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1.
Semin Immunol ; 26(5): 402-8, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24486057

ABSTRACT

The sympathetic nervous system (SNS) is part of an integrative network that functions to restore homeostasis following injury and infection. The SNS can provide negative feedback control over inflammation through the secretion of catecholamines from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Central autonomic structures receive information regarding the inflammatory status of the body and reflexively modulate SNS activity. However, inflammation and infection can also directly regulate SNS function by peripheral actions on postganglionic cells. The present review discusses how inflammation activates autonomic reflex pathways and compares the effect of localized and systemic inflammation on ACCs and postganglionic sympathetic neurons. Systemic inflammation significantly enhanced catecholamine secretion through an increase in Ca(2+) release from the endoplasmic reticulum. In contrast, acute and chronic GI inflammation reduced voltage-gated Ca(2+) current. Thus it appears that the mechanisms underlying the effects of peripheral and systemic inflammation neuroendocrine function converge on the modulation of intracellular Ca(2+) signaling.


Subject(s)
Calcium/metabolism , Catecholamines/metabolism , Inflammatory Bowel Diseases/metabolism , Neurons/metabolism , Sepsis/metabolism , Sympathetic Nervous System/metabolism , Animals , Calcium/immunology , Calcium Signaling , Catecholamines/immunology , Chromaffin Cells/immunology , Chromaffin Cells/metabolism , Chromaffin Cells/pathology , Cytokines/genetics , Cytokines/immunology , Feedback, Physiological , Gene Expression Regulation , Humans , Inflammation/genetics , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammatory Bowel Diseases/genetics , Inflammatory Bowel Diseases/immunology , Inflammatory Bowel Diseases/pathology , Neurons/immunology , Neurons/pathology , Sepsis/genetics , Sepsis/immunology , Sepsis/pathology , Sympathetic Nervous System/immunology , Sympathetic Nervous System/pathology
2.
Peptides ; 45: 48-60, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23608709

ABSTRACT

Cultured bovine adrenal chromaffin cells (BCCs) are employed to study first messenger-specific signaling by cytokines and neurotransmitters occurring in the adrenal medulla following immune-related stress responses. Here, we show that the cytokine TNF-alpha, and the neuropeptide transmitter PACAP, acting through the TNFR2 and PAC1 receptors, activate distinct signaling pathways, with correspondingly distinct transcriptomic signatures in chromaffin cells. We have carried out a comprehensive integrated transcriptome analysis of TNF-alpha and PACAP gene regulation in BCCs using two microarray platforms to maximize transcript identification. Microarray data were validated using qRT-PCR. More than 90% of the transcripts up-regulated either by TNF-alpha or PACAP were specific to a single first messenger. The final list of transcripts induced by each first messenger was subjected to multiple algorithms to identify promoter/enhancer response elements for trans-acting factors whose activation could account for gene expression by either TNF-alpha or PACAP. Distinct groups of transcription factors potentially controlling the expression of TNF-alpha or PACAP-responsive genes were found: most of the genes up-regulated by TNF-alpha contained transcription factor binding sites for members of the Rel transcription factor family, suggesting TNF-alpha-TNFR2 signaling occurs mainly through the NF-KB signaling pathway. Surprisingly, EGR1 was predicted to be the primary transcription factor controlling PACAP-modulated genes, suggesting PACAP signaling to the nucleus occurs predominantly through ERK, rather than CREB activation. Comparison of TNFR2-dependent versus TNFR1-dependent gene induction, and EGR1-mediated transcriptional activation, may provide a pharmacological avenue to the unique pathways activated by the first messengers TNF-alpha and PACAP in neuronal and endocrine cells.


Subject(s)
Adrenal Glands/drug effects , Chromaffin Cells/drug effects , Pituitary Adenylate Cyclase-Activating Polypeptide/pharmacology , Transcriptome/drug effects , Tumor Necrosis Factor-alpha/pharmacology , Adrenal Glands/cytology , Adrenal Glands/immunology , Animals , Cattle , Chromaffin Cells/cytology , Chromaffin Cells/immunology , Enhancer Elements, Genetic/drug effects , Extracellular Signal-Regulated MAP Kinases/genetics , Extracellular Signal-Regulated MAP Kinases/immunology , Gene Expression Profiling , Gene Expression Regulation , NF-kappa B/genetics , NF-kappa B/immunology , Primary Cell Culture , Promoter Regions, Genetic/drug effects , RNA, Messenger/genetics , RNA, Messenger/immunology , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide/immunology , Receptors, Tumor Necrosis Factor, Type II/genetics , Receptors, Tumor Necrosis Factor, Type II/immunology , Signal Transduction , Stress, Physiological , Transcriptome/immunology
3.
Mol Cell Endocrinol ; 371(1-2): 228-35, 2013 May 22.
Article in English | MEDLINE | ID: mdl-23295830

ABSTRACT

Systemic administration of endotoxin, which closely mimics the bacteria-induced systemic inflammatory response syndrome (SIRS) can ultimately lead to organ failure. Adrenal gland insufficiency is frequently diagnosed in critically ill patients; however, the underlying mechanisms are still unclear. In the present study, we studied comprehensively the characteristics of adrenal gland dysregulation, including inflammation, leukocyte infiltration and cell death in the adrenal glands in the course of LPS-induced systemic inflammation in mice. LPS enhanced expression of many proinflammatory cytokines, chemokines and adhesion molecules, which resulted in rapid recruitment of leukocytes into the adrenal gland. Furthermore, LPS-mediated inflammation was associated with increased apoptosis of adrenocortical and chromaffin cells. Our results performed in mice, suggest that LPS-induced adrenal gland inflammation and cell death might be mechanisms potentially involved in the adrenal gland dysfunction in patients with sepsis.


Subject(s)
Adrenal Glands/immunology , Adrenal Insufficiency/immunology , Inflammation/immunology , Systemic Inflammatory Response Syndrome/immunology , Adrenal Glands/metabolism , Animals , Apoptosis/immunology , Cell Adhesion Molecules/biosynthesis , Chemokines/biosynthesis , Chromaffin Cells/immunology , Chromaffin Cells/pathology , Cytokines/biosynthesis , Inflammation/chemically induced , Leukocytes/immunology , Lipopolysaccharides , Mice , Peroxidase/analysis , Sepsis/immunology
4.
Respir Res ; 13: 99, 2012 Nov 08.
Article in English | MEDLINE | ID: mdl-23137120

ABSTRACT

BACKGROUND: Studies have shown that epinephrine release is impaired in patients with asthma. The pregnancy of female rats (dams) with asthma promotes in their pups the differentiation of adrenal medulla chromaffin cells (AMCCs) into sympathetic neurons, mediated by nerve growth factor, which leads to a reduction in epinephrine secretion. However, the relatedness between the alteration of AMCCs and increased asthma susceptibility in such offspring has not been established. METHODS: In this study, we observed the effects of allergization via ovalbumin on rat pups born of asthmatic dams. RESULTS: Compared to the offspring of untreated controls, bronchial hyperreactivity and airway inflammation were more severe in the pups from sensitized (asthmatic) dams. In pups exposed to nerve growth factor (NGF) in utero these effects were aggravated further, but the effects were blocked in pups whose dams had been treated with anti-NGF. Furthermore, alterations in AMCC phenotype corresponded to the degree of bronchial hyperreactivity and lung lesions of the different treatment groups. Such AMCC alterations included degranulation of chromaffin granules, reduction of epinephrine and phenylethanolamine-n-methyl transferase, and elevation of NGF and peripherin levels. CONCLUSIONS: Our results present evidence that asthma during the pregnancy of rat dams promotes asthma susceptibility in their offspring, and that the transformation of AMCCs to neurons induced by NGF plays an important role in this process.


Subject(s)
Asthma/immunology , Chromaffin Cells/immunology , Chromaffin Cells/pathology , Neurons/immunology , Neurons/pathology , Pregnancy Complications/immunology , Pregnancy Complications/pathology , Allergens/administration & dosage , Animals , Asthma/pathology , Cell Differentiation/drug effects , Chromaffin Cells/drug effects , Disease Susceptibility/immunology , Disease Susceptibility/pathology , Female , Humans , Male , Neurons/drug effects , Ovalbumin/administration & dosage , Pregnancy , Pregnancy, Animal , Rats, Sprague-Dawley
5.
J Mol Neurosci ; 48(2): 413-9, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22421803

ABSTRACT

The bovine chromaffin cell represents an ideal model for the study of cell signaling to gene expression by first messengers. An abundance of GPCR, ionotropic, and growth factor receptors are expressed on these cells, and they can be obtained and studied as an abundant highly enriched cell population; importantly, this is true of no other postmitotic neuroendocrine or neuronal cell type. Chromaffin cells have now been shown to bear receptors for cytokines whose expression in the circulation is highly elevated in inflammation, including tumor necrosis factor, interferon, interleukin-1, and interleukin-6. The use of bovine-specific microarrays, and various biochemical measurements in this highly homogenous cell preparation reveals unique cohorts of distinct genes regulated by cytokines in chromaffin cells, via signaling pathways that are in some cases uniquely neuroendocrine. The transcriptomic signatures of cytokine signaling in chromaffin cells suggest that the adrenal medulla may integrate neuronal, hormonal, and immune signaling during inflammation, through induction of paracrine factors that signal to both adrenal cortex and sensory afferents of the adrenal gland, and autocrine factors, which determine the duration and type of paracrine secretory signaling that occurs in either acute or chronic inflammatory conditions.


Subject(s)
Adrenal Medulla/immunology , Cytokines/physiology , Neuroimmunomodulation/immunology , Transcriptome/immunology , Adrenal Medulla/cytology , Animals , Cattle , Chromaffin Cells/immunology , Cytokines/genetics , Gene Expression Regulation/immunology , Neuroimmunomodulation/genetics
6.
Life Sci ; 81(16): 1317-22, 2007 Sep 29.
Article in English | MEDLINE | ID: mdl-17928008

ABSTRACT

Controversy surrounds the expression of alpha7 nicotinic acetylcholine receptors (nAChRs) in adrenal chromaffin cells. In these studies, alpha7 nAChRs expressed in bovine adrenal chromaffin cells are investigated. Using radiolabeled ligand binding techniques, [(125)I]alpha-bungarotoxin (alphaBGT) binding reaches equilibrium within 4 h and is saturable with a K(d) value of 4.2 nM. Using homologous competition experiments, the K(i) for binding of alphaBGT was 1.9 nM. These data are consistent with the expression of homomeric alpha7 nAChRs. Methyllycaconatine (MLA), which binds alpha7 nAChRs with high affinity, inhibits [(125)I]alphaBGT binding in a concentration-dependent manner with a K(i) of 30.6 nM; this value is approximately 10 fold higher than the reported affinity of MLA for alpha7 nAChRs. We also document the ability of bromoacetylcholine (brACh) to alkylate alpha7 nAChRs, as has been previous demonstrated for bovine adrenal alpha3beta4 nAChRs. When adrenal nAChRs are immunoprecipated with mAb319, an antibody which recognizes alpha7 nAChR protein, and then probed with mAb319 using Western blot analysis, a single band of approximately 53 kDa is identified. When adrenal nAChRs are immunoprecipated with mAb35, an antibody which recognizes alpha3 and alpha5 nAChR proteins, and then probed with mAb319 using Western blot analysis, a single band of approximately 53 kDa is identified. Together, these results support the expression of alpha7 nAChRs in bovine adrenal chromaffin cells. However, these data suggest that the subunit composition of some of these receptors may include heteromeric alpha7 nAChRs.


Subject(s)
Cell Membrane , Chromaffin Cells , Receptors, Nicotinic , Alkylation , Animals , Binding Sites , Blotting, Western , Bungarotoxins/metabolism , Cattle , Cell Membrane/immunology , Cell Membrane/metabolism , Cells, Cultured , Chromaffin Cells/immunology , Chromaffin Cells/metabolism , Dose-Response Relationship, Drug , Immunoprecipitation , Ligands , Protein Binding , Radioligand Assay , Receptors, Nicotinic/chemistry , Receptors, Nicotinic/immunology , Receptors, Nicotinic/metabolism , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine Receptor
7.
Artif Organs ; 28(12): 1059-66, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15554933

ABSTRACT

Intrathecal transplants of adrenal medullary chromaffin cells relieve chronic pain by secreting catecholamines, opioids, and other neuroactive substances. Recently, macrocapsules with semipermeable membranes were used to isolate immunologically xenogenic chromaffin cells, but the poor viability in vivo of the encapsulated chromaffin cells limited the usefulness of this method. In this study, we used a novel method of encapsulation to increase the viability of chromaffin cells. We found that microencapsulated chromaffin cells that were implanted into the subarachnoid space of rats relieved cold allodynia in a model of neuropathic pain. Furthermore, microencapsulated chromaffin cells were morphologically normal and retained their functionality. These findings suggest that the intrathecal placement of microencapsulated chromaffin cells might be a useful method for treating chronic pain.


Subject(s)
Catecholamines/metabolism , Chromaffin Cells/immunology , Chromaffin Cells/transplantation , Cold Temperature/adverse effects , Pain Management , Subarachnoid Space/metabolism , Animals , Cattle , Cell Survival , Cell Transplantation , Chromaffin Cells/metabolism , Drug Compounding , Injections, Spinal , Male , Models, Animal , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Rats , Rats, Sprague-Dawley
9.
Biochem J ; 351(Pt 1): 33-7, 2000 Oct 01.
Article in English | MEDLINE | ID: mdl-10998344

ABSTRACT

We have examined the expression in bovine adrenal medulla of double C2 protein (DOC2), a vesicular protein which associates with intracellular phospholipid and Ca(2+) and is implicated in the modulation of regulated exocytosis. Extensive reverse transcription-PCR, Northern blot analyses and in vitro translation reactions have been combined with immunological studies to provide data to suggest that neither DOC2alpha nor DOC2beta is expressed at detectable levels in bovine adrenal chromaffin cells, and that a widely used monoclonal antibody directed against DOC2 also recognizes mitochondrial complex III core protein 2.


Subject(s)
Adrenal Medulla/metabolism , Antibodies, Monoclonal/immunology , Antigens/immunology , Calcium-Binding Proteins/metabolism , Cross Reactions/immunology , Mitochondria/immunology , Nerve Tissue Proteins/metabolism , Adrenal Medulla/cytology , Adrenal Medulla/immunology , Animals , Antigens/metabolism , Brain/metabolism , Calcium-Binding Proteins/chemistry , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/immunology , Cattle , Chromaffin Cells/immunology , Chromaffin Cells/metabolism , Immune Sera/immunology , Mice , Mitochondria/metabolism , Molecular Weight , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/immunology , Protein Biosynthesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction
10.
FEBS Lett ; 458(3): 383-6, 1999 Sep 24.
Article in English | MEDLINE | ID: mdl-10570945

ABSTRACT

Conjugates between anti-tetanus F(ab')2 fragments and the (37-72) fragment of the HIV Tat protein were taken up by chromaffin cells, NG108-15 neurohybridoma cells and Rev-2-T-6 lymphoma cells. The uptake could not be inhibited by competition with (37-72)Tat, but was reduced in the presence of metabolic inhibitors or at low temperature. The disulfide as well as the thioether conjugate were translocated to the cytoplasmic space, but only the disulfide conjugate moderately restored the stimulated transmitter release inhibited by tetanus toxin. Therefore, disulfide conjugates are more promising than thioethers for the neutralization of intracellular antigens. These conjugates provide new tools to study neuroprotection against bacterial neurotoxins.


Subject(s)
Antibodies/immunology , Chromaffin Cells/metabolism , Disulfides/immunology , Gene Products, tat/immunology , Peptide Fragments/immunology , Tetanus Toxin/immunology , Animals , Carbocyanines , Cattle , Chromaffin Cells/immunology , Exocytosis/drug effects , Immunoglobulin Fab Fragments/immunology , Microscopy, Fluorescence , Norepinephrine/metabolism , Sulfides/immunology , Tetanus Toxin/pharmacology , Tumor Cells, Cultured , tat Gene Products, Human Immunodeficiency Virus
12.
Cell Transplant ; 8(1): 103-9, 1999.
Article in English | MEDLINE | ID: mdl-10338279

ABSTRACT

We have found that immunosuppression is necessary for the survival of xenogeneic adrenal medullary transplants. Because chromaffin cells are essentially nonimmunogenic, it is likely that the highly immunogenic "passenger" cells in the transplant preparation bring about rejection. This article describes a procedure that produces an essentially pure preparation of chromaffin cells for transplantation. Bovine adrenal medullary cells were isolated and differentially plated, resulting in a semipurified preparation of chromaffin cells. Ferromagnetic beads were added to the cell suspension, some of which were phagocytized by endothelial cells, which allowed their removal by exposure to a magnet. The remaining cells were then exposed to ferromagnetic beads coated with isolectin B4 from Griffonia simplicifolia and once again to a magnetic field. The "semipurified" preparation contained approximately 90% chromaffin cells, whereas the "highly purified" preparation was > 99.5% chromaffin cells as determined immunohistochemically. The immunogenicity of the two cell preparations was assessed in vitro by determining their capacity to evoke lymphocyte proliferation. Rat spleen lymphocytes were mixed with either a highly purified or semipurified population of bovine chromaffin cells. The results of this assay demonstrated that the highly purified preparation was a much weaker stimulant of lymphocyte proliferation than was the semipurified preparation and may demonstrate better graft survival in vivo. Transplantation via intrathecal catheter of either 80,000 or 250,000 cells from the highly or partially purified preparations onto the lumbar spinal cord of nonimmunosuppressed and non-nicotine-stimulated rats produced a cell number-dependent antinociception for both A(delta) and C fiber-mediated thermonociception at 6 days after transplantation. After 6 days and up to 28 days, only the "highly purified" preparation showed antinociception. These results suggest that nearly complete purification of bovine chromaffin cells minimizes immunorejection of xenogeneic transplants of these cells.


Subject(s)
Adrenal Medulla/cytology , Cell Separation/methods , Chromaffin Cells/transplantation , Pain Management , Spinal Cord/surgery , Transplantation, Heterologous/immunology , Adrenal Medulla/immunology , Animals , Catheters, Indwelling , Cattle , Chromaffin Cells/cytology , Chromaffin Cells/immunology , Immunosuppression Therapy , Male , Pain Measurement , Rats , Rats, Sprague-Dawley
13.
FASEB J ; 13 Suppl 2: S277-80, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10619143

ABSTRACT

Our laboratory studies have shown that transplantation of adrenal medullary tissue or isolated chromaffin cells into central nervous system (CNS) pain modulatory regions (i.e., periaqueductal gray and subarachnoid lumbar spinal cord) can reduce pain sensitivity of rats in both acute and chronic pain. The analgesia produced by these transplants is thought to result from release of both opiate peptides and catecholamines. Morphologically, these animal studies also suggest that there is no development of tolerance over long periods of time, and the transplanted chromaffin cells appear to be robust and well integrated with the host tissue. In our initial clinical studies, where allografts of adrenal medullary tissue were transplanted intrathecally to relieve intractable cancer pain, patients obtained significant and long-lasting pain relief. Increased cerebrospinal fluid (CSF) levels of metenkephalin were correlated with the decreased pain scores. Histology of autopsy tissue obtained from two patients with 1 year transplants revealed viable transplanted chromaffin cells. Because of the limited availability of human adrenal glands, sources of xenogeneic chromaffin cells will need to be identified if effective transplantation therapy for chronic pain is to be developed further.


Subject(s)
Adrenal Medulla/cytology , Analgesia , Central Nervous System , Chromaffin Cells/transplantation , Adrenal Medulla/immunology , Adrenal Medulla/ultrastructure , Animals , Brain Tissue Transplantation/immunology , Cattle , Central Nervous System/immunology , Chromaffin Cells/immunology , Chromaffin Cells/ultrastructure , Graft Survival , Humans , Rats
14.
Brain Res ; 780(2): 270-93, 1998 Jan 12.
Article in English | MEDLINE | ID: mdl-9507161

ABSTRACT

Imidazoline (I) receptors have been implicated in the regulation of arterial blood pressure and behavior although their distribution in the central nervous system (CNS) remains in question. Presumptive I- receptor sites were detected in the rat central nervous system with a polyclonal antibody to an imidazoline receptor protein (IRP) with binding characteristics of the native receptor. IRP-like immunoreactivity (LI) was detected in neurons and glia by light and electron microscopy. Spinal cord: processes were heavily labeled in superficial laminae I and II of the dorsal horn, lateral-cervical and -spinal nuclei and sympathetic cell column. Medulla: label was concentrated in the area postrema, rostral, subpostremal and central subnuclei of nucleus tractus solitarii, spinal trigeminal nucleus caudalis, and inferior olivary subnuclei. Visceromotor neurons in the dorsal vagal and ambigual nuclei were surrounded by high concentrations of immunoreactive processes. In reticular formation, label was light, though predominant in the intermediate reticular zone and ventrolateral medulla. Pons: label was detected in the neuropil of the periventricular gray, concentrated in the dorsal- and external-lateral subnuclei of lateral parabrachial nucleus, and present intracellularly in the mesencephalic trigeminal nucleus. Midbrain: IRP-LI was most heavily concentrated in the interpeduncular nucleus, nuclei interfascicularis and rostral-linearis, the subcommissural organ, central gray, and in glia surrounding the cerebral aqueduct. Diencephalon: high densities were detected in the medial habenular nucleus, nucleus paraventricularis thalami, other midline-intralaminar thalamic nuclei, the supramammillary and mediobasal hypothalamic nuclei. In the median eminence, immunolabeled processes were restricted to the lamina interna and lateral subependymal zone. Telencephalon: IRP-LI was concentrated in the central amygdaloid nucleus, bed nucleus of stria terminalis and globus pallidus, followed by moderate labeling of the medial amygdaloid nucleus, amygdalostriatal zone and caudoputamen, the hilus of the dentate gyrus, and stratum lacunosum-moleculare of field CA1 of Ammon's horn. The subfornical organ and organum vasculosum lamina terminalis were filled with diffuse granular immunoreactivity. Ultrastructural studies identified IRP-LI within glia and neurons including presynaptic processes. I-receptor(s) localize to a highly restricted network of neurons in the CNS and circumventricular regions lying outside of the blood-brain barrier. Putative imidazoline receptors have a unique distribution pattern, show partial overlap with alpha 2 adrenoreceptors and are heavily represented in sensory processing centers and the visceral nervous system.


Subject(s)
Central Nervous System/chemistry , Receptors, Drug/analysis , Receptors, Drug/immunology , Animals , Antibody Specificity , Astrocytes/chemistry , Astrocytes/ultrastructure , Cattle , Central Nervous System/cytology , Cerebellum/chemistry , Cerebellum/cytology , Chromaffin Cells/chemistry , Chromaffin Cells/immunology , Imidazoles , Imidazoline Receptors , Immunohistochemistry , Male , Medulla Oblongata/chemistry , Medulla Oblongata/cytology , Mesencephalon/chemistry , Mesencephalon/cytology , Microscopy, Electron , Neurons/chemistry , Neurons/ultrastructure , Pons/chemistry , Pons/cytology , Prosencephalon/chemistry , Prosencephalon/cytology , Rats , Rats, Sprague-Dawley , Spinal Cord/chemistry , Spinal Cord/cytology
15.
Exp Neurol ; 147(1): 66-83, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9294404

ABSTRACT

During the early stages following neural transplantation, host immune responses are initiated that are not normally found in the CNS including the induction of major histocompatibility antigens (MHC I and II). Previous laboratory findings have demonstrated prolonged survival of bovine chromaffin cells (BCC) in the rat CNS following transient immunosuppression with cyclosporin A (CSA) providing chromaffin cells are isolated from highly immunogenic passenger cells. To assess the influence of passenger and chromaffin cells on host MHC I and II expression, either BCC, nonchromaffin cell adrenal constituents (NCC), or adrenal medullary endothelial cells (EC) were implanted into the host. At 2 weeks postimplantation, robust BCC survival was obtained in CSA-treated animals. This correlated with low expression of MHC I at the host-graft border and the virtual absence of MHC II. Good BCC survival with reduced MHC I expression only was seen at 6 weeks postimplantation in animals transiently immunosuppressed (4 weeks). In contrast, poor survival was seen in the EC group (even with CSA treatment). In addition, marked MHC I and II expression was found in and around these grafts at 2 weeks, and was particularly intense in EC implanted animals. The results of this study suggest that nonchromaffin passenger cells in BCC preparations, most notably endothelial cells, can induce strong immune responses even in the presence of immunosuppression. Based on MHC staining, removal of these passenger cells can reduce host responses and improve long term survival of xenogeneic chromaffin cells in the CNS.


Subject(s)
Brain/physiology , Chromaffin Cells/immunology , Chromaffin Cells/transplantation , Immunosuppression Therapy , Major Histocompatibility Complex/physiology , Transplantation, Heterologous/immunology , Adrenal Medulla/cytology , Animals , Antibodies/analysis , Cattle , Cell Survival , Chromaffin Cells/physiology , Cyclosporine/pharmacology , Endothelium/cytology , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class II/immunology , Immunosuppressive Agents/pharmacology , Periaqueductal Gray/physiology , Rats , Rats, Sprague-Dawley
17.
Nat Biotechnol ; 14(13): 1692-5, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9634853

ABSTRACT

Transplantation of neural tissue into the mammalian central nervous system has become an alternative treatment for neurodegenerative disorders such as Parkinson's disease. Logistical and ethical problems in the clinical use of human fetal neural grafts as a source of dopamine for Parkinson's disease patients has hastened a search for successful ways to use animal dopaminergic cells for human transplantation. The present study demonstrates that transplanted testis-derived Sertoli cells into adult rat brains survive. Furthermore, when cotransplanted with bovine adrenal chromaffin cells (xenograft), Sertoli cells produce localized immunoprotection, suppress microglial response and allow the bovine cells to survive in the rat brain without continuous systemic immunosuppressive drugs. These novel features support Sertoli cells as a viable graft source for facilitating the use of xenotransplantation for Parkinson's disease and suggest their use as facilitators, (i.e., localized immunosuppression) for cell transplantation in general.


Subject(s)
Chromaffin Cells/transplantation , Corpus Striatum/surgery , Graft Rejection/prevention & control , Sertoli Cells/transplantation , Transplantation, Heterologous/immunology , Animals , Cattle , Chromaffin Cells/immunology , Corpus Striatum/pathology , Histocytochemistry , Lectins/analysis , Male , Microglia/pathology , Parkinson Disease/therapy , Rats , Rats, Sprague-Dawley , Sertoli Cells/immunology
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