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1.
Am J Transplant ; 15(6): 1475-83, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25807873

ABSTRACT

The development of organ transplantation as a therapy for end-stage organ failure is among the most significant achievements of 20th century medicine, but chronic rejection remains a barrier to achieving long-term success. Current therapeutic regimens consist of immunosuppressive drugs that are efficient at delaying rejection but are associated with significant risks such as opportunistic infections, toxicity, and malignancy. Thus, the induction of specific immune tolerance to transplant antigens is the coveted aim of researchers. The use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (ECDI)-treated, autoantigen-coupled syngeneic leukocytes has been developed as a specific immunotherapy in preclinical models of autoimmunity and is currently in a phase II clinical trial for the treatment of multiple sclerosis. In this review, we discuss the use of allogeneic ECDI-treated apoptotic donor leukocytes (allo-ECDI-SP) as a strategy for inducing antigen-specific tolerance in allogeneic transplantation. Allo-ECDI-SP therapy induces long-term systemic immune tolerance to transplant antigens by subverting alloimmune recognition and exploiting apoptotic cell uptake pathways to recapitulate innate mechanisms of peripheral tolerance. Lastly, we discuss potential indications and challenges for transitioning allo-ECDI-SP therapy into clinical practice.


Subject(s)
Apoptosis/immunology , Immune Tolerance/immunology , Immunity, Innate/immunology , Leukocytes/immunology , Tissue Donors , Transplants/immunology , Animals , Apoptosis/physiology , Cytokines/physiology , Ethyldimethylaminopropyl Carbodiimide/pharmacology , Graft Rejection/immunology , Graft Rejection/prevention & control , Humans , Immune Tolerance/physiology , Immunity, Cellular/immunology , Immunity, Cellular/physiology , Immunity, Innate/physiology , Immunotherapy/methods , Leukocytes/cytology , Leukocytes/drug effects , Models, Animal , Transplantation, Homologous , Transplants/cytology , Transplants/physiology
2.
Am J Transplant ; 14(6): 1346-55, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24751150

ABSTRACT

TOL101 is a murine IgM mAb targeting the αß TCR. Unlike other T cell targets, the αß TCR has no known intracellular signaling domains and may provide a nonmitogenic target for T cell inactivation. We report the 6-month Phase 2 trial data testing TOL101 in kidney transplantation. The study was designed to identify a dose that resulted in significant CD3 T cell modulation (<25 T cell/mm(3) ), to examine the safety and tolerability of TOL101 and to obtain preliminary efficacy information. Thirty-six patients were enrolled and given 5-10 daily doses of TOL101; 33 patients completed dosing, while three discontinued after two doses due to a self-limiting urticarial rash. Infusion adjustments, antihistamines, steroids and dose escalation of TOL101 reduced the incidence of the rash. Doses of TOL101 above 28 mg resulted in prolonged CD3 modulation, with rapid recovery observed 7 days after therapy cessation. There were no cases of patient or graft loss. Few significant adverse events were reported, with one nosocomial pneumonia. There were five biopsy-confirmed acute cellular rejections (13.9%); however, no donor-specific antibodies were detected. Overall TOL101 was well-tolerated, supporting continued clinical development using the dose escalating 21-28-42-42-42 mg regimen.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Graft Rejection/prevention & control , Kidney Transplantation , Adult , Enzyme-Linked Immunosorbent Assay , Female , Humans , Kidney Transplantation/adverse effects , Male , Middle Aged
3.
Pediatr Pulmonol ; 46(2): 160-5, 2011 Feb.
Article in English | MEDLINE | ID: mdl-20963784

ABSTRACT

INTRODUCTION: This cross-sectional study was conducted to assess the relationship between iron levels in the plasma and sputum of cystic fibrosis (CF) patients. METHODS: Demographic, clinical, and iron-related laboratory data were prospectively obtained from 25 patients with stable clinical features and 14 patients with worsened clinical features since their most recent evaluations. RESULTS: Compared to patients with stable clinical features, those who experienced clinical deterioration demonstrated significantly worse lung function and were more frequently malnourished and diabetic. Members of the latter group were also significantly more hypoferremic and had higher sputum iron content than patients with stable clinical features. No significant correlation was found between plasma and sputum iron levels when the groups were analyzed together and separately. CONCLUSIONS: Sputum iron content does not correlate with iron-related hematologic tests. Hypoferremia is common in CF and correlates with poor lung function and overall health.


Subject(s)
Cystic Fibrosis/physiopathology , Iron/blood , Lung/physiopathology , Adult , Anemia/etiology , Cross-Sectional Studies , Cystic Fibrosis/blood , Cystic Fibrosis/complications , Diabetes Mellitus/etiology , Female , Humans , Iron, Dietary/blood , Male , Middle Aged , Prospective Studies , Sputum/chemistry , Young Adult
4.
Am J Transplant ; 10(8): 1774-84, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20626386

ABSTRACT

Dendritic cells (DCs) conditioned with the mammalian target of rapamycin (mTOR) inhibitor rapamycin have been previously shown to expand naturally existing regulatory T cells (nTregs). This work addresses whether rapamycin-conditioned donor DCs could effectively induce CD4(+)CD25(+)Foxp3(+) Tregs (iTregs) in cell cultures with alloantigen specificities, and whether such in vitro-differentiated CD4(+)CD25(+)Foxp3(+) iTregs could effectively control acute rejection in allogeneic islet transplantation. We found that donor BALB/c bone marrow-derived DCs (BMDCs) pharmacologically modified by the mTOR inhibitor rapamycin had significantly enhanced ability to induce CD4(+)CD25(+)Foxp3(+) iTregs of recipient origin (C57BL/6 (B6)) in vitro under Treg driving conditions compared to unmodified BMDCs. These in vitro-induced CD4(+)CD25(+)Foxp3(+) iTregs exerted donor-specific suppression in vitro, and prolonged allogeneic islet graft survival in vivo in RAG(-/-) hosts upon coadoptive transfer with T-effector cells. The CD4(+)CD25(+)Foxp3(+) iTregs expanded and preferentially maintained Foxp3 expression in the graft draining lymph nodes. Finally, the CD4(+)CD25(+)Foxp3(+) iTregs were further able to induce endogenous naïve T cells to convert to CD4(+)CD25(+)Foxp3(+) T cells. We conclude that rapamycin-conditioned donor BMDCs can be exploited for efficient in vitro differentiation of donor antigen-specific CD4(+)CD25(+)Foxp3(+) iTregs. Such in vitro-generated donor-specific CD4(+)CD25(+)Foxp3(+) iTregs are able to effectively control allogeneic islet graft rejection.


Subject(s)
CD4 Antigens/immunology , Dendritic Cells/immunology , Forkhead Transcription Factors/immunology , Interleukin-2 Receptor alpha Subunit/immunology , Sirolimus/pharmacology , T-Lymphocytes, Regulatory/immunology , Animals , Cell Differentiation/drug effects , Cell Differentiation/immunology , Dendritic Cells/drug effects , Graft Rejection/immunology , Islets of Langerhans Transplantation/immunology , Mice , Mice, Inbred C57BL , Transforming Growth Factor beta1/pharmacology
5.
Clin Exp Immunol ; 160(1): 15-21, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20415846

ABSTRACT

Human autoimmune diseases, such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus (SLE), are linked genetically to distinct major histocompatibility complex (MHC) class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins as well as geographical distribution of disease risk suggest a critical role for environmental factors in the triggering of these autoimmune diseases. Among potential environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. This review will discuss human autoimmune diseases with a potential viral cause, and outline potential mechanisms by which pathogens can trigger autoimmune disease as discerned from various animal models of infection-induced autoimmune disease.


Subject(s)
Autoimmune Diseases/virology , Virus Diseases/complications , Virus Diseases/immunology , Adjuvants, Immunologic , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Epitopes/genetics , Epitopes/immunology , Genetic Predisposition to Disease , Humans , Major Histocompatibility Complex/genetics , Molecular Mimicry/genetics , Molecular Mimicry/immunology
6.
Eur Respir J ; 35(5): 1155-63, 2010 May.
Article in English | MEDLINE | ID: mdl-19840955

ABSTRACT

alpha(1)-antitrypsin (alpha(1)-AT) deficiency is a genetic disease which manifests as early-onset emphysema or liver disease. Although the majority of alpha(1)-AT is produced by the liver, it is also produced by bronchial epithelial cells, amongst others, in the lung. Herein, we investigate the effects of mutant Z alpha(1)-AT (ZAAT) expression on apoptosis in a human bronchial epithelial cell line (16HBE14o-) and delineate the mechanisms involved. Control, M variant alpha(1)-AT (MAAT)- or ZAAT-expressing cells were assessed for apoptosis, caspase-3 activity, cell viability, phosphorylation of Bad, nuclear factor (NF)-kappaB activation and induced expression of a selection of pro- and anti-apoptotic genes. Expression of ZAAT in 16HBE14o- cells, like MAAT, inhibited basal and agonist-induced apoptosis. ZAAT expression also inhibited caspase-3 activity by 57% compared with control cells (p = 0.05) and was a more potent inhibitor than MAAT. Whilst ZAAT had no effect on the activity of Bad, its expression activated NF-kappaB-dependent gene expression above control or MAAT-expressing cells. In 16HBE14o- cells but not HEK293 cells, ZAAT upregulated expression of cIAP-1, an upstream regulator of NF-kappaB. cIAP1 expression was increased in ZAAT versus MAAT bronchial biopsies. The data suggest a novel mechanism by which ZAAT may promote human bronchial epithelial cell survival.


Subject(s)
Apoptosis/drug effects , Emphysema/metabolism , Epithelial Cells/metabolism , Respiratory Mucosa/metabolism , alpha 1-Antitrypsin/pharmacology , Adult , Biopsy , Blotting, Western , Caspase 3/metabolism , Cell Line , Cell Proliferation , Emphysema/genetics , Female , Gene Expression , Humans , Immunoenzyme Techniques , In Situ Nick-End Labeling , Inhibitor of Apoptosis Proteins/genetics , Male , NF-kappa B/metabolism , Phosphorylation , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation , alpha 1-Antitrypsin Deficiency/metabolism , bcl-Associated Death Protein/metabolism
7.
Clin Exp Immunol ; 155(1): 1-15, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19076824

ABSTRACT

Autoimmunity occurs when the immune system recognizes and attacks host tissue. In addition to genetic factors, environmental triggers (in particular viruses, bacteria and other infectious pathogens) are thought to play a major role in the development of autoimmune diseases. In this review, we (i) describe the ways in which an infectious agent can initiate or exacerbate autoimmunity; (ii) discuss the evidence linking certain infectious agents to autoimmune diseases in humans; and (iii) describe the animal models used to study the link between infection and autoimmunity.


Subject(s)
Autoimmune Diseases/microbiology , Bacterial Infections/immunology , Parasitic Diseases/immunology , Virus Diseases/immunology , Animals , Disease Models, Animal , Humans , Models, Animal
8.
Cell Mol Life Sci ; 65(17): 2702-20, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18516496

ABSTRACT

It has long been thought that astrocytes, like other glial cells, simply provide a support mechanism for neuronal function in the healthy and inflamed central nervous system (CNS). However, recent evidence suggests that astrocytes play an active and dual role in CNS inflammatory diseases such as multiple sclerosis (MS). Astrocytes not only have the ability to enhance immune responses and inhibit myelin repair, but they can also be protective and limit CNS inflammation while supporting oligodendrocyte and axonal regeneration. The particular impact of these cells on the pathogenesis and repair of an inflammatory demyelinating process is dependent upon a number of factors, including the stage of the disease, the type and microenvironment of the lesion, and the interactions with other cell types and factors that influence their activation. In this review, we summarize recent data supporting the idea that astrocytes play a complex role in the regulation of CNS autoimmunity.


Subject(s)
Astrocytes/cytology , Astrocytes/metabolism , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Animals , Astrocytes/immunology , Cell Movement , Cytokines/biosynthesis , Cytokines/immunology , Humans , Multiple Sclerosis/immunology , Myelin Sheath/metabolism , T-Lymphocytes/immunology
9.
J Inherit Metab Dis ; 31(1): 21-34, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18193338

ABSTRACT

Alpha-1 antitrypsin (A1AT) is a serine anti-protease produced chiefly by the liver. A1AT deficiency is a genetic disorder characterized by serum levels of less than 11 mumol/L and is associated with liver and lung manifestations. The liver disease, which occurs in up to 15% of A1AT-deficient individuals, is a result of toxic gain-of-function mutations in the A1AT gene, which cause the A1AT protein to fold aberrantly and accumulate in the endoplasmic reticulum of hepatocytes. The lung disease is associated with loss-of-function, specifically decreased anti-protease protection on the airway epithelial surface. The so-called 'Z' mutation in A1AT deficiency encodes a glutamic acid-to-lysine substitution at position 342 in A1AT and is the most common A1AT allele associated with disease. Here we review the current understanding of the molecular pathogenesis of A1AT deficiency and the best clinical management protocols.


Subject(s)
Liver Diseases/etiology , Lung Diseases/etiology , alpha 1-Antitrypsin Deficiency/complications , alpha 1-Antitrypsin Deficiency/genetics , alpha 1-Antitrypsin/chemistry , Animals , Autophagy/physiology , Humans , Liver Diseases/genetics , Liver Diseases/therapy , Lung Diseases/genetics , Lung Diseases/therapy , Models, Biological , Protein Conformation , Protein Folding , alpha 1-Antitrypsin/genetics , alpha 1-Antitrypsin Deficiency/physiopathology
10.
Med Teach ; 29(2-3): 156-9, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17701626

ABSTRACT

It can be challenging to teach and assess medical students successfully in the setting of a hospital ward using real patients. We describe a novel method of providing weekly formative clinical assessment and teaching to final year students on an acute medical ward: The Team Objective Structured Bedside Assessment (TOSBA). The TOSBA involves three groups of five students rotating through three ward-based stations (each station consists of an inpatient and facilitator). Each group spends 25 minutes at a bedside station where the facilitator asks consecutive students to perform one of five clinical tasks. Every student receives a standardised grade and is provided with educational feedback at each of the three stations. We report our 15-month experience using the TOSBA format to assess and teach a large number of medical students on a weekly basis. We discuss the advantages and potential drawbacks of our approach.


Subject(s)
Education, Medical, Undergraduate , Educational Measurement/methods , Hospitals, Teaching , Patients , Teaching , Educational Measurement/standards , Feasibility Studies , Feedback, Psychological , Humans , Surveys and Questionnaires , Teaching/standards
11.
Bone Marrow Transplant ; 38(6): 453-60, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16951693

ABSTRACT

We have investigated the influence of different hematopoietic growth factors, including granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), Flt-3 ligand (Flt-3L) and thrombopoietin (TPO), on the course of relapsing experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Disease course and central nervous system histology were evaluated in all groups. When given after immunization but before either disease onset or during remission, Flt-3L, SCF and G-CSF exacerbated disease severity whereas TPO had no effect compared to non-cytokine-treated controls. When compared to controls, TPO did not exacerbate disease. We conclude that autoimmune disease severity may be affected by hematopoietic growth factors currently being employed in hematopoietic stem cell transplantation of patients with autoimmune disease. The mechanism of their effects remains unknown: it may be related to both T helper (Th) 1/Th2 skewing and/or homing of inflammatory cells to the disease-affected organ.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/blood , Hematopoietic Cell Growth Factors/adverse effects , Hematopoietic Cell Growth Factors/pharmacology , Multiple Sclerosis/blood , Animals , Cell Movement/drug effects , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/pathology , Encephalomyelitis, Autoimmune, Experimental/therapy , Female , Hematopoietic Cell Growth Factors/blood , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Mice , Multiple Sclerosis/pathology , Multiple Sclerosis/therapy , Th1 Cells/metabolism , Th1 Cells/pathology , Th2 Cells/metabolism , Th2 Cells/pathology
12.
Curr Top Microbiol Immunol ; 296: 39-53, 2005.
Article in English | MEDLINE | ID: mdl-16323419

ABSTRACT

Multiple sclerosis1 (MS) is an immune-mediated autoimmune demyelinating disease in humans. The initiating event in MS is unknown, but epidemiological evidence suggests that virus infections may be important and one possible mechanism for induction of infection-induced autoimmune disease is molecular mimicry. To test the ability of a virus encoding a self myelin mimic epitope to induce an autoimmune response, we have developed a mouse model wherein the immunodominant myelin epitope PLP139-151, or mimics of this epitope, were inserted into a nonpathogenic variant of Theiler's murine encephalomyelitis virus (TMEV). SJL mice infected with TMEV containing PLP139-151 or a mimic of PLP139-151 expressed by the protease IV protein of Haemophilus influenzae, sharing only 6/13 amino acids with the native epitope, developed an early-onset demyelinating disease associated with activation of CD4+ T cells reactive with PLP139-151. We have used this molecular mimicry model to further address the requirements for mimic epitope processing and presentation during infection and the requirements for TCR recognition and MHC binding of mimic epitopes. We have also investigated whether molecular mimicry may require multiple infections, with either the mimic-encoding virus or an unrelated virus, to initiate autoimmune disease. Finally, we have asked whether a virus encoding a molecular mimic has to directly infect the target organ to induce autoimmune disease. Overall, this virus-induced molecular mimicry model has provided critical information regarding the mechanisms by which infection-induced molecular mimicry can induce autoimmune diseases.


Subject(s)
Molecular Mimicry/immunology , Multiple Sclerosis/etiology , Myelin Proteolipid Protein/immunology , Peptide Fragments/immunology , Amino Acid Sequence , Animals , Autoimmunity , CD4-Positive T-Lymphocytes/immunology , Disease Models, Animal , Epitopes/genetics , Haemophilus influenzae/enzymology , Haemophilus influenzae/genetics , Haemophilus influenzae/immunology , Humans , Mice , Models, Immunological , Multiple Sclerosis/immunology , Myelin Proteolipid Protein/genetics , Peptide Fragments/genetics , Peptide Hydrolases/genetics , Peptide Hydrolases/immunology , Theilovirus/genetics
13.
Nature ; 422(6927): 55-8, 2003 Mar 06.
Article in English | MEDLINE | ID: mdl-12621430

ABSTRACT

Understanding the physical mechanisms behind the generation of ocean waves by wind has been a longstanding challenge. Previous studies have assumed that ocean waves induce fluctuations in velocity and pressure of the overlying air that are synchronized with the waves, and numerical models have supported this assumption. In a complex feedback, these fluctuations provide the energy for wave generation. The spatial and temporal structure of the wave-induced airflow therefore holds the key to the physics of wind-wave coupling, but detailed observations have proved difficult. Here we present an analysis of wind velocities and ocean surface elevations observed over the open ocean. We use a linear filter to identify the wave-induced air flow from the measurements and find that its structure is in agreement with 'critical-layer' theory. Considering that the wave-induced momentum flux is then controlled by the wave spectrum and that it varies considerably in vertical direction, a simple parameterization of the total air-sea momentum flux is unlikely to exist.

14.
Radiat Prot Dosimetry ; 101(1-4): 53-8, 2002.
Article in English | MEDLINE | ID: mdl-12382704

ABSTRACT

Growth in the use of ionising radiation for medical sterilisation and the potential for wide-scale international food irradiation have created the need for robust, mass-producible, inexpensive, and highly accurate radiation dosemeters. The Sunna dosemeter, lithium fluoride injection-moulded in a polyethylene matrix, can be read out using either green photoluminescence or ultraviolet (UV) absorption. The Sunna dosemeter can be mass-produced inexpensively with high precision. Both the photoluminescent and the UV absorption reader are simple and inexpensive. Both methods of analysis display negligible humidity effects, minimal dose rate dependence, acceptable post-irradiation effects, and permit measurements with a precision of nearly 1% 1sigma. The UV method shows negligible irradiation temperature effects from -30 degrees C to +60 degrees C. The photoluminescence method shows negligible irradiation temperature effects above room temperature for sterilisation dose levels and above. The dosimetry characteristics of these two readout methods are presented along with performance data in commercial sterilisation facilities.


Subject(s)
Radiation Dosage , Radiometry/methods , Ultraviolet Rays , Humidity , Luminescent Measurements , Radiometry/instrumentation , Reproducibility of Results , Time Factors
15.
Alcohol Clin Exp Res ; 25(10): 1542-8, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11696676

ABSTRACT

BACKGROUND: Ethanol consumption impairs cell-mediated immunity and enhances humoral immunity. Among cell-mediated immune reactions, little is known of the effect of ethanol on chronic graft rejection. Allograft responses against the male-specific minor histocompatibility antigen, Hya, are widely used to study chronic graft rejection. METHODS: Female C57BL/6 (B6) mice were fed ethanol-containing liquid diets, were pair-fed an isocaloric liquid control diet, or were fed solid diet and water ad libitum. One week after diet initiation, the mice were grafted with split thickness, orthotopic male tail skin grafts, and the integrity of the grafts was monitored as the diet continued. Delayed hypersensitivity (DTH) was also determined in these same mice. In addition, Hya-cytolytic T-cell-deficient syngeneic major histocompatibility complex mutant B6.C-H2bm13 (bm13) and B6.C-H2bm14 (bm14) mice were assessed for skin graft rejection, DTH, and cytotoxic T-lymphocyte (CTL) activity. RESULTS: Ethanol-consuming female B6 mice are impaired in their ability to reject syngeneic male skin grafts and to develop Hya-specific DTH responses. To address the underlying mechanism, we show that Hya graft rejection correlates with DTH and not with CTL activity. Female B6 mice clearly differ from female bm13 and bm14 mice in their ability to generate CTLs against Hya antigen. Despite their inability to make Hya-specific CTL responses, bm13 and bm14 female mice, nevertheless, make Hya-specific DTH responses and ultimately reject Hya-disparate skin grafts, indicating that Hya-specific graft rejection results from DTH. Ethanol, by impairing Hya-specific DTH, inhibits Hya-specific skin graft rejection. CONCLUSIONS: We demonstrate that ethanol consumption impairs Hya-specific graft rejection. In addition, experiments with mice unable to generate anti-Hya CTLs support previous observations suggesting that DTH responses are sufficient to cause rejection of Hya-incompatible grafts.


Subject(s)
Alcohol Drinking , Graft Survival , H-Y Antigen/analysis , Skin Transplantation , Animals , Epitopes , Female , Graft Rejection/immunology , Graft Rejection/prevention & control , H-Y Antigen/immunology , Hypersensitivity, Delayed/immunology , Hypersensitivity, Delayed/physiopathology , Major Histocompatibility Complex/genetics , Male , Mice , Mice, Inbred C57BL , Mutation/immunology , Skin Transplantation/immunology , T-Lymphocytes, Cytotoxic/physiology , Time Factors
17.
J Neurovirol ; 7(5): 409-20, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11582513

ABSTRACT

Theiler's murine encephalomyelitis virus (TMEV) infection of the central nervous system (CNS) induces a chronic, progressive demyelinating disease in susceptible mouse strains characterized by inflammatory mononuclear infiltrates and spastic hind limb paralysis. Our lab has previously demonstrated a critical role for TMEV- and myelin-specific CD4(+) T cells in initiating and perpetuating this pathology. It has however, also been shown that the MHC class I loci are associated with susceptibility/resistance to TMEV infection and persistence. For this reason, we investigated the contribution of CD8(+) T cells to the TMEV-induced demyelinating pathology in the highly susceptible SJL/J mouse strain. Here we show that beta2M-deficient SJL mice have similar disease incidence rates to wild-type controls, however beta2M-deficient mice demonstrated earlier onset of clinical disease, elevated in vitro responses to TMEV and myelin proteolipid (PLP) epitopes, and significantly higher levels of CNS demyelination and macrophage infiltration at 50 days post-infection. beta2M-deficient mice also displayed a significant elevation in persisting viral titers, as well as an increase in macrophage-derived pro-inflammatory cytokine mRNA expression in the spinal cord at this same time point. Taken together, these results indicate that CD8(+) T cells are not required for clinical or histologic disease initiation or progression in TMEV-infected SJL mice. Rather, these data stress the critical role of CD4(+) T cells in this capacity and further emphasize the potential for CD8(+) T cells to contribute to protection from TMEV-induced demyelination.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8 Antigens/immunology , CD8-Positive T-Lymphocytes/pathology , Cardiovirus Infections/pathology , Theilovirus/physiology , beta 2-Microglobulin/deficiency , Amino Acid Sequence , Animals , Antigens, Viral/immunology , Brain/pathology , Brain/virology , CD8-Positive T-Lymphocytes/immunology , Capsid/immunology , Capsid Proteins , Cardiovirus Infections/genetics , Cardiovirus Infections/immunology , Cytokines/biosynthesis , Cytokines/genetics , Demyelinating Diseases , Epitopes/immunology , Female , Genetic Predisposition to Disease , Hypersensitivity, Delayed/etiology , Inflammation Mediators/metabolism , Macrophages/metabolism , Macrophages/pathology , Mice , Mice, Inbred Strains , Mice, Knockout , Molecular Sequence Data , Myelin Proteolipid Protein/immunology , Ovalbumin/immunology , Peptide Fragments/immunology , RNA, Messenger/biosynthesis , Spinal Cord/pathology , Spinal Cord/virology , Theilovirus/immunology , Theilovirus/isolation & purification , beta 2-Microglobulin/genetics
18.
Foot Ankle Int ; 22(9): 731-3, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11587390

ABSTRACT

We hypothesized that the posterior-to-anterior (PA) calcaneal interlocking screw of the Biomet Ankle Arthrodesis Nail would increase rotational stability secondary to increased bone purchase compared with the standard lateral-to-medial (transverse) screw. Each of 10 fresh human cadaver lower limbs (five matched pairs) were stabilized with a nail inserted retrograde through the calcaneus, talus, and tibia according to standard technique. One limb of each pair was fixed with a transverse calcaneal screw; the contralateral limb, with a PA calcaneal screw. Each limb was then subjected to torsional testing on an MTS Mini Bionix load frame. The PA screw construct was significantly stiffer than the transverse screw construct: 1.96 and 1.41 Nm/E, respectively (P < 0.036).


Subject(s)
Ankle Joint/surgery , Arthrodesis/methods , Bone Nails , Ankle Joint/physiology , Biomechanical Phenomena , Bone Screws , Cadaver , Humans
19.
Viral Immunol ; 14(3): 227-50, 2001.
Article in English | MEDLINE | ID: mdl-11572634

ABSTRACT

Virus infections have been implicated in the initiation of multiple human autoimmune diseases. This article focuses on reviewing the role of viruses in initiation, progression, and perpetuation of autoimmune diseases. Various mechanisms by which virus infections can induce autoimmune responses including molecular mimicry, epitope spreading, direct bystander activation, and release of cryptic epitopes are discussed. Evidence implicating virus infections in the pathogenesis of various human autoimmune diseases is reviewed. Last, the characteristics of animal models that have been developed for the study of the potential role of viruses in the initiation and progression of autoimmune disease are reviewed.


Subject(s)
Autoimmune Diseases/etiology , Autoimmunity/immunology , Virus Diseases/complications , Viruses/pathogenicity , Adult , Animals , Autoimmune Diseases/immunology , Disease Models, Animal , Humans , Mice , Mice, Inbred C57BL
20.
J Exp Med ; 194(5): 677-84, 2001 Sep 03.
Article in English | MEDLINE | ID: mdl-11535635

ABSTRACT

An increasing number of studies have documented the central role of T cell costimulation in autoimmunity. Here we show that the autoimmune diabetes-prone nonobese diabetic (NOD) mouse strain, deficient in B7-2 costimulation, is protected from diabetes but develops a spontaneous autoimmune peripheral polyneuropathy. All the female and one third of the male mice exhibited limb paralysis with histologic and electrophysiologic evidence of severe demyelination in the peripheral nerves beginning at 20 wk of age. No central nervous system lesions were apparent. The peripheral nerve tissue was infiltrated with dendritic cells, CD4(+), and CD8(+) T cells. Finally, CD4(+) T cells isolated from affected animals induced the disease in NOD.SCID mice. Thus, the B7-2-deficient NOD mouse constitutes the first model of a spontaneous autoimmune disease of the peripheral nervous system, which has many similarities to the human disease, chronic inflammatory demyelinating polyneuropathy (CIDP). This model demonstrates that NOD mice have "cryptic" autoimmune defects that can polarize toward the nervous tissue after the selective disruption of CD28/B7-2 costimulatory pathway.


Subject(s)
Antigens, CD/immunology , Membrane Glycoproteins/immunology , Nervous System Autoimmune Disease, Experimental/immunology , Peripheral Nervous System Diseases/immunology , T-Lymphocytes/immunology , Aging , Animals , Antigens, CD/genetics , B7-2 Antigen , Brain/immunology , Brain/pathology , Crosses, Genetic , Ganglia, Spinal/immunology , Ganglia, Spinal/pathology , Inflammation , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , Mice, Inbred NOD , Mice, Knockout , Nervous System Autoimmune Disease, Experimental/genetics , Nervous System Autoimmune Disease, Experimental/pathology , Peripheral Nervous System Diseases/genetics , Peripheral Nervous System Diseases/pathology , Ranvier's Nodes/immunology , Ranvier's Nodes/pathology , Sciatic Nerve/immunology , Sciatic Nerve/pathology
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