Bärbel Schäfer

Substance P and astrocytes: stimulation of the cyclooxygenase pathway of arachidonic acid metabolism.

Substance P (SP) may play an important role in the interactions between the nervous system and the immune system. Astrocytes carry receptors for SP on their surfaces. We examined whether ligand‐induced receptor activation would lead to the release of arachidonic acid metabolites. SP (10−10‐10−8 M) evokes the formation of prostaglandin E and thromboxane B2 in a dose‐dependent manner. Structure‐activity studies disclosed that the COOH‐terminal peptide sequence of SP is primarily responsible for this biological activity. The generation by astrocytes of arachidonate‐derived proinflammatory and immunoregulatory compounds in response to SP receptor activation may be relevant to immunoinflammatory responses within the central nervous system and emphasizes the concept of neuroimmunomodulation.— Hartung, H.‐P.; Heininger, K.; Schäfer, B.; Toyka, K. V. Substance P and astrocytes: stimulation of the cyclooxygenase pathway of arachidonic acid metabolism. FASEB J. 2: 48‐51; 1988.

Immune Mechanisms in Inflammatory Polyneuropathya

I t has been increasingly recognized that a small proportion of patients with the acute Guillain-Barrk syndrome (GBS) have a severe form of the disease with a poor prognosis. Clinical, pathologic, and electrophysiologic studies have demonstrated that axonal degeneration characterizes nerve pathology in these cases. Clinically, the disease reaches peak severity much earlier in these patients than in most other GBS patients, and they require ventilatory assistance more often. In some patients, conduction block occurred at distal sites, whereas in others there was electrophysiologic evidence of widespread muscle denervation. Thus, patients that fulfill all of the established diagnostic criteria for GBS may either-in the majority-have a demyelinating polyneuropathy with conduction slowing or block that is milder and yields better recovery, or have axonal damage with conduction failure, signaling severe disease with slower recovery (TABLE 1). It is unclear at present whether the axonal form is part of the spectrum of GBS

Ciclosporin A prevents P2 T cell line-mediated experimental autoimmune neuritis (AT-EAN) in rat

Adoptive transfer experimental autoimmune neuritis (AT-EAN) produced in Lewis rats by injection of P2-reactive T lymphocyte line cells offers the unique possibility to study the exclusive contribution of cell-mediated immune responses to the pathogenesis of autoimmune disease of the peripheral nervous system (PNS). It further lends itself to the evaluation of novel therapeutic approaches that may bear relevance to the human acute Guillain-Barré syndrome. The effects of the immunosuppressive agent ciclosporin A on the clinical, electrophysiological and morphological expression of AT-EAN were examined. We found that ciclosporin A suppressed development of the disease. In view of the known actions of ciclosporin A on T cells, these results indicate the requirement of activation and clonal proliferation of T lymphocytes to produce myelin damage in autoimmune diseases of the PNS.

Substance P Stimulates Release of Arachidonic Acid Cyclooxygenation Products from Primary Culture Rat Astrocytes

There is growing evidence that the neuropeptide substance P (SP), through stimulation of leukocytes, is involved in inflammatory responses. The recent demonstration that SP specifically binds to and activates both T lymphocytes and macrophages further suggests a role of this undecapeptide in immunoregu1ation.’-’ Astrocytes, which constitute key cellular components of immunoinflammatory responses within the central nervous system, express SP receptors on their s ~ r f a c e . ~ We examined the possible effects of SP on arachidonic acid metabolism in astrocytes.

Immune mechanisms in acute and chronic inflammatory polyneuropathies.

1. A c u t e polyneuri t i s Guil lain-Barr~ syndrome In this acute inflammatory demyelinating disorder, some patients show a fulminant clinical course with electrophysiologic studies pointing to acute conduction failure in addition to conduction slowing and block (LSffel et al., 1977; Feasby et al., 1986). It is now clear that the prognosis of this subgroup with axonal degeneration is less favorable with supportive treatment or even plasma exchange than other forms of the disease (French Cooperative Group, 1987; McKhann et al., 1988). The etiology of the acute Guillain-Barr6 syndrome (GBS) is still not clear. A new variant

Substance P stimulates release of arachidonic acid cyclooxygenation products from primary culture rat astrocytes

There is growing evidence that the neuropeptide Substance P (SP) through st imulat ion of leukocytes is involved in inf lammatory processes. The recent demons t rat ion that SP binds to and act ivates T cells and macrophages further suggests a role of this undecapeptide in immunoregulation (1-3). Astrocytes which const i tute key cellular components of immunoinf lammatory responses within the CNS express SP receptors on their surface (4). We examined possible e f f ec t s of SP on arachidonic acid metabolism in as t rocytes . Adherent primary culture as t rocytes from neonatal Lewis rats were exposed to various amounts of SP, SP fragments , and other peptides of the tachykinin family. Cells were incubated for up to 48 hours when culture supernatants were col lec ted for determinat ion of prostaglandin E (PGE), thromboxane B 2 (TXB), and 6-keto-pros taglandin F l a (PGI) by radioimmunoassay (2,5). SP at nanoto micromolar concentrat ions evoked a noncytotoxic release of PGE and TXB in a dose-dependent fashion while no immunoreact ive PGI was de tec tab le . Addition of indomethacin, BW755c or dexamethasone to incubates abrogated generat ion of arachidonate conversion products by astrocytes . Analysis of peptide s t ructural requirements disclosed that the s t imulatory properties of SP reside in its carboxyterminal sequence. Of the other tachykinins tested, physalaemin, eledoisin, kassinin, and neurokinin A also produced some e f fec t s although at much higher molar , that concentrat ions. We have shown the binding of SP to its receptor on cul tured as t rocytes ini t iates conversion of arachidonic acid with a t tendant release of PGE and TXB. In light of the varied proinf lammatory and immunomodulating properties that have been ascribed to eicosanoids, our findings raise the possibility that SP may also be involved in the regulation of normal and aberrant immune responses within the CNS and underscore its role in neuroimmunomodulation.

Immune mechanisms in inflammatory polyneuropathy

KLAUS V. TOYKA, H.P. HARTUNG, K. HEININGER, B. SCH~FER, W. FIERZ Dept. Neurology, U. D/~sseldorf, FRG, Div. Immunol. U. Zurich, Switzerland * In acute inf lammatory polyneuropathy (AIP) both ce l l -med ia ted and humoral immune mechanisms are considered important . AIP serum leads to demyelination and conduction block on intraneural transfer and plasma exchange therapy results in improvement. Complement-f ixing IgM-antibodies to glycolipid are corre la ted with disease act ivi ty and act ivated complement can be found in CSF. The antigen is still unknown. Viruses may serve as tr iggers for the se l f l imi ted autoimmune response. In chronic and chronic-relapsing inf lammatory demyelinating polyneuropathy (CIDP) humoral immune mechanisms have been demonstra ted by systemic passive transfer and by the response in some patients to plasma exchange. The antigen is unknown. Genetic linkage with HLA-ant igen has been reported. A subtype of AIP and CIDP occurs with HIV infection with pathognomonic CSF pleiocytosis but indistinguishable clinical and electrodiagnost ic features . Recent evidence from EAN and adoptive transfer P2T cell line mediated EAN points to important unspecific humoral factors such as a ra chidonic acid metaboli tes and toxic oxygen intermediates . During the amplif icat ion phase of adoptive transfer EAN monoclonal abs to the IL-2 receptor , an early T cell act ivation marker (ART 18, Diamantstein) virtually prevent EAN. From these exper i ments it seems likely that multiple cellular and humoral factors cooperate in the pathogenesis of AIP and CIDP. In paraproteinemic polyneuropathy monoclonal ant i -nerve abs are likely to be pathogenic, since they can induce demyelination upon intraneural t ransfer and patients somet imes respond to plasma exchange. The inf lammatory lesion in neuropathies associated with lepromatous leprosy and Chagas disease may also have a T ce l l -med ia ted autoimmune componert .as suggested by recent animal experiments . Supported by DFG, SFB 200/B5, Min. Wiss. Forsch. NRW, Hert ie Foundation

Suppression of P2-T cell-line mediated experimental autoimmune neuritis by interleukin 2 — Receptor blockade ☆

Experimental autoimmune neuritis (EAN) can be produced by adoptive transfer of P2-reactive cloned T lymphocytes. As an animal model of the acute GuillainBarre syndrome EAN can serve to evaluate novel therapeutic strategies for more specific immunosuppression in autoimmune disease of the peripheral nervous system. We examined whether interference with T cell activation achieved through administration of the monocional antibody ART 18 directed to the !!-2 receptor, would prevent or mitigate adoptive transfer EAN (AT-EAN). 8 weeks old Lewis rats were injected with 5 x 106 cells from a freshly activated P2-T cell line. Each treatment group comprised 6 animals. ART 18 (1 mg/kg) was injected i.p. shortly before cell transfer (group 1), in addition on day 1 (group 2) or through day 3 after transfer. Animals were inspected for development of clinical signs of the disease and monitored serially for evolving changes in the functional properties of the sciatic nerve by electrophysiologic methods (2). Rats were perfused on day 10 after transfer. Epon sections of roots and sciatic nerve were assessed semiquantitatively for morphological alterations (cellular infiltration, demyelination, edema, axonal damage). We found that in vivo administration of ART 18 even as one single injection markedly suppressed or completely prevented development of the disease by clinical, electrophysiologic and histopathologic examination. Sham-treatedrats came down with the fully developed disease. Thus, blockade of II-2 receptors on recently activated T lymphocytes in vivo provides protection of Lewis rats from the pathogenic effects of autoreactive T line cells and represents a selective immunosuppressive treatment modality for experimental autoimmune disease of the peripheral nervous system.