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Biomedical subjects

J D Pollard

Publications and source records attributed to J D Pollard.

At least 19 recordsLinked to original sources
PubMed1992

Immunosuppression in nerve allografting: is it desirable?

Immunologically incompatible sciatic nerve grafts were inserted into the severed sciatic nerves of Wistar rats. In an attempt to induce graft tolerance, low-dose cyclosporin A (CsA) was administered to some animals for 20 weeks, then gradually withdrawn. Behavioural, electrophysiological and histological studies indicated that some degree of regeneration took place in all animals regardless of treatment. Neither a daily dose of 5 mg/kg nor 10 mg/kg was sufficient to prevent the rejection and subsequent disruption of allograft structure, and as a consequence reinnervation of the distal stump was limited. This was manifest both in the poor functional recovery of the denervated foot, and in the large number of regenerated axons found outside of the perineurial membranes of the transplanted fascicles. Therefore, tolerance was not induced at these doses. Furthermore, the significant decrease in the amplitude of electromyographs recorded from experimental and unoperated (control) animals suggests CsA may have a deleterious effect on unlesioned nerve even at these low doses. It would be prudent, therefore, to exercise caution in the combined use of nerve allografts and CsA immunosuppression, until the neurotoxicity of CsA has been investigated further. This is particularly important since CsA is sometimes used in the treatment of certain neuropathic autoimmune diseases.

Action Potentials↗
PubMed1992

Peripheral nervous system demyelination from systemic transfer of experimental allergic neuritis serum.

The ability of systemically transferred experimental allergic neuritis (EAN) serum to produce EAN lesions in recipient animals was studied. Seventeen Lewis rats received five daily 1-ml intraperitoneal (i.p.) injections of sera from rabbits with EAN induced with bovine myelin/complete Freund's adjuvant (CFA). Another 17 rats received similar injections of sera from rabbits inoculated with CFA alone. On day 0 (the first day of i.p. injections), all rats were injected in the proximal tibial branch of the right sciatic nerve with a single 10-microliters injection of 0.03 M 5-hydroxytryptamine (5-HT) in sterile 0.15 M saline. Proximal tibial branches of left sciatic nerves received similar single injections of saline alone. Animals were then studied using electrophysiological and histological techniques. In all animals, intraneural saline injection had no significant effect upon nerve conduction. In the presence of circulating CFA serum, 5-HT injection caused a mild gradual decrease in amplitude ratio becoming maximal by day 17 (P < 0.005) and partially resolving by day 28. In contrast, in the presence of circulating EAN serum, 5-HT injection caused a more rapid and severe decrease in amplitude ratio becoming maximal by days 6-10 (P < 0.001 day 6; P < 0.0001 day 10) and completely resolving by day 28. Histological analysis of nerves injected with 5-HT in CFA serum-treated animals showed areas of mild demyelination, axonal degeneration and some fibre loss consistent with needle trauma. In contrast, 5-HT-injected nerves in animals administered EAN serum showed areas of marked cellular infiltration and severe demyelination in association with numerous debris-filled infiltrating cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Interactions between CD4+ T-cells and rat Schwann cells in vitro. 1. Antigen presentation by Lewis rat Schwann cells to P2-specific CD4+ T-cell lines.

Interactions between CD4+ P2-specific T-cell lines and Schwann cells were examined in vitro by scanning electron microscopy (SEM) and T-cell proliferation studies. CD4+ T-cell lines clustered around and attached to Schwann cells which expressed Major histocompatibility complex (MHC) class II molecules. Only those P2-specific T-cell lines capable of inducing experimental allergic neuritis (EAN) when injected into adult Lewis rats clustered around the Schwann cells. T-cell lines responsive to P2 but not able to induce EAN did not cluster around Schwann cells. The addition of exogenous P2 protein inhibited in a dose-dependent way clustering and proliferation of the P2-specific T-cell lines. Cytoplasmic P2 was detected in Schwann cells by immunofluorescent labelling and the results of proliferation assays in this study suggest that endogenous P2 protein was processed by the Schwann cells and presented to T-cell lines in association with MHC class II molecules. The clustering and proliferation of class II-restricted CD4+ P2-specific T-cell lines in the presence of Schwann cells provides evidence for a role for Schwann cells as facultative antigen presenting cells, processing and presenting 'self' endogenous antigen to CD4+ T-cell lines capable of inducing EAN.

Animals↗
PubMed1992

Interactions between CD4+ T-cells and rat Schwann cells in vitro. 2. Cytotoxic effects of P2-specific CD4+ T-cell lines on Lewis rat Schwann cells.

The cytotoxic effects of CD4+ P2-specific T-cell lines on Schwann cells were examined in vitro with 51Cr-release cytotoxicity assays. Only those P2-specific T-cell lines capable of inducing EAN when injected back into adult Lewis rats were cytotoxic to the Schwann cells. The addition of exogenous P2 protein was not necessary for the cytotoxic effect. The monoclonal antibody (mAb) OX6 directed against Major histocompatibility complex (MHC) class II molecules blocked cytotoxicity, indicating an essential role for MHC class II molecules in this interaction between CD4+ T-cell lines and Schwann cells.

Animals↗
PubMed1992

Patterns of conduction impairment in experimental allergic neuritis. An electrophysiological and histological study.

Electrophysiological and histological studies of peripheral nerve were performed in 24 Lewis rats with experimental allergic neuritis (EAN) in which disease had been induced by a single myelin and adjuvant inoculation in one footpad. Demyelination was demonstrated in transverse nerve sections from ventral roots, proximal sciatic nerves and also in distal plantar nerves. Histological and electrophysiological assessments showed that injected limbs were more affected than uninjected limbs. Neurophysiological studies demonstrated two distinct patterns of conduction failure based upon proximal/distal compound muscle action potential (CMAP) amplitude ratios in both uninjected and injected limbs. Slightly more than half of all nerve trunks showed a mildly reduced distal CMAP amplitude irrespective of stimulus origin. The rest displayed a more severe reduction of distal amplitude that was length-dependent, becoming smaller with proximal stimulation. Histological lesions in plantar nerves were often more severe than those in proximal sciatic nerves or ventral roots. Axonal degeneration was an uncommon finding. This study has demonstrated patterns of peripheral nerve conduction impairment similar to those reported in patients with inflammatory demyelinating neuropathy. Moreover, it has shown that a low distal CMAP amplitude may result from demyelination of distal motor nerve segments and not necessarily from axonal degeneration.

Animals↗
PubMed1991

Interferon-gamma inhibition suppresses experimental allergic neuritis: modulation of major histocompatibility complex expression of Schwann cells in vitro.

This study examines the modulation of major histocompatibility complex (MHC) expression on Lewis rat Schwann cells (Scs) cultured in the presence of dorsal root ganglion neurons (DRG). MHC class I and II molecules were induced on Scs using recombinant murine interferon-gamma (IFN-gamma), lymph node cells (LNC), removed at day 9 from Lewis rats with experimental allergic neuritis (EAN) and syngeneic T-cell line cells responsive to P2 basic protein. EAN LNC induced MHC class I on Scs but only IFN-gamma or P2-responsive T-cells induced MHC class II. Control LNC from animals injected with Freund's adjuvant alone or naive spleen cells did not induce MHC class II. P2 T-cells clustered in aggregates to the Scs. Similar studies were performed with inhibitors of IFN-gamma; hydrocortisone, cyclosporin A, dibutyryl cyclic AMP, methyl-xanthine and prostaglandin E2. Each agent produced a dose-dependent inhibition of MHC expression and prevented clustering of P2-responsive T-cells to Scs.

Animals↗
PubMed1991

Vasculitic neuropathy. A clinical and pathological study.

The clinical, electrophysiological and pathological features and prognosis of 34 patients with peripheral neuropathy caused by necrotizing vasculitis were evaluated. The causes included polyarteritis nodosa and its Churg-Strauss variant, rheumatoid arthritis, undifferentiated connective tissue disease, Wegener's granulomatosis, primary Sjögren's disease, and chronic lymphocytic leukaemia with cryoglobulinaemia; 2 patients had no evidence of systemic vasculitis. Mononeuritis multiplex was the most common clinical manifestation, followed by asymmetrical polyneuropathy and distal symmetrical polyneuropathy. Pain was a frequent symptom. Nerve conduction studies were abnormal in all cases, and in 3 patients there was conduction block or severe slowing of motor conduction. Necrotizing vasculitis was present in sural nerve biopsies of most cases, and severe active axonal degeneration was a dominant feature. Immunofluorescent staining of blood vessels for immunoglobulin, C3 and fibrinogen was positive in all cases in which it was performed, even when there was no cellular infiltration. All patients were treated with prednisone alone or in combination with other immunosuppressive agents, or with plasmapheresis. Long-term follow-up studies demonstrated that although the peripheral neuropathy usually improved and caused only mild to moderate functional disability, the long-term prognosis of the systemic disease was poor with a 5-yr survival of only 37%.

Adult↗
PubMed1990

Low dose, short term cyclosporin A does not protect the Schwann cells of allogeneic nerve grafts.

The question of whether Cyclosporin A, at the low doses reported to allow survival of nerve allografts, allows the allogeneic Schwann cells to survive has been investigated. Nerve allografts were inserted by microsurgical techniques into trembler mice treated with 10 mg/kg or 15 mg/kg Cyclosporin A, daily for 12 weeks post-operatively. Electrophysiological recordings were made one week prior to surgery, and at the end of the immunosuppression period, after which the grafts were processed for electron microscopy. All grafts showed signs of rejection and donor Schwann cells had been replaced by host cells. The results suggest that Cyclosporin A in these doses is insufficient to overcome rejection problems or to induce tolerance to donor Schwann cells.

Action Potentials↗
PubMed1990

Rat and human Schwann cells in vitro can synthesize and express MHC molecules.

The expression of MHC class I and II molecules on cultured rat and human Schwann cells (SCs) was studied to determine whether these molecules could be synthesized by SCs in the absence of T cells. Normal rat and human SCs in vitro expressed low levels of class I MHC, but this was markedly increased by incubation with interferon gamma (IFN-gamma). Untreated SCs of rat or human origin did not express detectable class II MHC molecules, but after 48 hours incubation with IFN-gamma 100 U/ml, 20% of rat SCs and 90% of human SCs were class II positive. Immunoelectron microscopy confirmed the surface expression of MHC molecules on SCs and demonstrated class II MHC within endocytotic vesicles. These findings provide further evidence for an immunological role for SCs as antigen presenting cells or as targets for cytotoxic T cells.

Animals↗
PubMed1990

Immunopathological factors in peripheral nerve allograft rejection: quantification of lymphocyte invasion and major histocompatibility complex expression.

The numbers of helper T and cytotoxic T lymphocytes and macrophages were quantified, and the expression of major histocompatibility complex (MHC) class I and class II molecules was examined in rat peripheral nerve allografts from 1 to 14 days after implantation, using the indirect immunoperoxidase method for light and electron microscopy. Two centimetre segments of peripheral nerve freshly obtained from inbred Dark Agouti strain rats were inserted in a gap created in n. fibularis or n. tibialis of young adult inbred Wistar strain rats, using fascicular nerve repair techniques under general anaesthesia. There was a gradual increase in the number of helper T and cytotoxic/suppressor T cells from day 2 with peak numbers of both types of T cells observed around day 7. The results suggest that the critical time for T cell proliferation is between day 6 and day 7 post-operatively. The number of macrophages increased over 10 days, with peak numbers being observed at day 10 post-operatively. This is in accord with the pattern of rejection observed in allografts of other tissue. Schwann cells were found to express MHC class I and class II molecules by day 2 post-operatively, which is well before there is any substantial T cell and macrophage infiltration. It may be that the donor Schwann cells act as antigen presenting cells, triggering the immune response and finally becoming a target of the rejection process.

Animals↗
PubMed1990

HLA antigens in chronic inflammatory demyelinating polyneuropathy.

HLA typing of 71 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) showed an overall increase in frequencies of HLA-A3, -B7, -DR2 as well as concomitantly decreased frequencies of HLA-44 and DR7. The strongest associations were seen with HLA-DR2, -DR7 and -B44 in CIDP overall, although they did not reach statistical significance.

Chronic Disease↗
PubMed1990

Cyclosporin A in the treatment of chronic demyelinating polyradiculoneuropathy.

Eight patients with chronic inflammatory demyelinating polyneuropathy, five of whom had an associated paraproteinaemia, were treated with cyclosporin in a pilot, uncontrolled study for periods up to three and a half years after failing to respond adequately to corticosteroid and azathioprine therapy and plasmapheresis. Three patients had an excellent response, two with complete remission. In other cases it was possible to reduce the corticosteroid therapy and frequency of plasmapheresis. There were no serious complications of the treatment.

Adrenal Cortex Hormones↗
PubMed1990

Mitomycin C induces a delayed and prolonged demyelination and conduction block due to Schwann cell destruction.

The intraneural injection of 25 micrograms/ml of mitomycin C produced a prolonged conduction block of delayed onset within the injected nerve. No change in electrophysiological parameters was seen for 6 days after injection, but thereafter a marked drop in the compound muscle action potential (CMAP) amplitude from stimulation proximal to the site of injection occurred, with recovery not being complete until day 97. CMAP amplitude from stimulation distal to the injection site remained unchanged. The reason for this prolonged period of conduction block was apparent from histological examination of the nerve. Light and electron microscope studies demonstrated Schwann cell death, clearly evident at day 8 and followed by subsequent macrophage removal of myelin and Schwann cell debris. Remyelination was not seen until day 40. Hence for periods of about 30 days naked axons persisted through the area of injection. Schwann cells associated with unmyelinated fibres were relatively unaffected, suggesting that myelinating Schwann cells were vulnerable to this agent by virtue of the metabolic processes associated with their myelin maintenance and renewal. These findings indicate that mitomycin C injected intraneurally provides an excellent model to study the effects of Schwann cell disease.

Action Potentials↗
PubMed1989

Induction of experimental allergic neuritis with synthetic peptides from myelin P2 protein.

P2 protein and 4 synthetic peptides were tested for induction of experimental allergic neuritis (EAN). A peptide comprising the residues 62-78 of the bovine P2 protein sequence has been shown to contain an important neuritogenic determinant. A peptide comprising residues 66-78 produced no clinical symptoms of EAN. These results indicate that some or all of the residues 62 65 (Ile-Ser-Phe-Lys), are necessary for EAN induction.

Amino Acid Sequence↗
PubMed1989

Gm haplotypes in inflammatory demyelinating polyneuropathies.

The possible association of Gm haplotypes with inflammatory neuropathies has been studied in 59 patients with Guillain-Barré syndrome and 55 patients with chronic inflammatory demyelinating polyradiculoneuropathy. The frequency of Gm haplotype 1,2,17;21 (or z,a,x;g) was significantly raised in the patients with Guillain-Barré syndrome. These findings provide further evidence for an association of chromosome 14 genes with inflammatory neuropathies.

Demyelinating Diseases↗
PubMed1989

IgG immunoadsorption in experimental allergic neuritis: effect on antibody levels and clinical course.

The effect of IgG immunoadsorption upon the course of chronic experimental allergic neuritis (EAN) is described. Miniature membrane plasma separators coupled with a Protein A (PA)-Sepharose immunoadsorbent column were used to perform upon conscious rabbits 5 IgG immunoadsorption treatments over 6 days. Quantitation of anti-myelin IgG and IgM by ELISA revealed that 55-65% of plasma IgG was removed per treatment. Rapid post-treatment antibody rebound was observed for anti-myelin IgG although no antibody overshoot above control levels could be observed. Anti-myelin IgM levels remained relatively unaffected by PA immunoadsorption. Comparisons of clinical scores between control and treatment animals showed that IgG immunoadsorption was significantly beneficial (day 1 post-treatment p less than 0.001; day 2 post-treatment p less than 0.05). However, rapid relapse was observed in all treatment animals such that by day 3 post-treatment no significant clinical difference between control and treatment groups could be observed. IgG immunoadsorption suppresses the clinical progression of chronic EAN in a manner similar to that seen with plasma exchange. This finding suggests that antibody modulates early disease pathogenesis.

Animals↗
PubMed1989

Experimental allergic neuritis: effect of plasma infusions.

The effect of intravenous fresh frozen plasma (FFP) and artificial plasma infusions upon the clinical course of chronic experimental allergic neuritis (EAN) in the rabbit was investigated. A total of 12 animals allocated to treatment groups received rabbit FFP or a gelatin plasma expander Haemaccel (Hoechst) and were compared to 13 control non-treated animals. Animals receiving Haemaccel at a rate of 15 ml/kg/day for 7 days showed no significant clinical benefit at any stage. However, animals receiving 15 ml/kg/day FFP for 8 days showed significant clinical benefit during treatment initiated at the onset of definite neurological symptoms of EAN (Mann-Whitney U test, day 4 post-allocation P less than 0.05; day 6 post-allocation P less than 0.01; day 8 post-allocation P less than 0.05). Relapse was observed after cessation of treatment such that comparisons of clinical scores at day 14 and 22 post-allocation revealed no significant differences. Analysis of plasma anti-myelin IgG levels by ELISA showed that non-immunogenic plasma volume expansion decreased anti-myelin IgG concentrations immediately by an average of 34% but had no long-term effect. In contrast, anti-myelin IgG concentrations in FFP infused animals were significantly decreased, compared to controls, when measured 24 h after the last infusion (Student's t-test P less than 0.05). Identical percentage weight losses for both control and treatment groups post-allocation indicated that this decrease was immunologically mediated and not due to plasma dilution. Similar plasma cortisol concentrations measured in both groups showed no significant artifactual induction of endogenous steroid production. Infusions of FFP during early disease progression are able to mediate clinical remission in animals with chronic EAN.

Animals↗