliferative response of rat spleen cells to concanavalin A (ConA). In addition, the influence of BEP administration on the primary and secondary antibody-forming cell (AFC) response to the soluble antigen keyhole-limpet hemocyanin (KLH) was examined. Intravenous administration of BEP enhanced the spleen cell proliferative response to ConA assessed 3 hr after a single bolus infusion. Conversely, infusion with AcBEP(1-27) suppressed the proliferative response, whereas no effects of intravenous gamma EP or Met-ENK treatment were observed. The enhancing effect of BEP administration was not detectable 24 hr after a single infusion, but could be maintained over a 44 hr period by multiple infusions. The primary AFC response to KLH was suppressed by a dose of 1 nmole BEP only. On the other hand, the secondary IgG AFC response to KLH was enhanced by 10 pmoles BEP, while the IgM and IgA AFC responses remained unaltered by BEP treatment. The anamnestic in vitro proliferative response of spleen cells cultured with KLH was not altered if BEP was administered at the time of secondary KLH immunization. These results extend previous observations of BEP-induced modulation of in vitro immune function by demonstrating that opioid and nonopioid forms of BEP administered in vivo alter the capacity of spleen cells to proliferate and develop antibody responses to antigen.

Routes of priming and challenge for IgA antibody-containing cell responses in the intestine

The characteristic unresponsiveness of gut-associated lymphoid tissue (GALT) to orally administered antigen has hampered studies of mucosal immunity and the development of effective vaccines to control diseases of mucosal organs. Our previous studies have shown that priming by the intraperitoneal route can overcome this unresponsiveness and enables a vigorous IgA antibody-containing cell (ACC) response from GALT to subsequent intraduodenal (ID) antigen challenge. However the involvement of a concomitant systemic response arising from intraperitoneal priming complicates the analysis of the mucosal component of this response. The studies reported here indicate that immunization of a single Peyers patch (PP) by subserosal deposition of antigen adjacent to the patch primes for an equivalent IgA ACC response following ID challenge and immunization of multiple PP generates a substantial IgA ACC response in the gut lamina propria even in the absence of luminal challenge. This response persists for at least 84 days. These techniques provide a means by which the requirements for induction of IgA responses can be studied in the absence of a response in systemic lymphoid tissue.