Peptide immunotherapy in allergic asthma generates IL-10–dependent immunological tolerance associated with linked epitope suppression

Treatment of patients with allergic asthma using low doses of peptides containing T cell epitopes from Fel d 1, the major cat allergen, reduces allergic sensitization and improves surrogate markers of disease. Here, we demonstrate a key immunological mechanism, linked epitope suppression, associated with this therapeutic effect. Treatment with selected epitopes from a single allergen resulted in suppression of responses to other (“linked”) epitopes within the same molecule. This phenomenon was induced after peptide immunotherapy in human asthmatic subjects and in a novel HLA-DR1 transgenic mouse model of asthma. Tracking of allergen-specific T cells using DR1 tetramers determined that suppression was associated with the induction of interleukin (IL)-10⁺ T cells that were more abundant than T cells specific for the single-treatment peptide and was reversed by anti–IL-10 receptor administration. Resolution of airway pathophysiology in this model was associated with reduced recruitment, proliferation, and effector function of allergen-specific Th2 cells. Our results provide, for the first time, in vivo evidence of linked epitope suppression and IL-10 induction in both human allergic disease and a mouse model designed to closely mimic peptide therapy in humans.In previous clinical studies, intradermal (i.d.) injection of allergen-derived peptides resulted in modulation of surrogate markers of disease in allergic asthma; early- and late-phase skin responses to allergen were reduced (Oldfield et al., 2002), along with nasal symptoms (Alexander et al., 2005a) and airway hyperreactivity (AHR; Alexander et al., 2005b). Peptide treatment suppressed allergen-specific T cell proliferation and production of IL-4, IL-13, and IFN-γ, whereas IL-10 production was enhanced (Oldfield et al., 2001; Oldfield et al., 2002). The immunological mechanisms responsible have yet to be defined, but may include clonal deletion, induction of anergy (for review see Schwartz 2003), and/or active regulation (Sundstedt et al., 2003; Apostolou and Von Boehmer, 2004). We recently demonstrated induction of functional allergen-specific regulatory T cells after peptide therapy (Verhoef et al., 2005).Our clinical studies have focused on peripheral blood responses to allergen before and after therapy. A limitation of studying asthmatic human subjects is that it is not possible to directly examine local allergen-specific T cell responses within lung tissue. To address this issue, we have developed a model of Fel d 1 (the major allergen of the domestic cat, Felis domesticus)–induced allergic lung inflammation in a mouse transgenic for the human MHC class II molecule (HLA-DR1; DRA/DRB1*0101) and lacking endogenous mouse MHC class II (H2-Aβ^o). We were thus able to investigate mechanisms of peptide therapy–induced immunomodulation using the same peptides and route of treatment as that used in human therapy. Low-dose (1 µg) peptide therapy was used, reflecting our current clinical practice, and was substantially lower than previously used in mouse models. Immunological mechanisms were investigated by analyzing T cell responses to treatment peptides and nontreatment peptides from the same allergen molecule and using MHC class II (HLA-DR1) tetramers.Here, we provide evidence for the induction of linked epitope suppression in both human and mouse responses, together with substantial induction of IL-10 in T cells of mice, which was not limited to cells specific for the treatment peptide. In mice, reduced Th2 cell recruitment to the lung and suppressed effector cell function resulted in IL-10–dependent resolution of allergic lung inflammation, directly demonstrating treatment efficacy of peptide therapy in this model. The common responses to cat peptide therapy in humans and mice, as well as clear reduction in allergic inflammation in the mouse model, provide evidence that peptide therapy suppresses allergic asthma via induction of IL-10 and linked epitope suppression.     

圆二色谱在单萜和木脂体化合物结构分析中的应用

报道了10个化合物的CD谱,其中栀子酮(1)、栀二醇(2)和木脂体(3～7)均为新化合物。应用5种规则,确定了它们的绝对构型。     

小檗碱对局灶性脑缺血大鼠血小板聚集及血浆TXB2和6－keto－PGF1a水平的影响

以大鼠可逆性大脑中动脉梗塞（ＭＣＡＯ）致局灶性脑缺血为模型，观察小檗碱对大鼠ＭＣＡＯ２４ｈ后血小板粘附、聚集、血栓形成及血浆ＴＸＢ２和ＰＧＩ２生成的影响。结果表明，小檗碱２０ｍｇ·ｋｇ－１·ｄ－１ｉｐｌ，３或５ｄ，明显降低ＭＣＡｏ２４ｈ后血小板粘附性及ＡＤＰ、胶原和花生四烯酸诱导的血小板聚集率，抑制血浆ＴＸＢ２水平。同剂量ｉｐ３或５ｄ，则抑制血栓形成。提示小檗碱可能通过其抗血小板粘附和聚集及影响花生四烯酸代谢而发挥抗脑缺血作用。     

Validation of the NOSCA – nurses’ observation scale of cognitive abilities

Aims and objectives. To examine the psychometric properties of the Nurses’ Observation Scale for Cognitive Abilities. Background. Nurses’ Observation Scale for Cognitive Abilities is a behavioural rating scale comprising eight subscales that represent different cognitive domains. It is based on observations during contact between nurse and patient. Design. Observational study. Methods. A total of 50 patients from two geriatric wards in acute care hospitals participated in this study. Reliability was examined via internal consistency and inter‐rater reliability. Construct validity of the Nurses’ Observation Scale for Cognitive Abilities and its subscales were explored by means of convergent and divergent validity and post hoc analyses for group differences. Results. Cronbach’s αs of the total Nurses’ Observation Scale for Cognitive Abilities and its subscales were 0·98 and 0·66–0·93, respectively. The item–total correlations were satisfactory (overall > 0·4). The intra‐class coefficients were good (37 of 39 items > 0·4). The convergent validity of the Nurses’ Observation Scale for Cognitive Abilities against cognitive ratings (MMSE, NOSGER) and severity of dementia (Clinical Dementia Rating) demonstrated satisfactory correlations (0·59–0·70, p < 0·01), except for IQCODE (0·30, p > 0·05). The divergent validity of the Nurses’ Observation Scale for Cognitive Abilities against depressive symptoms was low (0·12, p > 0·05). The construct validity of the Nurses’ Observation Scale for Cognitive Abilities subscales against 13 specific neuropsychological tests showed correlations varying from poor to fair (0·18–0·74; 10 of 13 correlations p < 0·05). Conclusions. Validity and reliability of the total Nurses’ Observation Scale for Cognitive Abilities are excellent. The correlations between the Nurses’ Observation Scale for Cognitive Abilities subscales and standard neuropsychological tests were moderate. More conclusive results may be found if the Nurses’ Observation Scale for Cognitive Abilities subscales were to be validated using more ecologically valid tests and in a patient population with less cognitive impairment. Relevance to clinical practice. Use of the Nurses’ Observation Scale for Cognitive Abilities yields standardised, reliable and valid information about patient’s cognitive behaviour in daily practice. The Nurses’ Observation Scale for Cognitive Abilities aids in tailoring nursing interventions to patients’ specific cognitive needs. We advocate the implementation of the Nurses’ Observation Scale for Cognitive Abilities both in research and at geriatric units in acute care hospitals.     

The impact of motherless paternity testing in a South African population

BackgroundPaternity investigations play an important role in determining biological relatedness, and in South Africa, the outcome of these investigations impacts medical, judicial and home affairs decisions. Short Tandem Repeat (STR) analysis is utilised to perform paternity and kinship analysis, due to the polymorphic nature of STR loci. The cost associated with paternity testing is high, and there is a demand for motherless testing.ObjectivesThis study aims to determine what the impact of motherless testing would have been by evaluating 6182 paternity trio cases.MethodsThe AmpFLSTR™ Identifiler™ PCR Amplification kit was used to profile each of the trio cases. A scenario was created where the mother was eliminated from the test results to determine if the paternity outcome would change.ResultsPutative fathers were excluded in 27% of all cases, and in 2.5% of those cases, putative fathers would have been falsely included, had the mother not been tested. These false inclusions are attributed to coincidental STR loci that are shared between the mother and the putative father. The addition of loci to the STR profiling kit may resolve the issue; however, comparable STR data with more loci will have to be evaluated to ensure it overcomes the issue of coincidentally shared loci between unrelated individuals.ConclusionWe would recommend that within our setup and within similar setups, the mother always be included for testing, except in extreme scenarios such as death. False inclusion of putative fathers could have serious legal implications for testing laboratories.     

Regulatory T cells and transplantation tolerance

Rodent models of transplantation have demonstrated that it is possible to induce specific immunological tolerance of donor antigens and indefinite graft survival in the absence of any continued immunosuppression. If this situation could be achieved clinically it would avoid many of the longer term complications of organ grafting, such as the increased risk of infection and cancer and the nephrotoxicity of many immunosuppressive agents. In this review we shall consider the interplay between regulatory T cells, dendritic cells and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We will discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T cell and antigen-presenting cell activity. The induction and maintenance of tolerance via acquired local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression.