Lost in translation: barriers to implementing clinical immunotherapeutics for autoimmunity

Induction of selective, autoantigen-specific tolerance is the “holy grail” for the treatment and prevention of autoimmune diseases. Despite successes in many differential murine models, rational and efficient translation to the clinic has been difficult. During the 5th Annual Federation of Clinical Immunological Societies (FOCIS) Meeting, May 12–16, 2005, in Boston, MA, a Kirin-sponsored “Ideashop” was convened to discuss this theme amongst scientists, clinicians, industry partners, and funding agencies

Geschlechterdifferenzierung in technischen Berufen unter dem Aspekt wachsender Heterogenität: Eine Untersuchung in der betrieblichen Berufsausbildung

Den Schwerpunkt dieser Arbeit bildet der Umgang des Ausbildungspersonals mit der Geschlechterdifferenzierung in der betrieblichen Ausbildung in technischen Berufen. Die Auswertungsergebnisse der qualitativen Inhaltsanalyse nach Mayring zeigten, dass das bewusste Erkennen von Geschlechterdifferenzen im engen Zusammenhang mit den langjährigen beruflichen Erfahrungen und Konfrontationen mit der Zielgruppe der weiblichen Auszubildenden steht. Die Verhaltensspezifik der männlichen Auszubildenden ist für Ausbilder/-innen bereits alltäglich geworden. Die Ausbilder der TBZ-Werkstätte (Interviewprobanden 3 und 4) nehmen Geschlechterdifferenzen wahr und gehen mit diesen bewusster um, was keine großartige lernprozessbezogene Probleme zulässt, interaktives Handeln zwischen Auszubildenden bzw. ihren Ausbildern unterstützt und die Entwicklung des technischen Verständnisses sowie Fertigkeiten gleichermaßen bei beiden Geschlechtern sichert

HLA-DR and HLA-DQ typing: a comparative study using serology and restriction fragment length polymorphism (RFLP) analysis

Embora as tipificações sorológicas dependam da expressão adequada de moléculas HLA de classe II, nas superfícies celulares, da viabilidade celular e da presença de um painel adequado de anti-soros, esse método tem sido utilizado há muitos anos e as tipificações por biologia molecular têm suplantado os problemas. A avaliação do polimorfismo dos genes HLA por intermédio da variação do tamanho dos fragmentos gerados pós digestão com enzimas de restrição (RFLP) foi o primeiro método molecular a ser utilizado para esse fim. A sorologia e o método utilizando RFLP definem os alelos HLA sem muita resolutividade, no entanto, o método utilizando RFLP tem sido considerado melhor do que a sorologia. Assim, neste estudo, fizemos análise das tipificações dos antígenos/alelos HLA de classe II (HLA-DR e HL-DQ), comparando os dois métodos.Serology has been used for HLA typing for many decades; however, serological typing of histocompatibility class II molecules depends on the adequate expression of these molecules on the surface of B lymphocytes, the availability of viable cells and a complete set of antisera. HLA typing at the genomic level has supplanted these pitfalls. The utilization of restriction fragment length polymorphism (RFLP) was the first approach to the HLA typing at molecular level. Although serology and RFLP methods define HLA specificities at low resolution level, RFLP has been considered to be better than serology. In this study, we performed HLA class II (HLA-DR and DQ) typing comparing these two methods

Associations of HLA DR and DQ molecules with Lyme borreliosis in Latvian patients

Copyright: Copyright 2012 Elsevier B.V., All rights reserved.Background: Many autoimmune diseases are associated with variants of HLA genes such as those encoding the MHC complex. This correlation is not absolute, but may help in understanding of the molecular mechanism of disease. The purpose of this study was to determine HLA-DR,-DQ alleles in Latvian patients with Lyme borreliosis and control (healthy) persons. Case patients and control subjects were similar in age, gender and ethnic heritage and differed only as regards the presence of Borrelia burgdorferi infection. The study included 25 patients with clinical stage - erythema migrans and 30 control (healthy) persons. HLA genotyping was performed by PCR with sequence-specific primers. Results: The results show difference in HLA-DRB1 alleles distribution between patients and control subjects. The frequencies of HLA-DRB1 *04 (OR 11.24; p<0.007) and HLA-DRB1 *17 (03) (OR 8.05; p<0.033) were increased in the Lyme disease patients. And the frequency of allele DRB1*13 (OR 0.12; p<0.017) was lower in Borreliosis patients and higher in control group. But, significant differences in frequencies of HLA-DQ alleles we did not detect. Conclusions: HLA predisposition to Lyme borreliosis appears not to be limited to HLA molecules, but some HLA-DR alleles also have a significant influence, and, may have implications in our understanding of pathogenesis of this disease. In particular, HLA-DRB1*04 and DRB1 *17 (03) may contribute to the Lyme borreliosis development in Latvian population.publishersversionPeer reviewe

Tolerance induction in memory CD4 T cells requires two rounds of antigen-specific activation

Autoimmune diseases are driven by immune cells that recognize self-tissues. A major goal for treatment strategies for autoimmune diseases is to turn off or tolerize self-reactive immune cells such as CD4 T cells that coordinate tissue damage in many autoimmune diseases. Autoimmune diseases are often diagnosed many years following their onset. The self-reactive CD4 T cells that must be tolerized, therefore, are previously activated or memory CD4 T cells. Little is known about whether tolerance can be induced in memory CD4 T cells. This paper demonstrates that memory CD4 T cells survive initial exposure to tolerance-inducing signals but that a second activation signal leads to cell death. This study has important implications for immunotherapeutic strategies for autoimmune diseases

A Randomized Controlled Trial of Ethyl Glucuronide-Based Contingency Management for Outpatients With Co-Occurring Alcohol Use Disorders and Serious Mental Illness.

OBJECTIVE: The authors examined whether a contingency management intervention using the ethyl glucuronide (EtG) alcohol biomarker resulted in increased alcohol abstinence in outpatients with co-occurring serious mental illnesses. Secondary objectives were to determine whether contingency management was associated with changes in heavy drinking, treatment attendance, drug use, cigarette smoking, psychiatric symptoms, and HIV-risk behavior. METHOD: Seventy-nine (37% female, 44% nonwhite) outpatients with serious mental illness and alcohol dependence receiving treatment as usual completed a 4-week observation period and were randomly assigned to 12 weeks of contingency management for EtG-negative urine samples and addiction treatment attendance, or reinforcement only for study participation. Contingency management included the variable magnitude of reinforcement prize draw procedure contingent on EtG-negative samples (/mL) three times a week and weekly gift cards for outpatient treatment attendance. Urine EtG, drug test, and self-report outcomes were assessed during the 12-week intervention and 3-month follow-up periods. RESULTS: Contingency management participants were 3.1 times (95% CI=2.2-4.5) more likely to submit an EtG-negative urine test during the 12-week intervention period, attaining nearly 1.5 weeks of additional alcohol abstinence compared with controls. Contingency management participants had significantly lower mean EtG levels, reported less drinking and fewer heavy drinking episodes, and were more likely to submit stimulant-negative urine and smoking-negative breath samples, compared with controls. Differences in self-reported alcohol use were maintained at the 3-month follow-up. CONCLUSIONS: This is the first randomized trial utilizing an accurate and validated biomarker (EtG) to demonstrate the efficacy of contingency management for alcohol dependence in outpatients with serious mental illness

Involvement of Mhc Loci in immune responses that are not Ir-gene-controlled

Twenty-nine randomly chosen, soluble antigens, many of them highly complex, were used to immunize mice of two strains, C3H and B10.RIII. Lymphnode cells from the immunized mice were restimulated in vitro with the priming antigens and the proliferative response of the cells was determined. Both strains were responders to 28 of 29 antigens. Eight antigens were then used to immunize 11 congenic strains carrying different H-2 haplotypes, and the T-cell proliferative responses of these strains were determined. Again, all the strains responded to seven of the eight antigens. These experiments were then repeated, but this time -antibodies specific for the A (AA) or E (EE) molecules were added to the culture to block the in vitro responsiveness. In all but one of the responses, inhibition with both A-specific and E-specific antibodies was observed. The response to one antigen (Blastoinyces) was exceptional in that some strains were nonresponders to this antigen. Furthermore, the response in the responder strains was blocked with A-specific, but not with E-specific, antibodies. The study demonstrates that responses to antigens not controlled by Irr genes nevertheless require participation of class II Mhc molecules. In contrast to Ir gene-controlled responses involving either the A- or the E-molecule controlling loci (but never both), the responses not Ir-controlled involve participation of both A- and E-controlling loci. The lack of Ir-gene control is probably the result of complexity of the responses to multiple determinants. There is thus no principal difference between responses controlled and those not controlled by Ir genes: both types involve the recognition of the antigen, in the context of Mhc molecules

Antibiotic-refractory Lyme arthritis is associated with HLA-DR molecules that bind a Borrelia burgdorferi peptide

An association has previously been shown between antibiotic-refractory Lyme arthritis, the human histocompatibility leukocyte antigen (HLA)–DR4 molecule, and T cell recognition of an epitope of Borrelia burgdorferi outer-surface protein A (OspA163–175). We studied the frequencies of HLA-DRB1-DQA1-DQB1 haplotypes in 121 patients with antibiotic-refractory or antibiotic-responsive Lyme arthritis and correlated these frequencies with in vitro binding of the OspA163–175 peptide to 14 DRB molecules. Among the 121 patients, the frequencies of HLA-DRB1-DQA1-DQB1 haplotypes were similar to those in control subjects. However, when stratified by antibiotic response, the frequencies of DRB1 alleles in the 71 patients with antibiotic-refractory arthritis differed significantly from those in the 50 antibiotic-responsive patients (log likelihood test, P = 0.006; exact test, P = 0.008; effect size, Wn = 0.38). 7 of the 14 DRB molecules (DRB1*0401, 0101, 0404, 0405, DRB5*0101, DRB1*0402, and 0102) showed strong to weak binding of OspA163–175, whereas the other seven showed negligible or no binding of the peptide. Altogether, 79% of the antibiotic-refractory patients had at least one of the seven known OspA peptide–binding DR molecules compared with 46% of the antibiotic-responsive patients (odds ratio = 4.4; P < 0.001). We conclude that binding of a single spirochetal peptide to certain DRB molecules is a marker for antibiotic-refractory Lyme arthritis and might play a role in the pathogenesis of the disease

HLA and Disease Associations in Koreans

The human leukocyte antigen (HLA), the major histocompatibility complex (MHC) in humans has been known to reside on chromosome 6 and encodes cell-surface antigen-presenting proteins and many other proteins related to immune system function. The HLA is highly polymorphic and the most genetically variable coding loci in humans. In addition to a critical role in transplantation medicine, HLA and disease associations have been widely studied across the populations world-wide and are found to be important in prediction of disease susceptibility, resistance and of evolutionary maintenance of genetic diversity. Because recently developed molecular based HLA typing has several advantages like improved specimen stability and increased resolution of HLA types, the association between HLA alleles and a given disease could be more accurately quantified. Here, in this review, we have collected HLA association data on some autoimmune diseases, infectious diseases, cancers, drug responsiveness and other diseases with unknown etiology in Koreans and attempt to summarize some remarkable HLA alleles related with specific diseases