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COVID-19 infection tends to be more lethal in older persons than in the young; death results from an overactive inflammatory response, leading to cytokine storm and organ failure. Here we describe immune regulation of the inflammatory response phenotype as emerging from a process that is analogous to machine-learning algorithms used in computers. We briefly describe some strategic similarities between immune learning and computer machine learning. We reason that a balanced response to COVID-19 infection might be induced by treating the elderly patient with a wellness repertoire of antibodies obtained from healthy young people. We propose that a beneficial training set of such antibodies might be administered in the form of intravenous immunoglobulin (IVIg).

An association between T‐cell lymphopenia and autoimmunity has long been proposed, but it remains to be elucidated whether T‐cell lymphopenia affects B‐cell responses to autoantigens. Human neonatal thymectomy (Tx) results in a decrease in T‐cell numbers and we used this model to study the development of autoreactivity. Two cohorts of neonatally thymectomized individuals were examined, a cohort of young (1–5 years post‐Tx, n = 10–27) and older children (>10 years, n = 26), and compared to healthy age‐matched controls. T‐cell and B‐cell subsets were assessed and autoantibody profiling performed. Early post‐Tx, a decrease in T‐cell numbers (2.75 × 109/L vs. 0.71 × 109/L) and an increased proportion of memory T cells (19.72 vs. 57.43%) were observed. The presence of autoantibodies was correlated with an increased proportion of memory T cells in thymectomized children. No differences were seen in percentages of different B‐cell subsets between the groups. The autoantigen microarray showed a skewed autoantibody response after Tx. In the cohort of older individuals, autoantibodies were present in 62% of the thymectomized children, while they were found in only 33% of the healthy controls. Overall, our data suggest that neonatal Tx skews the autoantibody profile. Preferential expansion and preservation of Treg (regulatory T) cell stability and function, may contribute to preventing autoimmune disease development after Tx.

Objective To address whether a targeted modulation of the abnormal expression of Hsp70 and autoantibodies against this molecule in systemic lupus erythematosus can influence disease. Methods Lupus-prone (NZB × NZW)F1 mice that had been DNA-vaccinated with plasmids encoding Hsp70 and controls were monitored for lupus disease parameters including anti-double stranded DNA (anti-dsDNA) autoantibodies and cytokines using enzyme-linked immunosorbent assay, and for kidney function and pathology. The phenotypic and numerical changes in relevant immune cells were evaluated by flow cytometry, and cell function was assessed. Results Mice that had been DNA-vaccinated with Hsp70 displayed marked suppression of anti-dsDNA antibody production, reduced renal disease, and antiinflammatory responses that are associated with a significantly extended survival, compared to controls. These protective effects in Hsp70-vaccinated mice were associated with an induction of tolerogenic immune responses and an expansion of functional Treg cells. Conclusion DNA vaccination with Hsp70 suppresses murine lupus by inducing tolerogenic immune responses and antiinflammatory immune responses associated with reduced disease manifestations and increased mouse survival.

Here, we outline an overview of the mammalian immune system that updates and extends the classical clonal selection paradigm. Rather than focusing on strict self-not-self discrimination, we propose that the system orchestrates variable inflammatory responses that maintain the body and its symbiosis with the microbiome while eliminating the threat from pathogenic infectious agents and from tumors. The paper makes four points: The immune system classifies healthy and pathologic states of the body-including both self and foreign elements-by deploying individual lymphocytes as cellular computing machines; immune cells transform input signals from the body into an output of specific immune reactions.Rather than independent clonal responses, groups of individually activated immune-system cells co-react in lymphoid organs to make collective decisions through a type of self-organizing swarm intelligence or crowd wisdom.Collective choices by swarms of immune cells, like those of schools of fish, are modified by relatively small numbers of individual regulators responding to shifting conditions-such collective inflammatory responses are dynamically responsive.Self-reactive autoantibody and T-cell receptor (TCR) repertoires shared by healthy individuals function in a biological version of experience-based supervised machine learning. Immune system decisions are primed by formative experience with training sets of self-antigens encountered during lymphocyte development; these initially trained T cell and B cell repertoires form a Wellness Profile that then guides immune responses to test sets of antigens encountered later. This experience-based machine learning strategy is analogous to that deployed by supervised machine-learning algorithms. We propose experiments to test these ideas. This overview of the immune system bears clinical implications for monitoring wellness and for treating autoimmune disease, cancer, and allograft reactions.

We describe here the development, verification and validation of the SLE-key ® rule-out test for a definitive rule-out of a diagnosis of systemic lupus erythematosus (SLE). The test uses the proprietary iCHIP ® micro-array technology platform (Fattal et al., 2010) to identify discriminating patterns of circulating autoantibodies among SLE patients compared with self-declared healthy individuals. Given the challenges associated with the diagnosis of SLE and the healthcare costs of delayed diagnosis and misdiagnosis, a definitive rule-out test can provide significant clinical benefits to patients and potentially major cost savings to healthcare systems.

Alzheimer's disease (AD) is a neurodegenerative disorder which is the most prevalent cause of dementia in the western world. Currently, it is the most expensive disease in America, costing more than heart diseases and cancer and as the world population is getting older it is expected to become the most expensive medical disorder in the world. AD is characterized by three core pathologies: accumulation of amyloid β (Aβ) plaques, neurofibrillary tangles (NFT) and sustained inflammation. It is now believed that inflammation provides the link between Aβ and NFT. The immune system is therefore, a major player in the pathogenesis of AD. Here we propose that Bacillus Calmette-Guerin (BCG) could affect the incidence of AD. Bacillus Calmette-Guerin (BCG) is a live attenuated Mycobacterium bovis preparation first developed as a vaccine against M. tuberculosis. It has been shown to be moderately effective in preventing tuberculosis, while noted to induce modifications in inflammatory response and to regulate the immune system. Intra-vesical administration of BCG is used successfully in the past four decades to prevent recurrence of non-muscle invasive bladder cancer. In this manuscript we investigate the hypothesis that exposure to BCG decreases the prevalence of AD in elderly population and that this occurs through modulation of the immune system. Our hypothesis is based on several lines of evidence: lower prevalence of AD in countries with high BCG coverage, ability of BCG to ameliorate several conditions involving the immune system like type 1 diabetes mellitus and multiple sclerosis, animal models of AD in which BCG shows therapeutic potential and a plausible molecular mechanism which may be the basis for this hypothesis. Namely, elevated systemic levels of IL-2 (as found when BCG is given intra-vesically) that amplify Treg cells that inhibit AD associated inflammation, decreased plaque formation and restore cognitive function. To test this hypothesis one may study cognition in the large available "natural adult population" exposed to high dose of BCG through the bladder. Bladder cancer survivors not given BCG can serve as control group. This population can be used without adding any medical intervention.

OBJECTIVE: We previously described the multiplex autoantibody SLE-key Rule-Out test, which detects a signature of autoantibody reactivity that distinguishes healthy subjects from SLE patients with 94% sensitivity, 75% specificity and 93% negative predictive value; thus, an individual manifesting a positive Rule-Out test score is unlikely to have SLE (e.g. lupus is excluded). The objective of this current study was to evaluate the stability of the lupus-associated signature over time. METHODS: We used banked serum samples from healthy subjects (n = 51) and lupus patients (n = 50 individual samples and n = 181 paired samples, for a total of n = 412 serum samples). The samples were drawn at different times after diagnosis to analyse the impact on the SLE-key Rule-Out test of time elapsed since diagnosis and any changes in disease activity (as reflected by the SLEDAI score). RESULTS: The SLE signature remains stable for the first 10 years after diagnosis; in this time frame

Background The SLE-key® RuleOut iCHIP® antigen microarray-based test rules out a diagnosis of SLE with a sensitivity of 94%1. Objectives Here we report the use of the iCHIP® platform and a set of synthetic oligonucleotide antigens to distinguish between SLE subjects and those with a diagnosis of Rheumatoid Arthritis (RA), Scleroderma (SSc), Sjogren9s syndrome (SS), or healthy individuals (HC). Methods We examined IgM and IgG antibody binding to 22 synthetic oligonucleotides (44 features) in the sera of HC subjects (N=40); SLE (N=30); SSc (N=40); SS (N=20); or RA (N=30) patients. Univariate analysis (FDR adjusted p-values) was used to determine the ability of each feature to separate between SLE and the different classes of subjects. Results Table 1 shows that multiple oligonucleotides successfully distinguished SLE patients from all other groups. All significant features were IgG antibodies, except for 1 IgM. Table 2 shows the impact of single nucleotide change on autoantibody binding. PolyG (G17) separates SLE from all but SS. T1G16 separates SLE from HC subjects, while G16T1 gave no significant separation. The addition of a G to the 59 and 39 end of T16 enhanced IgG antibody binding and improved separation between SLE and other autoimmune diseases with at least 10-fold improved significance as compared to T20. PolyG sequence length impacts the ability of the oligonucleotides to separate between SLE and the other groups (Fig. 1A). Unexpectedly, sequences either shorter or longer than G14 were effective in separating SLE from HC, RA, and SSc, while G14 was not effective. Furthermore, none of the polyG homopolymers could separate SLE from SS. Sequences rich in C or T were more effective at separating between SLE and SS patients (Fig. 1B). Conclusions Autoantibody binding to oligonucleotides can be used to differentiate SLE from other autoimmune conditions and healthy subjects. The structural basis for the differences in binding of antibodies from disease sera to the various oligonucleotides is not yet understood, but may be due to immunologically unique conformations and secondary structures of oligonucleotides of defined length and sequence. SSc can be differentiated from SLE based on particular antibody binding to epitopes of oligonucleotides containing C and T. RA can be differentiated from SLE more significantly than the other autoimmune conditions. The iCHIP® microarray technology is being further developed to generate a clinically useful test to rule in a diagnosis of SLE relative to other related autoimmune diseases. References Putterman et al., J Immunol Methods 2016. Fattal et al., Immunology, 2010. Fattal et al., Immunology, 2015. Acknowledgements Authors wish to acknowledge Cohen-Gindi O, Lerner M, Tarnapolski O, Blumenstein Y, Javaherian A, Pitts J, Barton M and Wong E. and the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115308 BIOVACSAFE. Disclosure of Interest C. Putterman Consultant for: ImmunArray, A. Gabrielli: None declared, A. Balbir-Gurman: None declared, P. Safer Employee of: ImmunArray, K. Jakobi-Brook: None declared, R. Sorek Employee of: ImmunArray, I. Gluzman Employee of: ImmunArray, S. Wallace Employee of: ImmunArray, I. Cohen Shareholder of: ImmunArray, Consultant for: ImmunArray

Background We previously described the SLE-key® RuleOut test1,2 to rule out the presence of systemic lupus erythematosus (SLE) with 94% sensitivity, 75% specificity, and 93% negative predictive value. We also reported that the SLE-key® signature appeared to be independent of disease activity or duration3 suggesting4 that that the SLE-key® signature might persist over time in the same subject. Objectives Here we report that the SLE-key® signature remains stable over time in paired samples drawn from most individual subjects, regardless of disease activity. Methods We determined the SLE-key® RuleOut scores for 113 paired serum samples submitted by clinics specializing in SLE. SLEDAI scores at the time of the blood draw ranged from 0 to 22. The mean SLEDAI difference within the pairs was 2.7±6.3. Samples were collected from subjects with a T1-T2 time difference that ranged from 0 to 11.5 years (mean =2±2.6 years). Results The SLE-Key® RuleOut test identifies an SLE-specific signature based on a profile of autoantibodies to a combination of nucleic acids (complex ssDNA and a defined oligonucleotide) and protein biomarkers. Patients with an SLE-key® score of >0.18 are considered not ruled out for a diagnosis of SLE. In 84% of paired samples, patients9 SLE-key® scores remained essentially the same (Figure 1, closed circles). The scores for these subjects were stable, persistent, and independent of SLEDAI score or time between sampling. Significant changes in the SLE-key® scores of 18/113 patient pairs (open circles) appear to be independent of time between blood draws and change in SLEDAI score. In 7 cases there was a change in Rule Out status of the patients. In 3 cases, both scores were close to the 0.18 threshold and the change was deemed not significant. In 4 cases, patients9 status changed from RuledOut to Not Ruled Out, but with no correlation to change in SLEDAI score or time between sampling dates. Records of patients with changing SLE-key® scores are being studied to determine the reasons and the clinical implications of the change. Conclusions The SLE-key® RuleOut test detects a serologic signature which remains stable between sampling dates and over a long period of time after diagnosis in 84% of subjects. Subjects who were ruled out at T1 were generally ruled out at T2. Patients not ruled out at T1 remained not ruled out at T2. The clinical implications of a changing SLE-key® RuleOut score in the remaining 16% of patients may be meaningful, and are currently being carefully investigated. References Fattal et al; Immunology 2010. Putterman et al., J Immunol Methods, 2016. Putterman et al., Lupus 2016. Cohen IR, Lupus Open Access 2016. Acknowledgements The authors wish to acknowledge the invaluable contributions of Cohen-Gindi O, Lerner M, Tarnapolski O, Blumenstein Y, Javaherian A, Pitts J, Barton M and Wong E and Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115308 BIOVACSAFE. Disclosure of Interest C. Putterman Consultant for: ImmunArray, M. Petri: None declared, R. Caricchio: None declared, P. Safer Employee of: ImmunArray, K. Jakobi Employee of: ImmunArray, R. Sorek Employee of: ImmunArray, I. Gluzman Employee of: ImmunArray, S. Wallace Employee of: ImmunArray, I. Cohen Shareholder of: ImmunArray, Consultant for: ImmunArray

Background Alzheimer’s disease (AD) affects one in ten people older than 65 years. Thus far, there is no cure or even disease-modifying treatment for this disease. The immune system is a major player in the pathogenesis of AD. Bacillus Calmette-Guerin (BCG), developed as a vaccine against tuberculosis, modulates the immune system and reduces recurrence of non-muscle invasive bladder cancer. Theoretical considerations suggested that treatment with BCG may decrease the risk of AD. We tested this hypothesis on a natural population of bladder cancer patients. Methods and findings After removing all bladder cancer patients presenting with AD or developing AD within one-year following diagnosis of bladder cancer, we collected data on a total of 1371 patients (1134 males and 237 females) who were followed for at least one year after the diagnosis of bladder cancer. The mean age at diagnosis of bladder cancer was 68.1 years (SD 13.0). Adjuvant post-operative intra-vesical treatment with BCG was given to 878 (64%) of these patients. The median period post-operative follow-up was 8 years. During follow-up, 65 patients developed AD at a mean age of 84 years (SD 5.9), including 21 patients (2.4%) who had been treated with BCG and 44 patients (8.9%) who had not received BCG. Patients who had been treated with BCG manifested more than 4-fold less risk for AD than those not treated with BCG. The Cox proportional hazards regression model and the Kaplan-Meier analysis of AD free survival both indicated high significance: patients not treated with BCG had a significantly higher risk of developing AD compared to BCG treated patients (HR 4.778, 95%CI: 2.837–8.046, p = 4.08x10-9 and Log Rank Chi-square 42.438, df = 1, p = 7.30x10-11, respectively). Exposure to BCG did not modify the prevalence of Parkinson’s disease, 1.9% in BCG treated patients and 1.6% in untreated (Fisher’s Exact Test, p = 1). Conclusions Bladder cancer patients treated with BCG were significantly less likely to develop AD at any age than patients who were not so treated. This finding of a retrospective study suggests that BCG treatment might also reduce the incidence of AD in the general population. Confirmation of such effects of BCG in other retrospective studies would support prospective studies of BCG in AD.

In October of 2015, the startup company ImmunArray announced the launch of a microarray platform – the iChip® – to profile repertoires of serum antibodies and autoantibodies. The first iChip® product – the SLE-key® RuleOut test – is designed to help the physician rule out a diagnosis of systemic lupus erythematosus (SLE) in suspected patients. The aim of this review is threefold: the first aim is to describe how basic observations and a philosophical notion led me to undertake the development of what has turned out to be a clinically useful aid in dealing with complex diseases; the second aim is to describe the role of a company in overcoming the technological and informatics challenges involved in translating basic research into patient welfare; the third aim is to discuss why SLE, like other complex medical problems, can be better managed using immune profiling. Basic scientist readers might learn here about the path to clinical application; clinician readers might learn here about the complicated origins of seemingly simple tests.

In his pioneering 1952 paper, “The chemical basis of morphogenesis”, Alan Turing introduced, perhaps for the first time, a model of the morphogenesis of embryo development. Central to his theory is the concept of cells with chemical entities that interact with morphogens to drive embryonic development through changes in what he termed ‘the state of the system’. Turing's concepts have inspired many mathematical and computational models proposed since then. Here we discuss the way Turing's ideas inspired our approach to the state-based modeling of morphogenesis, which results in a fully executable program for the interactions between chemical entities and morphogens. As a representative example we describe our modeling of pancreatic organogenesis, a complex developmental process that develops from a flat sheet of cells into a 3D cauliflower-like shape. We show how we constructed the model and tested the relations between morphogens and cells, and illustrate the analysis of the model against experimental data. Finally, we discuss a variant of the original Turing-Test for a machine's ability to demonstrate intelligence as a future means to validate computerized biological models, like the one presented here.

Up to one in four lung-transplanted patients develop pulmonary infiltrates and impaired oxygenation within the first days after lung transplantation. Known as primary graft dysfunction (PGD), this condition increases mortality significantly. Complex interactions between donor lung and recipient immune system are the suspected cause. We took an integrative, systems-level approach by first exploring whether the recipient's immune response to PGD includes the development of long-lasting autoreactivity. We next explored whether proteins displaying such differential autoreactivity also display differential gene expression in donor lungs that later develop PGD compared with those that did not. We evaluated 39 patients from whom autoantibody profiles were already available for PGD based on chest radiographs and oxygenation data. An additional nine patients were evaluated for PGD based on their medical records and set aside for validation. From two recent donor lung gene expression studies, we reanalysed and paired gene profiles with autoantibody profiles. Primary graft dysfunction can be distinguished by a profile of differentially reactive autoantibodies binding to 17 proteins. Functional analysis showed that 12 of these proteins are part of a protein-protein interaction network (P=3 x 10⁻⁶) involved in proliferative processes. A nearest centroid classifier assigned correct PGD grades to eight out of the nine patients in the validation cohort (P=0·048). We observed significant positive correlation (r=0·63, P=0·011) between differences in IgM reactivity and differences in gene expression levels. This connection between donor lung gene expression and long-lasting recipient IgM autoantibodies towards a specific set of proteins suggests a mechanism for the development of autoimmunity in PGD.

Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self-antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self-antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states – SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long-term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), Epstein–Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin-like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.

Obliterative bronchiolitis (OB) continues to be the major limitation to long-term survival after lung transplantation. The specific aetiology and pathogenesis of OB are not well understood. To explore the role of autoreactivity in OB, we spotted 751 different self molecules onto glass slides, and used these antigen microarrays to profile 48 human serum samples for immunoglobulin G (IgG) and IgM autoantibodies; 27 patients showed no or mild bronchiolitis obliterans syndrome (BOS; a clinical correlate of OB) and 15 patients showed medium to severe BOS. We now report that these BOS grades could be differentiated by a profile of autoantibodies binding to 28 proteins or their peptides. The informative autoantibody profile included down-regulation as well as up-regulation of both IgM and IgG specific reactivities. This profile was evaluated for robustness using a panel of six independent test patients. Analysis of the functions of the 28 informative self antigens showed that eight of them are connected in an interaction network involved in apoptosis and protein metabolism. Thus, a profile of autoantibodies may reflect pathological processes in the lung allograft, suggesting a role for autoimmunity in chronic rejection leading to OB.

Complex biological systems involve incorporated behaviors of numerous processes, mechanisms and objects. However, experimental analysis, by its nature, divides biological systems into static interactions with little dynamics. To bridge the gap between experimental data and the underlying behavior, our group has been formalizing biological findings into mathematically and algorithmically rigorous specifications, which are then compiled into reactive models. To realistically animate our models, we designed a generic architecture for the earlier idea of reactive animation, in a way that allows it to link up reactive models with animation tools. Here, we describe the reactive animation approach and some of the benefits of employing it to simulate and analyze complex biological systems. We illustrate our approach with a model of pancreatic development, a highly complex system with a unique 3D structure, and also mention more recent work on adding animation to the generic cell project (GemCell).

The mass and complexity of biological information requires computer-aided simulation and analysis to help scientists achieve understanding and guide experimentation. Although living organisms are composed of cells, actual genomic and proteomic data have not yet led to a satisfactory model of working cell in silico. We have set out to devise a user-friendly generic platform, GemCell, for Generic Executable Modeling of Cells, based on whole, functioning cells. Starting with the cell simplifies life, because all cells expresses essentially five generic types of behavior: replication, death, movement (including change of shape and adherence), export (secretion, signaling, etc.) and import (receiving signals, metabolites, phagocytosis, etc.). The details of these behaviors are specified in GemCell for particular kinds of cells as part of a database of biological specifics (the DBS), which specifies the cell properties and functions that depend on the cell’s history, state, environment, etc. The DBS is designed in an intuitive fashion, so users are able to easily insert their data of interest. The generic part of GemCell, built using Statecharts, is a fully dynamic model of a cell, its interactions with the environment and its resulting behavior, individually and collectively. Model specificity emerges from the DBS, so that model execution is carried out by the statecharts executing with the aid of specific data extracted from the DBS dynamically. Our long term goal is for GemCell to serve as a broadly applicable platform for biological modeling and analysis, supporting user-friendly in silico experimentation, animation, discovery of emergent properties, and hypothesis testing, for a wide variety of biological systems.

Here I present the idea that the immune system uses a computational strategy to carry out its many functions in protecting and maintaining the body. Along the way, I define the concepts of computation, Turing machines and system states. I attempt to show that reframing our view of the immune system in computational terms is worth our while.

Type 1 diabetes mellitus (T1DM) results from a specific autoimmune mediated destruction of the pancreatic beta-cells. PDX-1 induced developmentally redirected liver cells were suggested to restore the ablated pancreatic function in chemically induced diabetes. However, developmentally redirected liver cells, may have acquired along with the desired beta-cell characteristics and functions, also undesired sensitivity to autoimmune attack and therefore may be inefficient in ameliorating T1DM. This study analyzes whether subjects with beta-cell autoimmunity could benefit from Ad-CMV-PDX-1 gene therapy. Using the model of cyclophosphamide-accelerated diabetes in non-obese diabetic (CAD-NOD) mice, we report that recombinant adenovirus mediated PDX-1 gene therapy, ameliorates hyperglycemia in CAD-NOD mice. Our data demonstrate that 43% of the overtly diabetic CAD-NOD mice treated with Ad-CMV-PDX-1 became normoglycemic and maintained a stable body weight. Ectopic PDX-1 expression induced pancreatic gene expression and insulin production in the mice livers. The amelioration of hyperglycemia, in PDX-1 treated diabetic mice was associated with an immune modulation manifested by Th1 to Th2 shift in the autoimmune T-cell response to antigens associated with NOD diabetes. Thus, liver-to-pancreas transdifferentiation ameliorates T1DM in a process which is associated with a concomitant modulation of the autoimmune attack. Our findings suggest a beneficial therapeutic effect of the PDX-1 gene therapy for treating autoimmune type 1 diabetes mellitus (T1DM).

Treatment with DiaPep277, a peptide derived from HSP60, has been shown to preserve beta-cell function in non-obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10-month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements.Thirty-five male patients (aged 16-58) with a basal C-peptide greater than 0.1 nmol/L were assigned to periodic treatment with DiaPep277 (1 mg) or placebo for a 12-month treatment and 18-month observation protocol, later extended to an additional year of treatment. Stimulated C-peptide, HbA1c, and an exogenous insulin dose were the clinical endpoints.At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA1c concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred.Periodic treatment of subjects with DiaPep277 over 2 years was safe and associated preservation of endogenous insulin secretion up to 18 months was observed.

An informational landscape refers to an array of information related to a particular theme or function. The Internet is an example of an informational landscape designed by humans for purposes of communication. Once it exists, however, any informational landscape may be exploited to serve a new purpose. Listening Post is the name of a dynamic multimedia work of art that exploits the informational landscape of the Internet to produce a visual and auditory environment. Here, I use Listening Post as a prototypic example for considering the creative role of informational landscapes in the processes that beget evolution and science.

Some complex systems are transformational, of an input-process-output type, repeatedly carrying out their prescribed work for each new set of inputs. A far more problematic class comprises large systems that are heavily controlor event-driven. Such systems (dubbed reactive because they react to various kinds of events, signals, and conditions in intricate ways) are often concurrent and distributed. Reactive animation, a patent pending technology, offers great promise as a way to enhance the visualization of system behavior, especially for reactive systems, which are a central part of most current computerized technologies.

Myelin autoreactive T cells are involved in the pathogenesis of multiple sclerosis (MS) and lead to propagation of the disease. We evaluated the efficacy of T cell vaccination (TCV) therapy for patients with aggressive relapsing-remitting MS who failed to respond to immunomodulatory treatments. Twenty nonresponders relapsing-remitting MS patients were immunized with autologous attenuated T cell lines after activation with synthetic myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) encephalitogenic peptides. Each patient received three vaccinations in 6- to 8-week intervals. Annual relapse rate decreased from 2.6 to 1.1, P = 0.026. Neurological disability stabilized as compared with the 2- and 1-year pretreatment progression rates. Significant reduction in the number and volume of active lesions, as well as reduction in T2 lesion burden, was demonstrated by quantitative MRI analysis. No serious adverse events were observed. Our findings suggest that TCV has beneficial clinical effects in MS patients who, in spite of immunomodulatory treatments, continue to deteriorate. TCV could serve as a potential alternative therapy for this subgroup of nonresponders patients.

Informatic methodologies are being applied successfully to analyze the complexity of the genome. But beyond the genome, the immune system reflects the state of the body in health and disease. Traditionally, immunologists have reduced the immune system, where possible, to one-to-one relationships between particular antigens and particular antibodies or T-cell clones. Autoimmune diseases, caused by an immune attack against a body component, are usually investigated by following the response to single self-antigens. In this study, we apply informatics to analyze patterns of autoantibodies rather than single species of autoantibodies. This study was designed not to replace traditional approaches to immune diagnosis, but to test whether meaningful patterns of autoantibodies might exist. Using an unbiased solid-phase ELISA antibody test, we detected serum IgG and IgM antibodies in the sera of 20 healthy persons and 20 persons with type 1 diabetes mellitus binding to an array of 87 different antigens, mostly self-antigens. The healthy subjects manifested autoantibodies to a variety of self-antigens, many known to be associated with autoimmune diseases. We investigated the patterns of these autoantibodies using a coupled two-way clustering algorithm developed for analyzing data from gene arrays. We now report that the reactivity patterns of autoantibodies to particular subsets of self-antigens exhibited non-trivial structure, which significantly discriminated between healthy persons and persons with type 1 diabetes. The results show that despite the wide prevalence of autoantibodies, the patterns of reactivity to defined subsets of self-antigens can provide information about the state of the body.

We studied T-cell proliferative responses (stimulation index: SI) and autoantibodies to human HSP60, HSP70 and HSP90 proteins in 25 children (mean age 10.1+/-3.8 years) newly diagnosed with Type 1 diabetes. The control group for T cells included 25 adults and three pediatric donors without Type 1 diabetes. Controls for antibodies included 10 pediatric subjects. The T-cell responses to HSP70 of the test group (mean SI=4.5+/-3.1) were significantly greater than those of the control group (meanSI=1.4+/-0.6; p

Naive non-obese diabetic (NOD/LtJ) mice spontaneously produce natural IgG autoantibodies against self-antigens associated with the experimental autoimmune diseases to which they are susceptible: insulin-dependant diabetes mellitus, systemic lupus erythematosus and experimental autoimmune encephalomyelitis. We discovered recently that NOD/LtJ mice also spontaneously produce IgG antibodies to the acetylcholine receptor (AchR), an antigen that can induce experimental autoimmune myasthenia gravis (EAMG) in susceptible rodents. However, there are no reports indicating that NOD/LtJ mice are susceptible to EAMG. To test whether the presence of spontaneous IgG autoantibodies can predict susceptibility to an autoimmune disease, we challenged NOD/LtJ mice using a standard protocol to induce EAMG. We now report that NOD/LtJ mice developed EAMG, although to a somewhat lesser degree than did C57BL/6 mice, a strain regarded as highly susceptible to the disease. Both strains produced comparable levels of immune antibodies to AchR of the complement-fixing isotypes IgG2a and IgG2b; however, NOD/LtJ mice produced significantly more IgG1. An antigen-specific T cell proliferative response to AchR of the same magnitude was detected in both strains, together with the secretion of similar amounts of IFN-gamma. Thus, NOD/LtJ mice are susceptible to EAMG and disease induction is accompanied by immune responses comparable to those seen in the susceptible strain C57BL/6. These results support the association between specific, natural IgG autoantibodies and susceptibility to the induction of a particular autoimmune disease.

The target antigens of anti-nuclear autoantibodies in autoimmune hepatitis (AIH) are poorly characterised. Since antibodies to the p53 nuclear protein have been reported in various autoimmune diseases, we have assessed the prevalence of these antibodies in patients with AIH (n = 45), primary biliary cirrhosis (n = 60), hepatitis B (n = 22), hepatitis C (n = 55), and in a control group of subjects with various non-liver diseases (n = 56). A significant proportion of patients with AIH (31%) had elevated levels of autoantibodies to the p53 protein. In contrast, the prevalence of these antibodies in primary biliary cirrhosis (8%) and viral hepatitis (6%) was similar to that in the control group (4%). The clinical features of the anti-p53 seropositive AIH patients were similar to those of the seronegative ones. Thus, the prevalence of p53 autoantibodies in AIH is higher than in other forms of chronic hepatitis, and may be useful in differential diagnosis.

Immune response genes determine the magnitude of many immune responses. A low response is often ascribed to a genetic defect. Here Irun Cohen argues that a poor response instead reflects a heightened sensitivity to the conditions in which antigen is encountered. When these are optimal the response is normal. Poor responders thus have the advantage of a greater fexibility of response over individuals who respond strongly regardless of prevailing circumstances.

OBJECTIVE Endogenous insulin secretion, measured by C-peptide area under the curve (AUC), can be tested using both the glucagon stimulation test (GST) and the mixed-meal tolerance test (MMTT). This study compares these two stimulation methods using long-term data from patients newly diagnosed with type 1 diabetes or with latent autoimmune diabetes. RESEARCH DESIGN AND METHODS A recently completed phase 3 intervention study with DiaPep277 demonstrated improved glycemic control and a significant treatment effect of glucagon-stimulated C-peptide secretion. Unexpectedly, MMTT failed to detect differences between the treated and control groups. Data from 343 patients in two balanced-randomized, double-blind, placebo-controlled, parallel-group trials of DiaPep277 were used to compare and correlate between GST- and MMTT-derived C-peptide AUC. Pearson’s correlations were calculated for absolute C-peptide AUC at baseline and 12 and 24 months and for long-term changes in AUC (∆AUC). RESULTS The absolute AUC values obtained at any single time point by the two tests were well correlated in both data sets (r = 0.74–0.9). However, the correlations between the ∆AUC were much weaker (r = 0.39–0.58). GST-stimulated C-peptide secretion was stable over the fasting glucose range permitted for the test (4–11.1 mmol/L), but MMTT-stimulated C-peptide secretion decreased over the same range, implying differences in sensitivity to glucose. CONCLUSIONS Measurement of long-term changes in stimulated C-peptide, reflecting endogenous insulin secretion, during the course of intervention trials may be affected by the method of stimulation, possibly reflecting different sensitivities to the physiological status of the tested subject.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.

OBJECTIVE To evaluate safety and efficacy of DiaPep277 in preserving β-cell function in type 1 diabetic patients. RESEARCH DESIGN AND METHODS DIA-AID 1 is a multinational, phase 3, balanced-randomized, double-blind, placebo-controlled, parallel-group clinical study. Newly diagnosed patients (N = 457, aged 16–45 years) were randomized to subcutaneous injections of DiaPep277 or placebo quarterly for 2 years. The primary efficacy end point was the change from baseline in the area under the glucagon-stimulated C-peptide curve. Secondary end points were the change from baseline in mixed-meal stimulated C-peptide secretion and in fasting C-peptide and achieving target HbA1c ≤7% (≤53 mmol/mol). Partial remission (target HbA1c on insulin ≤0.5 units/kg/day) and hypoglycemic event rate were exploratory end points. RESULTS DiaPep277 was safe and well tolerated. Significant preservation of C-peptide secretion was observed in the DiaPep277-treated group compared with the placebo (relative treatment effects of 23.4%, P = 0.037, and 29.2%, P = 0.011, in the modified intent-to-treat [mITT] and per-protocol [PP] populations, respectively). The mixed-meal stimulation failed to distinguish between the groups. There was a trend toward efficacy in fasting C-peptide levels, though not statistically significant. Significantly more DiaPep277-treated than placebo-treated patients maintained target HbA1c (mITT 56% versus 44%, P = 0.03; PP 60% versus 45%, P = 0.0082) and entered partial remission (mITT 38% versus 29%, P = 0.08; PP 42% versus 30%, P = 0.035). DiaPep277 treatment reduced the relative hypoglycemic event risk (mITT by 20%; PP by 28%). CONCLUSIONS DiaPep277 safely contributes to preservation of β-cell function and to improved glycemic control in patients with type 1 diabetes.

Type 1 diabetes results from autoimmune destruction of insulin-producing pancreatic beta cells. The 60 kDa heat-shock protein (hsp60) is one of the known target self antigens. An immunomodulatory peptide from hsp60, p277, arrested beta-cell destruction and maintained insulin production in newly diabetic NOD mice. We did a randomised, double-blind, phase II study of peptide treatment in patients with newly diagnosed (6 months) type 1 diabetes.35 patients with type 1 diabetes and basal C-peptide concentrations above 0.1 nmol/L were assigned subcutaneous injections of 1 mg p277 and 40 mg mannitol in vegetable oil (DiaPep277; n=18) at entry, 1 month, and 6 months, or three placebo injections (mannitol in vehicle; placebo; n=17). The primary endpoint was glucagon-stimulated C-peptide production. Secondary endpoints were metabolic control and T-cell autoimmunity to hsp60 and to p277 (assayed by cytokine secretion). 31 patients completed 10 months of follow-up and were included in the intention-to-treat analysis.At 10 months, mean C-peptide concentrations had fallen in the placebo group (n=16) but were maintained in the DiaPep277 group (n=15; 0.26 [SD 0.11] vs 0.93 [0.35] nmol/L; p=0.039). Need for exogenous insulin was higher in the placebo than in the DiaPep277 group (0.67 [0.33] vs 0.43 [0.17] U/kg; p=0.042). Haemoglobin A1c concentrations were low (around 7%) in both groups. T-cell reactivity to hsp60 and p277 in the DiaPep277 group showed an enhanced T-helper-2 cytokine phenotype. No adverse effects were noted.Although this study was small, treatment of newly diagnosed type 1 diabetes with DiaPep277 seems to preserve endogenous insulin production, perhaps through induction of a shift from T-helper-1 to T-helper-2 cytokines produced by the autoimmune T cells.

Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats either by active immunization with myelin basic protein (MBP) or by adoptive transfer using anti-MBP specific CD4+T cells. Treatment with human polyclonal immunoglobulins (IgG) effectively suppressed active EAE. Time-dependent experiments demonstrated that the effect of IgG was manifested only when treatment was given immediately after immunization; administration from day 7 after disease induction did not suppress the disease. In the adoptive transfer model of EAE, IgG had no effect in vivo. However, pretreatment in vitro of the antigen-specific T-cells with IgG inhibited their ability to mediate adoptive EAE, as it did in active EAE. Similarly, in vitro IgG pretreatment of the antigen-specific T-cells suppressed the proliferative response to MBP. Fluorescent Activated Cell Sorter (FACS) analysis demonstrated the binding of IgG to activated T-cell lines that was inhibited by soluble Fc molecules. The differential effects of IgG on active EAE and on the adoptive transfer of EAE suggest that IgG in vivo can suppress disease by acting during the early phase of the immune response which involves naive T cells. The inhibition of T-cell proliferation and adoptive transfer of EAE by incubation of T cells in vitro appears to require higher concentrations of IgG than those obtained in vivo.

Cyclophosphamide (CY), an alkylating cytostatic drug, is known for its ability to accelerate a number of experimental autoimmune diseases including spontaneous diabetes in NOD mice. The mechanism(s) by which CY renders autoreactive lymphocytes more pathogenic is largely unknown, but it has been postulated that the drug preferentially depletes regulatory (suppressor) T cells. It has been suggested that in cell-mediated autoimmune diseases, Th2-like lymphocytes secreting IL-4 and/or IL-10 provide protection, while Th1-like cells secreting IFN-gamma are pathogenic. In this study, we analysed the effects of CY on autoimmune diabetes and cytokines in two mouse models: the spontaneous diabetes of NOD mice and the diabetes induced in C57BL/KsJ mice by multiple injections of low dose streptozotocin (LD-STZ). In both models, CY induced severe lymphopenia and accelerated the progression to hyperglycemia. This was associated with changes in splenic cytokine patterns indicating a shift towards the IFN-gamma-secreting phenotype. We provide here evidence that IFN-gamma producers are relatively resistant to depletion by CY and that Th0 clones can be shifted towards Th1. However, direct exposure of T lymphocytes to CY may not be a necessary condition for exacerbation of diabetes; NOD.scid mice treated with CY before adoptive transfer of NOD splenocytes developed diabetes at a higher rate than did controls. Thus, the acceleration of diabetes by CY seems to be a complex event, which includes the relatively high resistance of IFN-gamma producers to the drug, their rapid reconstitution, and a Th1 shift of surviving T cell clones.

Heat shock protein-60 (HSP60) is implicated in several autoimmune diseases as a triggering antigen. Based on the autoimmune hypothesis of schizophrenia, we examined cellular and humoral responses against HSP60 and a series of its peptide fragments with peripheral blood samples of schizophrenic patients and healthy subjects each of group size between 12 to 32 participants. The average stimulation indices of peripheral blood mononuclear cells (PBMC) to HSP60 were 3.17 +/- 0.36 (mean +/- SE) for schizophrenic patients and 2.23 +/- 0.24 (mean +/- SE) for healthy subjects, with a significant difference between the groups (P = 0.0457). In parallel, 38 synthetic peptide fragments of HSP60, each of 18-21 amino acids, were tested for in vitro sensitization of PBMC. With one peptide (p32) the average stimulation index of PBMC from schizophrenic patients was significantly higher than that obtained for PBMC of control subjects (P = 0.0006). Comparing the cellular immune response to p32 between patients who were distinctive responders (n = 10) or non-responders (n = 10) to neuroleptic treatment indicated a similar elevation of cellular response in these groups. Antibodies against HSP60 were screened by dot-blot and ELISA in the sera of the above blood samples. Titers of IgG and IgM against HSP60 were found to be of similar magnitude in schizophrenic patients and in controls. Titers of IgA against HSP60 were somewhat higher in the sera of schizophrenic patients in comparison to sera of control subjects (P = 0.0605).

The present study was undertaken to investigate whether active induction of systemic lupus erythematosus (SLE) in non-obese diabetic (NOD) mice could affect their development of insulin-dependent diabetes mellitus (IDDM). NOD mice were immunized with a human IgM mAb carrying the 16/6 idiotype (MIV-7) or with control human IgM. The mice were bled monthly and tested for SLE-associated autoantibodies in the serum and for the presence of leukopenia, thrombocytopenia, proteinuria and immunoglobulin deposits in the kidneys. The development of diabetes was determined by a blood glucose level exceeding 15 mM on two consecutive weekly determinations and by the presence of insulitis in the pancreas. The NOD mice immunized with MIV-7 developed high and persistent levels of autoantibodies, including anti-DNA, anti-histones and anti-cardiolipin, untreated mice and those immunized with normal human IgM did not produce these autoantibodies. The MIV-7immunized mice also manifested an elevated erythrocyte sedimentation rate, leukopenia, thrombocytopenia and significant proteinuria, as well as deposits of Ig in their kidney glomeruli. Thus, NOD mice immunized with MIV-7 developed both autoantibodies and clinical features of SLE. The MIV-7-treated mice, however, showed a significantly lower incidence of IDDM (25% vs. 90%, P

We have previously reported that very low doses of low molecular weight heparin compounds (LMWH) inhibit a variety of T-cell-mediated reactions by down-regulation of TNF-alpha production. This study tested the efficacy of LMWH in organ transplantation.Skin and heterotopic heart transplantations were performed between recipient Wistar rats and donor BN rats. Two doses of LMWH were given sc, 1 and 20 micrograms, each in three protocols, with day of grafting as Day 0: (A) Daily: -1, 0, 1 ellipsis, (B) Late Weekly: -1, 6, 13 ellipsis, and (C) Early Weekly: -7, 0, 7 ellipsis. Doses and schedules were selected based on efficacy in autoimmune models. Skin graft rejection was defined by complete separation of the graft, and heart transplant rejection was defined as cessation of heartbeat.Treatment with 1 microgram (26.8 +/- 2.0 days) and 20 micrograms (24.5 +/- 2.3 days) of LMWH using the Early Weekly protocol significantly prolonged skin allograft survival compared to controls (17.8 +/- 4.4 days), P0.001 for both, whereas other protocols did not. Compared to controls (8.3 +/- 1.4 days), treatment with both 1 and 20 micrograms of LMWH using all three protocols significantly prolonged cardiac allograft survival. The efficacy, however, varied considerably. Increase in graft survival ranged from 18% (1 microgram, Daily, 9.8 +/- 0.7 days, P = 0.02) to more than twofold (20 micrograms, Early Weekly, 20.8 +/- 5.5 days, P0.001) according to the dose and schedule of LMWH.Treatment with very low doses of nonanticoagulant LMWH preparations having anti-TNF-alpha activity significantly prolongs rat skin and cardiac allograft survival in a dose- and schedule-dependent manner.

T cell responses to peptide epitopes of the 60 kDa heat shock protein (hsp60) have been shown to play a role in the pathogenesis of type 1 insulin-dependent diabetes mellitus (IDDM) in mice. To test whether hsp60 autoimmunity might be involved in human type 1 diabetes, we studied T cell proliferative responses (stimulation index; SI) to intact human hsp60, to hsp60 peptides and to a recall antigen (tetanus toxoid) in 25 newly diagnosed type 1 diabetes patients, in 22 type 2 (non-insulin-dependent diabetes mellitus, NIDDM) patients, and in 25 healthy blood donors. There were no significant differences between the T cell responses of the three groups to tetanus toxoid. However, the responses to hsp60 of the type 1 diabetes group (median SI=5) were significantly greater (P0. 01) than those of the type 2 group (median SI=1.67) and of the blood donors (median SI=1.7). Epitope mapping revealed significant responses to at least seven different peptides, with prevalent responses to the p277 peptide previously mapped in NOD mice and to peptide p32. Thus, newly diagnosed type 1 diabetes patients, similar to prediabetic and newly diabetic NOD mice, show heightened autoimmunity to hsp60 and hsp60 peptides.

Glucocorticoids, since their spectacular introduction into clinical medicine in 1948 (1), remain a classically efficient treatment for arthritis and other inflammatory conditions (2). Indeed, the discoverers of this therapy were awarded an immediate Nobel Prize. Since then, glucocorticoids have remained a cornerstone in the treatment of chronic inflammation, and despite the introduction of novel therapies such as tumor necrosis factor–blocking agents (3), we have lately witnessed the increased use of glucocorticoids in arthritis. Recent studies confirm the capacity of glucocorticoids both to diminish inflammation and to reduce the pace of joint destruction (4–8), particularly when these agents are used at high doses and in the early phases of arthritis (6–8). Unfortunately, glucocorticoids are equally well known for their undesirable side effects, particularly with long-term use and systemic administration (2). A major problem has been achieving effective concentrations of active drug at the site of chronic inflammation and while avoiding too-high concentrations systemically and in uninflamed sites. The first attempt to reduce the undesirable effects of glucocorticoids on the rest of the body involved injecting them directly into the inflamed joints (9,10). This route of administration is still frequently used in practice, and it offers an efficient complement to other currently used therapies, despite the obvious drawbacks of repeated joint needling and the problem of polyarthritis involving small and inaccessible joints. Nevertheless, there is convincing evidence that glucocorticoids delivered in sufficiently high concentrations to an inflamed joint are beneficial. An attractive way to guide glucocorticoid treatment selectively to affected joints is to attach them to molecular delivery vehicles that, following systemic administration, accumulate in inflamed tissues to a relatively greater degree than they do in healthy tissues. Because of increased blood flow and vascular permeability at inflamed sites, liposomes could theoretically carry glucocorticoid drugs to arthritic joints (11). Despite efforts over the years, and some reports of success (12), liposome delivery of glucocorticoids has not been developed into a clinically useful therapy; this may be due, at least in part, to insufficient encapsulation of the drug into the liposomes and to lack of controlled release at the diseased joints. In this issue of Arthritis & Rheumatism, Avnir and colleagues report the engineering of a novel glucocorticoid-loaded liposome preparation, with promising results (13). The authors devised stabilized liposomes of !80 nm that could be loaded with relatively large amounts of an amphipathic weak acid glucocorticoid. This preparation manifested controlled release of the glucocorticoid in the circulation and especially in the swollen paws of rats with adjuvant-induced arthritis. This special liposome–glucocorticoid preparation produced a clinical effect on the rat arthritis much superior to that obtained with free glucocorticoid drug (13). The hope is that such glucocorticoid-loaded liposomes will safely work in humans to release sufficient amounts of drug into inflamed joints without exposing other body tissues to the hazards of too-high levels of the glucocorticoid. In view of the evidence that timely systemic administration of glucocorticoids can both ameliorate inflammation and prevent joint destruction (14), it is of great interest to explore the liposome formulation used by Avnir and colleagues in controlled clinical trials.

Background: Low-dose heparin devoid of anticoagulant activity inhibits T-lymphocyte heparanase activity, which is crucial in T-cell migration to target tissues. Objective: The purpose of this study was to assess the efficacy of low-dose enoxaparin (Clexane), a low-molecular-weight heparin, as monotherapy in lichen planus. Methods: Included in the study were 10 patients with widespread histopathologically proven lichen planus (LP) associated with intense pruritus of several months' duration. Patients were given 3 mg enoxaparin, subcutaneously once weekly; three patients received four injections, and seven patients received six injections. Results: In nine patients the itch disappeared within 2 weeks. Within 4 to 10 weeks in eight of these patients, there was complete regression of the eruption with residual postinflammatory hyperpigmentation; in one patient, there was marked improvement. In one patient, no effect was observed. Of the four patients who also had oral LP, only one showed improvement. No side effects were observed in any of the patients. Conclusion: These findings indicate that enoxaparin may be a simple, effective treatment for cutaneous LP. (J Am Acad Dermatol 1998;38:564-8.)

Type 1 diabetes is a chronic immune-mediated disease resulting in destruction of insulin-producing β-cells. Several studies have been performed aiming to halt disease progression after diagnosis; to reduce the increased diabetes risk in islet-autoantibody positive subjects; and to prevent the onset of β-cell autoimmunity in subjects genetically at risk but without autoantibodies. Whereas secondary prevention trials failed, trials in newly diagnosed patients have shown partial success in preserving C-peptide. These studies target T-cells and inflammation and make use of antigen-specific immune modulation or stem cell approaches. However, thus far no immune-based therapeutic regimen has cured type 1 diabetes after its clinical onset or has stabilized the decline of C-peptide to achieve the status of an approved drug. This review summarizes immune intervention trials and the current knowledge of DiaPep277® peptide as a form of immune intervention in type 1 diabetes.

Immunization with pathogenic lymphoid cells has been shown to induce resistance to disease in experimental animal models of cell mediated autoimmunity. In the present work we tested the effectiveness of this approach in a spontaneous murine autoimmune disease, the MRL/lpr/lpr (MRL/1) murine lupus model. We now report that the anti-DNA anti bodies and glomerulonephritis of MRL/1 mice could be prevented by the adoptive transfer of spleen cells from MRL/+ mice that had been vaccinated with MRL/1 lymph node T lymphocytes, but not by direct vaccination of MRL/1 mice with their cells. These results indicate that the lupus of MRL/1 mice is susceptible to regulation by adoptive vaccination and that these autoimmune mice lack the ability to raise a suppressive response against their own pathogenic cells.

We previously reported that immunity to the p277 peptide of the human 60-kDa heat shock protein (hsp60) was a causal factor in the diabetes of non-obese diabetic (NOD) mice, which are genetically prone to develop spontaneous autoimmune diabetes. The present study was done to test whether immunization with the p277 peptide could cause diabetes in standard strains of mice. We now report that a single administration of the p277 peptide conjugated to carrier molecules such as bovine serum albumin or ovalbumin can induce diabetes in C57BL/6 mice and in other strains not genetically prone to develop diabetes. The diabetes was marked by hyperglycemia, insulitis, insulin autoantibodies, glucose intolerance and low blood levels of insulin. The diabetes could be transferred to naive recipients by anti-p277 T cell lines. Similar to other experimentally induced autoimmune diseases, the autoimmune diabetes remitted spontaneously. After recovery, the mice were found to have acquired resistance to a second induction of diabetes. Susceptibility to induced diabetes in C57BL/6 mice was influenced by sex (males were much more susceptible than were females) and by class II genes in the major histocompatibility complex (B6.H-2bm12 mice with a mutation in the MHC-II molecule were relatively resistant). Other strains of mice susceptible to induced diabetes were C57BL/KSJ, C3HeB/FeJ, and NON/Lt. BALB/c and C3H/HeJ strains were relatively resistant. Immunization to p277-carrier conjugates could also induce transient hyperglycemia in young NOD mice, but upon recovery from the induced diabetes, the NOD mice were found to have acquired resistance to later development of spontaneous diabetes. Thus, T cell immunity to the p277 peptide can suffice to induce diabetes in standard mice, and a short bout of induced diabetes can affect the chronic process that would otherwise lead to spontaneous diabetes in diabetes-prone NOD mice.

Background T-cell vaccination (TCV) for multiple sclerosis (MS) refers to treatment with autologous anti-myelin T-cells, attenuated by irradiation. Previously published clinical trials have been all open-labeled. Aim To evaluate the safety and efficacy of TCV in progressive MS, in a double-blind, controlled clinical trial. Methodology Twenty-six patients with relapsing-progressive MS were enrolled in the study (mean age: 39±9.8 years; mean EDSS: 4.4±1.7). T-cell lines reactive to 9 different peptides of the myelin antigens, MBP, MOG and PLP were raised from the patients' peripheral blood. The patients were randomized into two groups: 19 were treated with TCV (four subcutaneous injections of 10–30×106 T-cells, attenuated by irradiation, on days 1, 30, 90 and 180) and 7 patients were treated with sham injections. Twenty-four patients (17 in the TCV group and 7 in the placebo) were eligible for per-protocol analysis. Results At one year following the inclusion, an increase in the EDSS (+0.50) and an increase in 10-meter walking time (+0.18 sec), were observed in the placebo group; in the TCV group there was a decrease in the EDSS (−0.44; p

Multiple sclerosis (MS) is a central nervous system demyelinating disease of implicated autoimmune aetiology. The effect was evaluated of intravenous gammaglobulin (IVIg), a successful therapy in various autoimmune diseases, in relapsing-remitting MS patients treated for three years. IVIg treatment significantly reduced the number and severity of acute exacerbations and resulted in a lesser neurological disability. There were no significant short or long-term adverse effects to IVIg treatment. To clarify the putative therapeutic effects of IVIg, this treatment was examined in the animal model of experimental autoimmune encephalomyelitis (EAE) in the rat. IVIg suppressed active EAE in relation to disease severity and duration, despite the presence of T-cell reactivity to specific antigens, while the treatment had no effect on passive EAE induced by adoptive transfer of myelin basic protein specific CD4 + T-cells. It is concluded that IVIg treatment may be a promising treatment in relapsing-remitting MS as it can alter the natural course of the disease.