Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8(+) T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein-specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8(+) T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation.

SummaryThe Standards of Care Committee of the British Society for Allergy and Clinical Immunology (BSACI) and an expert panel have prepared this guidance for the management of immediate and non-immediate allergic reactions to penicillins and other beta-lactams. The guideline is intended for UK specialists in both adult and paediatric allergy and for other clinicians practising allergy in secondary and tertiary care. The recommendations are evidence based, but where evidence is lacking, the panel reached consensus. During the development of the guideline, all BSACI members were consulted using a Web-based process and all comments carefully considered. Included in the guideline are epidemiology of allergic reactions to beta-lactams, molecular structure, formulations available in the UK and a description of known beta-lactam antigenic determinants. Sections on the value and limitations of clinical history, skin testing and laboratory investigations for both penicillins and cephalosporins are included. Cross-reactivity between penicillins and cephalosporins is discussed in detail. Recommendations on oral provocation and desensitization procedures have been made. Guidance for beta-lactam allergy in children is given in a separate section. An algorithm to help the clinician in the diagnosis of patients with a history of penicillin allergy has also been included.Keywords allergy, anaphylaxis, beta-lactam, BSACI, carbapenem, cephalosporin, children, cross-reactivity, desensitization, drug provocation test, epidemiology, hypersensitivity, monobactam, oral challenges, paediatrics, penicillin, serum-specific IgE, skin tests, Standards of Care Committee • This guideline addresses immediate and non-immediate allergic reactions to beta-lactams.• Up to 20% of drug-related anaphylaxis deaths in • Individuals with a positive skin test to an aminopenicillin but negative skin tests to penicillin determinants are likely to be sensitized to the aminopenicillin side chain. (B) In this situation, a cautious challenge to benzyl or phenoxymethyl penicillin can be considered to ascertain whether the patient has a selective penicillin allergy. (D) • If a cephalosporin is required in a patient with a clinical history of penicillin allergy and positive skin tests -the patient should undergo skin testing using a cephalosporin with a different side chain and, if negative, provocation testing should be undertaken to exclude allergy to the specific cephalosporin. (D)• If penicillin is required in a patient with a clinical history of cephalosporin allergy, skin testing should be undertaken with penicillins and, if negative, provocation testing to exclude allergy to penicillin. (B) If skin tests are positive, then penicillin avoidance or desensitization can be considered. (B)• If a cephalosporin is required by a patient with a previous reaction, skin testing to penicillins and the required cephalosporin should be carried out to establish whether sensitization is to the beta-lactam core or side chain. (B) This should be followed by either provo...

SummaryThis is the first multi-centre retrospective survey from the United Kingdom to evaluate the aetiology and diagnostic performance of tryptase in anaphylaxis during general anaesthesia (GA). Data were collected retrospectively (2005-12) from 161 patients [mean ± standard deviation (s.d.), 50 ± 15 years] referred to four regional UK centres. Receiver operating characteristic curves (ROC) were constructed to assess the utility of tryptase measurements in the diagnosis of immunoglobulin (Ig)E-mediated anaphylaxis and the performance of percentage change from baseline [percentage change (PC)] and absolute tryptase (AT) quantitation. An IgE-mediated cause was identified in 103 patients (64%); neuromuscular blocking agents (NMBA) constituted the leading cause (38%) followed by antibiotics (8%), patent blue dye (6%), chlorhexidine (5%) and other agents (7%). In contrast to previous reports, latex-induced anaphylaxis was rare (0·6%). A non-IgE-mediated cause was attributed in 10 patients (6%) and no cause could be established in 48 cases (30%). Three serial tryptase measurements were available in 34% of patients and a ROC analysis of area under the curve (AUC) showed comparable performance for PC and AT. A ≥ 80% PPV for identifying an IgEmediated anaphylaxis was achieved with a PC of >141% or an AT of >15·7 mg/l. NMBAs were the leading cause of anaphylaxis, followed by antibiotics, with latex allergy being uncommon. Chlorhexidine and patent blue dye are emerging important health-care-associated allergens that may lead to anaphylaxis. An elevated acute serum tryptase (PC >141%, AT >15·7 mg/l) is highly predictive of IgE-mediated anaphylaxis, and both methods of interpretation are comparable.

These observations demonstrate that acute graft rejection in this model is associated with the expression of Th1 cytokines, IL-2, and IFN-gamma, whereas long-term survival is associated with predominant expression of Th2 cytokines, IL-4, and IL-10. The expression of IFN-gamma in long-surviving allografts in the absence of IL-2 provides evidence for altered activation of the Th1 response in this intrathymic immune modulation model.