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Objectives The immune trypanolysis test ( TL) is an accurate sero-diagnostic tool increasingly implemented for sleeping sickness medical surveillance, but it is restricted to the reference laboratories. To facilitate storage and transport of the test specimen, we developed a protocol for the examination of blood spotted on filter paper ( TL-fp) that can be stored and shipped at ambient temperature. We compared its performance with the classical TL on plasma ( TL-pl) that needs to be kept frozen until use. Methods The study was conducted in active foci of the Republic of Guinea. In total, 438 specimens from treated and untreated sleeping sickness patients and serological suspects were tested with both methods. Result TL-fp gave significantly less positive results than TL-pl, but all the confirmed sleeping sickness cases were positive with the TL-fp protocol. Conclusion TL-fp appears to offer a good compromise between feasibility and sensitivity to detect currently infected subjects who play a role in the transmission of Trypanosoma brucei gambiense and is useful for contributing to the elimination of gambiense sleeping sickness. [ABSTRACT FROM AUTHOR]

Background: Priming with ChAdOx1 followed by heterologous boosting is considered in several countries. Nevertheless, analyses comparing the immunogenicity of heterologous booster to homologous primary vaccination regimens and natural infection are lacking. In this study, we aimed to conduct a comparative assessment of the immunogenicity between homologous primary vaccination regimens and heterologous prime‐boost vaccination using BNT162b2 or mRNA‐1273. Methods: We matched vaccinated naïve (VN) individuals (n = 673) with partial vaccination (n = 64), primary vaccination (n = 590), and primary series plus mRNA vaccine heterologous booster (n = 19) with unvaccinated naturally infected (NI) individuals with a documented primary SARS‐CoV‐2 infection (n = 206). We measured the levels of neutralizing total antibodies (NTAbs), total antibodies (TAbs), anti‐S‐RBD IgG, and anti‐S1 IgA titers. Results: Homologous primary vaccination with ChAdOx1 not only showed less potent NTAb, TAb, anti‐S‐RBD IgG, and anti‐S1 IgA immune responses compared to primary BNT162b2 or mRNA‐1273 vaccination regimens (p < 0.05) but also showed ~3‐fold less anti‐S1 IgA response compared to infection‐induced immunity (p < 0.001). Nevertheless, a heterologous booster led to an increase of ~12 times in the immune response when compared to two consecutive homologous ChAdOx1 immunizations. Furthermore, correlation analyses revealed that both anti‐S‐RBD IgG and anti‐S1 IgA significantly contributed to virus neutralization among NI individuals, particularly in symptomatic and pauci‐symptomatic individuals, whereas among VN individuals, anti‐S‐RBD IgG was the main contributor to virus neutralization. Conclusion: The results emphasize the potential benefit of using heterologous mRNA boosters to increase antibody levels and neutralizing capacity particularly in patients who received primary vaccination with ChAdOx1. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are intensively investigated for their therapeutic potential and application as drug delivery vehicle. A broad perception of favourable safety profiles and low immunogenicity make EVs an attractive alternative to synthetic nanoparticles. We recently showed that repeated intravenous administration of human cell‐derived EVs into pig‐tailed macaques unexpectedly elicited antibody responses after three or more injections. This coincided with decreasing EV circulation time, and may thus hamper successful EV‐mediated cargo delivery into tissues. Here, we share the custom ELISA protocol that we used to measure such antibody responses. This protocol may help other researchers evaluate immune responses to EV‐based therapies in preclinical studies. [ABSTRACT FROM AUTHOR]

It has previously been shown that rats do not expel a primary infection of Nippostronglus brasiliensis during lactation. In the present paper, three aspects of the immune response of the lactating rat to the parasite were examined and compared with the response of non-lactating rats. Protective and reaginic antibodies were present in the circulation of rats first infected during lactation, in titres as high or higher than those in non-lactating controls. The intestinal mast cell response was similar both in timing and magnitude and lactating rats became susceptible to shock with the i.v. injection of antigen. Attention was drawn to the similarity between the response of the lactating rat and that of the neonate to this infection. [ABSTRACT FROM AUTHOR]

Conditionally activated molecules, such as Probody therapeutics (PbTx), have recently been investigated to improve antitumoral response while reducing systemic toxicity. PbTx are engineered to be proteolytically activated by proteases that are preferentially active locally in the tumor microenvironment (TME). Here, we perform an exploratory study using our recently published quantitative systems pharmacology model, previously validated for other drugs, to evaluate the effectiveness and targeting specificity of an anti‐PD‐L1 PbTx compared to the non‐modified antibody. We have informed the model using the PbTx dynamics and pharmacokinetics published in the literature for anti‐PD‐L1 in patients with triple‐negative breast cancer (TNBC). Our results suggest masking of the antibody slightly decreases its efficacy, while increasing the localization of active therapeutic component in the TME. We also perform a parameter optimization for the PbTx design and drug dosing regimens to maximize the response rate. Although our results are specific to the case of TNBC, our findings are generalizable to any conditionally activated PbTx molecule in solid tumors and suggest that design of a highly effective and selective PbTx is feasible. [ABSTRACT FROM AUTHOR]

Summary: Mass vaccination of the global population against SARS‐CoV‐2 will, we hope, turn the tide against this devastating pandemic. To complement vaccinations, better tools are needed to enable viral infections and immunological protection to be monitored. Accurate tools provide sound data for informed decision‐making at many levels, from personal to governmental. The measurement of viral RNA is currently routinely used to detect active infections, but only gives a positive result during infection and is unable to reveal historic infections. Tests involving a detection of SARS‐CoV‐2‐specific antibodies can reveal prior exposures to virus and can measure anti‐viral immune responses induced after natural infection or after vaccination. They may eventually also be used to predict an individual's likelihood of becoming re‐infected. Here, we report on the development of a sensitive ELISA technique to detect multiple isotypes of antibodies against the spike glycoprotein, in samples of both serum and saliva. This paper provides an important step towards understanding the immune response to SARS‐CoV‐2 and may therefore eventually help us to effectively control it. [ABSTRACT FROM AUTHOR]

Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Seidman et al. (2012) Quantitative review of antibody response to inactivated seasonal influenza vaccines. Influenza and Other Respiratory Viruses 6(1), 52-62. Background Seasonal influenza epidemics are associated with significant morbidity and mortality each year, particularly amongst young children and the elderly. Seasonal influenza vaccines have been available for decades, yet influenza remains a major public health threat in the US, sparking interest in studies evaluating the effectiveness of vaccination. Objectives We sought to identify determinants of serological responses to inactivated seasonal influenza vaccines including number of doses, adjuvant, and subject characteristics. Methods We reviewed 60 articles published between 1987 and 2006. We used weighted multiple logistic regression and random-effects models to evaluate how seroconversion and seroprotection rates varied with host and vaccine factors. Results Both children and seniors tended to have poorer immune responses compared to adults whereas use of adjuvant and a second vaccine dose tended to improve immune response. Pre-vaccination serological status had a large impact on the immune response to vaccination. We found substantial heterogeneity among studies, even with similar population settings and vaccination regimen. Conclusions Future studies should stratify their results by pre-vaccination serological status in an effort to produce more precise summary estimates of vaccine response. [ABSTRACT FROM AUTHOR]

Introduction: Sarcoidosis is a granulomatous disorder of unknown aetiology, affecting young adults and frequently involving the lungs. Objective: The aim of the present review was to give an overview of the clinical aspects in sarcoidosis. Results: The majority of patients recover, but some develop a chronic disease that may result in fibrosis and respiratory failure. Besides the lungs, peripheral lymph nodes, the skin, the liver and the eyes are commonly affected as well. The genetic background, as well as environmental factors, is of importance for developing sarcoidosis. The incidence varies in different populations, in the Nordic countries approximately with 20/100 000 new patients yearly. Sarcoidosis is diagnosed when clinical and radiological findings are supported by histological evidence in the form of non-caseating epithelioid cell granulomas, and when other causes of these features are excluded. Patients in need of treatment are usually treated with corticosteroids, topically or as oral steroids. A clinical effect of immunomodulatory drugs blocking tumour necrosis factor (TNF)α has been suggested from several case reports, while two controlled studies showed only minor effects; however, with a tendency to a more pronounced effect on patients with a more severe disease. The immune response in sarcoidosis, with a typical accumulation of CD4+ T-cells to the lungs, indicate the existence of specific antigens in this disease. Recently, antigens derived from infectious agents such as Mycobacteria and Proprionibacterium acnes have come into focus. Lymphocyte populations with immunoregulatory functions have recently been investigated and seem to be dysfunctional in sarcoidosis, opening the possibility of developing new treatment strategies in this disease. Conclusion: Recent technical developments have provided better tools, enabling detailed and more thorough analyses of the inflammatory process in sarcoidosis. Please cite this paper as: Grunewald J. Clinical aspects and immune reactions in sarcoidosis. The Clinical Respiratory Journal 2007; 1:64–73. [ABSTRACT FROM AUTHOR]

There is no doubt that HLA-DR molecules are acting as the products of HLA-linked immune response genes (Ir-genes), because (i) HLA-DR molecules are the restriction elements in the interaction between CD4+ helper T cells and antigen-presenting cells (APC) to respond to many antigens such as streptococcal cell wall antigen (SCW) (Nishimura & Sasazuki, 1983; Sone et al., 1985; Hizayama et al., 1986), schistosomal antigen (Sj) (Hirayama et al., 1987), Mycobacterium leprae antigen (ML) (Kikuchi et al., 1986) and so on; and (ii) anti-HLA-DR monoclonal antibodies completely abolish the immune response to those antigens (Nishimura & Sasazuki, 1983; Sone et al., 1985). However, genetic analysis of the immune response to those antigens in families or populations revealed that responsiveness is recessive and non-responsiveness to those antigens is a dominant genetic trait that is tightly linked to HLA (Sasazuki et al., 1980a, 1983; Watanabe et al., 1988). This is completely opposite to the situation under the Ir-gene control where responsiveness is dominant and non-responsiveness is recessive. In this paper, we report evidence of how we came across the concept of HLA-linked immune suppression genes (Is-genes) besides Ir-genes, and show evidence for the epistatic interaction between HLA-DR and DQ to determine the immune response to several antigens in humans. [ABSTRACT FROM AUTHOR]

As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone. [ABSTRACT FROM AUTHOR]

The experiments described in this paper were designed to determine the degradation of soluble IgG aggregates (AIgG) bearing C3b by guinea-pig peritoneal macrophages with different numbers of functional C3b receptors. The number of functional Fc receptors for AIgG containing 40 molecules of IgG per aggregate (AIgG40) were kept constant during these experiments. By increasing the concentration of trypsin for the treatment of normal peritoneal macrophages a dose-dependent inactivation of C3b receptors was achieved as determined by the binding of tetrameric [125I]-C3b([125I]-AC3b). Normal peritoneal macrophages bound 148,500 AIgG40 and 60,300 AC3b per cell. Treatment of the macrophages for 15 rain at 37° with incremental amounts of trypsin from 60 to 1000 µg/ml did not affect the binding of AIgG40 to macrophages but caused a dose-related loss of up to 95% of AC3b binding, indicating functional inactivation of C3b receptors. Degradation of trichloroacetic acid non-precipitable protein of [125I]-AIgG40 by 106 macrophages was 38±6% in medium alone and 60 ±8% in the presence of 10% fresh guinea-pig serum (NGPS) after 60 rain at 37°. The inactivation of 25%, 50%, 72% and 94% of C3b receptors by trypsin did not affect the degradation of AIgG40 in medium alone, but decreased degradation from 69% to 58%, 47%, 32% and 13% of AIgG40 respectively, in the presence of 10% GPS. Macrophages (106) in medium alone degraded 40%, 47%, 65% and 68% of AIgG40 beating 0, 5, 10, 16 and 20 C3b molecules per aggregate, indicating a dose-dependent enhancement of degradation by bound C3b; conversely, inactivation of 95% of C3 receptor on the macrophages resulted in 39%, 30%, 12%, 5% and 6% degradation of these AIgG40-C3b, indicating a dose-related inhibition by aggregate-bound C3b in the absence of cellular C3 receptor. These experiments stress the importance of Fc and C3b receptor co-operation and immune complex bound C3b. [ABSTRACT FROM AUTHOR]

Plaque-forming cell responses and antibody titres to sheep red cells (SRC) were elevated in normally-fed irradiated adult mice reconstituted with spleen cells from young mice which had received a 4% albumin diet, compared with those given cells from normally-fed littermates. This was independent of the dose of cells transferred (5 × 106-4 × 107), the day of assay (3–10) and the duration of protein-deficiency (1 or 3 weeks). It suggests that the depressed responses produced by protein-deficient (donor) mice reported in earlier papers resulted from an impairment of reticuloendothelial function or a shortage of protein reserves, not directly associated with the spleen. As protein-deficiency (of the donor) accelerated the initiation of the adoptive response and increased the cell yields of the recipients it is considered likely that an enhancement of cell proliferation during the first 3-5 days after transfer was responsible for the elevated responses. [ABSTRACT FROM AUTHOR]

This paper describes the induction of immunosuppression by multiple injections of carrageenan-lambda (cgn) in BALB/c mice. While cgn alone induced non-specific suppression that persisted for up to 25 days, priming with sheep red blood cells (SRBC) of mice within l0 days of cgn treatment prolonged the suppressive state. Also, antigen (SRBC)-specific suppression was observed when these mice were siren a secondary challenge 25–30 days after priming. Thus multiple cgn treatment along with priming SRBC generated non-specific and specific suppressive states which were transferable by Thy-l+ Lyt-2+ splenocytes. [ABSTRACT FROM AUTHOR]

Red cells sensitized with naturally occurring or 'immune' fowl antibody were lysed by fresh fowl serum. This fowl complement could not be replaced by that of human, rabbit or guinea pig. Both naturally occurring and 'immune' antibodies to red cells in the mammalian species tested did not lyse with fowl complement. Lysis by fresh fowl serum of sheep red cells sensitized with mammalian antibody is due to the presence of naturally occurrent antibody to these cells in the fowl serum; the enhancement of this lysis by the mammalian antibody will be described more fully in the next paper. Naturally occurring antibody to sheep red cells present in turkey serum and 'immune' antibody to fowl red cells were not lytic with fresh turkey serum, with fowl complement, with guinea-pig complement or with any combination of these. Some properties of fowl complement are given. [ABSTRACT FROM AUTHOR]

Summary: Background: Eosinophilic oesophagitis (EoE) is associated with elevated IgG4 in oesophageal tissue and serum. Previously, we showed brush‐collected oesophageal secretions of EoE patients contained food antigen‐specific antibodies IgA and IgG4. It is unknown whether other food‐specific antibodies are present along the surface of the oesophagus in EoE. Aim: To identify whether immunoglobulins other than IgG4 and food‐specific antibodies are elevated along the oesophageal mucosal surface in oesophageal secretions in EoE patients Methods: Concentrations of total IgA, IgG1, IgG2, IgG3, IgG4, IgM and IgE were measured in oesophageal secretions from patients with active (n = 19) and inactive EoE (n = 9), and non‐EoE controls (n = 10). Food‐specific antibodies were measured using beads coupled to protein components from dairy, wheat and egg. Total immunoglobulin and cytokine and chemokine concentrations were measured in serum, saliva and oesophageal secretions of four patients with active EoE. Results: Oesophageal secretions have a unique immune profile. Patients with active EoE had elevated IgG2, IgG4 and IgM concentrations in oesophageal secretions compared to those with inactive EoE. Food‐specific IgG1, IgG2, IgG4 and IgM were significantly increased in patients with active EoE compared to inactive EoE and non‐EoE patients. Furthermore, active patients with a known dairy trigger display higher dairy‐specific IgG1, IgG2, IgG4, IgM, IgA and IgE. Conclusions: There is a distinct localised profile of immunoglobulins and food‐specific antibodies found within oesophageal secretions in EoE. These findings expand our knowledge about the currently identified immune responses in EoE and suggest possible roles for multiple immunoglobulins and food‐specific antibodies in the pathophysiology of EoE. [ABSTRACT FROM AUTHOR]

Little is known about the long-term persistence of specific antibodies (Ab) in natural host-parasite systems despite its potential epidemiological and ecological importance. In long-lived species, knowledge of the dynamics of individual immunological profiles can be important not only for interpreting serology results, but also for assessing transmission dynamics and the potential selective pressures acting on parasites. The aim of this paper was to investigate temporal variation in levels of specific Ab against the bacterium Borrelia burgdorferi sensu lato in adults of a long-lived colonial seabird, the Black-legged Kittiwake Rissa tridactyla. In wild populations, adults are naturally exposed each breeding season to a Borrelia vector, the tick Ixodes uriae. Breeding birds were captured during four consecutive breeding seasons, and parasite infestation quantified. Using enzyme-linked immunosorbent assay (ELISA) and immunoblots, we found that the immunological profiles of anti-Borrelia Ab were highly repeatable among years, reflecting the interannual persistence of Ab levels. We nevertheless also observed that year-to-year changes of Ab levels were related to exposure to ticks in the previous year. The long-term persistence of Ab levels may be an important mechanism of individual protection against future exposure to the microparasite. It will also affect the availability of susceptible hosts, and thus the transmission dynamics of the bacterium. These results illustrate the need to consider the dynamics of the immune response in order to better understand the evolutionary ecology of host-parasite interactions in natural populations. [ABSTRACT FROM AUTHOR]

The outbreak of the coronavirus disease 2019 (COVID‐19) has gathered 1 year of scientific/clinical information. This informational asset should be thoroughly and wisely used in the coming year colliding in a global task force to control this infection. Epidemiology of this infection shows that the available estimates of SARS‐CoV‐2 infection prevalence largely depended on the availability of molecular testing and the extent of tested population. Within molecular diagnosis, the viability and infectiousness of the virus in the tested samples should be further investigated. Moreover, SARS‐CoV‐2 has a genetic normal evolution that is a dynamic process. The immune system participates to the counterattack of the viral infection by pathogen elimination, cellular homoeostasis, tissue repair and generation of memory cells that would be reactivated upon a second encounter with the same virus. In all these stages, we still have knowledge to be gathered regarding antibody persistence, protective effects and immunological memory. Moreover, information regarding the intense pro‐inflammatory action in severe cases still lacks and this is important in stratifying patients for difficult to treat cases. Without being exhaustive, the review will cover these important issues to be acknowledged to further advance in the battle against the current pandemia. [ABSTRACT FROM AUTHOR]

The development of donor‐specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post‐transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor‐specific antibodies post‐transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet‐based donor:recipient matching, including unavailability of allele‐level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long‐read genotyping methods, compilation of large data sets with allele‐level genotypes, and standardization of methods to verify eplets as determinants of immune‐mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes. [ABSTRACT FROM AUTHOR]

HLA donor‐specific antibodies developed de novo after transplant remain a major cause of chronic allograft dysfunction. Our study main purpose was to determine whether HLA MM, assessed traditionally and by HLA total and AbVer eplet mismatch load (EptMM and EpvMM) assessed with HLAMatchMaker, had impact on dnDSA development after living donor kidney transplantation (LDKT). We retrospectively analysed a cohort of 96 LDKT between 2008 and 2017 performed in Hospital Santo António. Seven patients developed dnDSA‐II and EpvMM and EptMM were greater in dnDSA‐II group compared to the no dnDSA‐II (18.0 ± 8.7 versus 9.9 ± 7.9, p =.041 and 41.3 ± 18.9 versus 23.1 ± 16.7, p =.018), which is not observed for AgMM (2.29 versus 1.56; p =.09). In a multivariate analysis, we found that preformed DSA (HR = 7.983; p =.023), living unrelated donors (HR = 8.052; p =.024) and retransplantation (HR = 14.393; p =.009) were predictors for dnDSA‐II (AUC = 0.801; 0.622–0.981). HLA‐II EpvMM (HR = 1.105; p =.028; AUC = 0.856) showed to be a superior predictor of dnDSA‐II, when compared to AgMM (HR = 1.740; p =.113; AUC = 0.783), when adjusted for these clinical variables. Graft survival was significantly lower within dnDSA‐II patient group (36% versus 88%, p <.001). HLA molecular mismatch analysis is extremely important to minimize risk for HLA‐II dnDSA development improving outcome and increasing chance of retransplant lowering allosensitization. [ABSTRACT FROM AUTHOR]

A theoretical framework is presented which explores two models of suppressor cell-target cell interactions in T-dependent antibody responses. The first is the full-dominance model, in which a single or limited number of suppressor cells can entirely suppress an immune response irrespective of the multiplicity of other effector cells present. The second is the ratio-dominance model, in which a suppressor cell is capable of inactivating only a certain number of target cells. Thus, the multiplicity of target cells in a given microculture well influences the degree of suppression. Both models are evaluated using limiting dilution analysis and two systems are explored, in the first model, suppressor cells alone are titrated into microculture wells containing all other cells required for an immune response. In the second, suppressor cells are added from populations containing a mixture of helper T cells as well as suppressor cells. This latter type of analysis is similar to that in which populations of T cells primed to alloantigens in mixed lymphocyte cultures are analysed for positive (help) and negative (suppression) allogeneic effects. The analysis allows us to conclude that such suppressor cells operate via a mechanism best described by a ratio-dominance model. [ABSTRACT FROM AUTHOR]

When 2,4-dinitrophenylated cells (DNP-E. coli) and lipopolysaccharides (DNP-LPS) of Escherichia coli were injected i.p. into guinea-pigs, they were capable of inducing sequential production of IgM and IgG2 anti-DNP antibodies, both of which were substantially thymus-independent, but only a trace of IgG1 anti-DNP antibody was produced. On the other hand, thymus-dependent DNP-bovine serum albumin (DNP-BSA) induced concomitantly both the IgG1 and IgG2 antibody responses in the presence of LPS. Therefore, the preferential IgG2 antibody response against DNP-LPS seems to be elicited with DNP-LPS itself and not by a combination of mitogenic stimulation with LPS and haptenic stimulation with other contaminating substances carrying DNP residues. Furthermore, it may not be related to affinity of the antibodies produced since there was no significant difference in the affinity for DNP residue between the IgG2 and IgG1 anti-DNP antibodies produced with DNP-E. coli and DNP-BSA, respectively. [ABSTRACT FROM AUTHOR]

Two methods are described for linking chlorambucil to antibodies. At low pH an association is formed which is not stable under physiological conditions and the cytotoxicity is the result of the independent action of chlorambucil and antibody. At pH 8 a more stable linkage is formed and this complex shows specific toxicity for cells carrying the appropriate antigen. Uncombined chlorambucil and antibody are more cytotoxic than chlorambucil alone, especially if the cells are exposed first to the chlorambucil. [ABSTRACT FROM AUTHOR]

Rabbits made immunologically unresponsive by neonatal administration of HSA, HGG or BSA were given a course of intravenous injections of the respective antigens, adsorbed on alum, after a lapse of 13-27 months since the last administration of antigen. 8/12 responded to HSA, 4/5 to HGG, 9/10 to BSA, as judged by immune elimination of antigen, but this was delayed in onset and slow compared with that in previously untreated rabbits. The antibody formed was small in quantity and usually failed to precipitate with antigen. The sedimentation coefficients of 131I-labelled antigens, in the presence of excess antibody, were measured by ultracentrifugation through a sucrose density gradient. These showed that only small complexes were formed in some of the non-precipitating antisera. In one instance the diffusion coefficient of the complex was also measured, by a technique based on diffusion through agar gel. The calculated molecular weight of the complex, 330,000 indicated the presence of only two combining sites on the antigen. Combination of the anti-HSA sera with an HSA fragment was also measured. Whereas the amount of the fragment bound by ordinary hyperimmune anti-HSA sera was about one-fifth the HSA bound, the amounts bound by the test sera were relatively much less. Some non-precipitating sera failed to bind the fragment, although they bound HSA. These findings indicate that following neonatally induced immunological unresponsiveness the capacity to respond to antigen returns piecemeal in respect of different parts of the antigenic mosaic, and that it may be severely restricted. The theoretical implications are discussed. [ABSTRACT FROM AUTHOR]

The immunological responses of rabbits to HSA, HGG or BSA were tested at various times later in animals which had received the corresponding antigens before or shortly after birth. As judged by the criterion of failure to show immune elimination of antigen, a high proportion of the rabbits remained unresponsive at times when it was calculated that all the originally administered antigen would have been eliminated from the circulation. Furthermore, removal of antigen by passively administered antibody failed to restore the capacity to respond. It is concluded that, in respect of the antigens used, their persistence in the extracellular body fluids is not a prerequisite for maintenance of immunological unresponsiveness.
Further administration of the same antigen to rabbits which had escaped from a state of specific immunological unresponsiveness generally produced a very weak response, and in a few instances resulted in a return to the unresponsive state.
When the cross-reacting antigens HSA and BSA were administered adsorbed on alum to rabbits made unresponsive by neonatal contact with BSA and HSA respectively, and at the same time a further dose of the original antigen was given, antibodies were formed which were specific for the second antigen and did not cross-react with the first. In only 1/9 animals was responsiveness to the first antigen restored. The significance of these results is discussed. [ABSTRACT FROM AUTHOR]

Cold agglutinins were separated from the sera of eleven patients suffering from the cold-antibody type of acquired haemolytic anaemia by the dissociation of the specific antigen-antibody complexes. The electrophoretic mobility of the cold antibody was found to correspond to that of γl globulin in each case. Ultracentrifugal studies carried out on eluted cold antibodies prepared from the sera of seven patients demonstrated that the antibodies were macromolecules (S20,w∼18.1). In one instance the sedimentation coefficient of the cold antibody was demonstrated to be similar to that of electrophoretically separated ‘γ1 globulin’ prepared from the same serum, indicating their identical physical state. The results of treating the sera of nineteen patients with the cold-antibody type of acquired haemolytic anaemia with mercapto-ethanol further confirmed that the cold antibodies were all macromolecules, whether derived from idiopathic cases or cases secondary to some other known disorder. [ABSTRACT FROM AUTHOR]

Cold antibodies were separated from the sera of six patients suffering from the cold-haemagglutinin syndrome and from one patient with acquired haemolytic anaemia secondayr to lymphosarcoma by dissociation of the specific antigen-antibody complexes. The eluted antibodies were studied (a) by immuno-electrophoresis along with the parent sera against horse anti-human serum and (b) by double diffusion in agar gel along with electrophoretically separated ‘γ1 globulin’† against anti-19S ‘γ-globulin’ rabbit sera. The protein forming the cold antibody was localized in the β2-M position on immuno-electrophoresis in each instance. It was found by double diffusion in agar gel to be immunologically identical with the protein forming the abnormal ‘γl-globulin’ electrophoretic peak in the parent serum. The results of these experiments indicate that the cold antibodies derived from patients with the cold-antibody type of acquired haemolytic anaemia are macro-molecular globulins. [ABSTRACT FROM AUTHOR]

A critical review is given of Goldberg's (1952, 1953) theory of Antigen-Antibody reactions in vitro. Goldberg's assumptions and the mathematical development of his theory are described in detail. Comparisons of Goldberg's predictions with experimental results are given in graphical form. Some criticisms are made of Goldberg's use of equations in regions in which the derivations given by him are not valid. [ABSTRACT FROM AUTHOR]

The effect of an horse anti-mouse thymocyte globulin (ALG) preparation on the primary and secondary immune responses to sheep erythrocytes (RBC) was studied in 2-3-month-old male A/HeJ, C57B1, BALB/c, DBA/1, CBA and C3H mice. A wide variation in the primary and secondary responses of the individual strains was noticed but in ail cases these were significantly suppressed by ALG pretreatment. The capacity of the ALG to suppress the primary immune response was not overcome by increasing the antigen dose from 3 × 107 to 3 × 109 sheep RBC. [ABSTRACT FROM AUTHOR]

Irradiated (NZB × BALB/c)F1 mice were injected with syngeneic bone marrow cells, syngeneic or parental thymus cells, and sheep red cells. The antibody plaque-forming cell response depended on the number of sheep cells and the age and strain of the thymus cells. Young or adult BALB/c thymus, and young hybrid thymus, responded best to low numbers of sheep cells; with higher numbers they became tolerant. Adult hybrid thymus, and young or adult NZB thymus, responded better to high numbers of sheep cells. Hybrid mice irradiated and restored with BALB/c bone marrow developed thymus cells with the reactivity of BALB/c thymus. It is argued that NZB mice, and older hybrids, may develop autoimmunity because of an abnormality of tolerance induction manifested in their thymus cells, but of bone marrow origin. [ABSTRACT FROM AUTHOR]

A complete evaluation of the immunogenicity of oligo-L-lysines and their mono-ε-DNP derivatives requires a determination of their capacity to prepare animals for secondary responses to a highly immunogenic analogue and to elicit secondary responses in animals prepared with such an analogue. It is shown here that 1-ε-DNP-tetra-L-lysine is not effective, or only marginally effective, in preparing PLL+ guinea-pigs for secondary anti-DNP responses to DNP-poly-L-lysine whereas 1-ε-DNP-nona-L-lysine is active in such preparation. Similarly, in animals primed to DNP-ovalbumin, supplemental immunization with tetra-L-lysine is not effective in preparing strain 2 guinea-pigs for a secondary anti-DNP response to DNP-poly-L-lysine whereas both nona-L-lysine and poly-L-lysine are effective, the latter to a considerably greater degree. In animals primed with DNP-poly-Llysine or with DNP-ovalbumin and poly-L-lysine, DNP-poly-L-lysine elicits secondary anti-DNP responses whereas neither 1-ε-DNP-nona-L-lysine or 1-εDNP-tetra-L-lysine do. The data indicate that a hierarchy in the degree of immunogenicity exists within the lysyl peptides series with poly-L-lysine more immunogenic than nona-L-lysine and this, in turn, more immunogenic than tetra-L-lysine which is either nonimmunogenic or marginally immunogenic. Further, the determination of immunogenicity is a feature either of the 'helper' cell population or of a step in the response which is prior to the activation of 'helper' cells. [ABSTRACT FROM AUTHOR]

The onset of the exponential expulsion of Nippostrongylus brasiliensis worms in the rat is associated with a sharp burst of intestinal mast cell activity and increased permeability of the bowel wall. It was found that the onset of maximum velocity of worm expulsion occurred earlier in female rats than in male rats and proceeded at a faster rate. There was a corresponding difference in the timing of the mast cell rise and macromolecular leak between the sexes. This suggested that there is a relationship between these events. Cortisone, a drug known to stop worm expulsion and to suppress the mast cell response, also prevented the macromolecular leak. Electron microscopy showed that during the period of increased permeability a pathway for protein tracers had opened up between the epithelial cells and it is suggested that this is the route for enhanced antibody transfer across mucous membranes. We suggest that a stimulus or stimuli from the parasite cause synchronous development of new populations of mast cells, IgE-producing plasma cells and plasma cells synthesizing antibodies of other classes possessing an anti-worm effect. It is also suggested that these mast cells discharge their pharmacological mediators by an allergen-reaginic antibody mediated system and that these mediators create a pathway through the intestinal mucosa for the translocation of antibody. [ABSTRACT FROM AUTHOR]

The enhancement effect of some antigens on in vitro colony formation by normal mouse bone marrow cells is mediated through a normal serum αmacroglobulin (αM) which is present in newborn animals and shows no immunological specificity. The proportion of antigen and αM affects colony enhancement, and it has also been shown that specific antibody successfully competes with αM for the antigen. It seems likely that antigen-αM complex acts directly on the colony forming cell, rather than indirectly through release of colony stimulating factor. The possible relevance of this phenomenon to immune induction and, to the effect of antigens in promoting irradiation survival is discussed. [ABSTRACT FROM AUTHOR]

The immunological response of the primitive mammal Tachyglossus aculeatus has been studied. We have shown that this animal responds to flagella from Salmonella adelaide with production of mercaptoethanol-resistant antibodies during both primary and secondary responses. Although an anamnestic secondary response could be demonstrated, it was of much smaller magnitude than that of phylogenetically higher placental mammals. Serological investigations demon- strated the presence of a mercaptoethanol-sensitive antibody of high molecular weight and an antibody of lower molecular weight which was mercaptoethanol resistant. These two antibodies seem to be analogous to IgM and IgG antibodies of higher mammals. [ABSTRACT FROM AUTHOR]

Background: Botulinum neurotoxin A (BoNT/A) has been used for cosmetic indications for many decades. Consumption of BoNT/A usage has been markedly increased for a few years. Even new formulations of BoNT/A to decrease immunogenicity have been released, repeated treatment to maintain efficacy outcome is inevitable and could finally provoke immune response. In the past, prevalence of botulinum treatment failure (BTF) in cosmetic indication was rare leading to less medical concern. Current decade, case reports on BTF, especially antibody‐induced botulinum toxin treatment failure (ABTF), have been increasingly revealed and risk factors associated with ABTF have been intensively studied. Aims: In this article, we will review antibody‐induced botulinum toxin treatment failure (ABTF), risk‐associated ABTF, prevalence and recent case reports of ABTF, and new approach to deal with ABTF. Methods: Literature search was conducted using PubMed. The relevant literatures published between January 2000 and May 2020 concerning BTF and ABTF including investigation for ABTF were included and analyzed. Results: Possible causes of BTF were summarized. ABTF could be a tip of iceberg of BTF, its prevalence, and currently, 10‐year case reports of ABTF were published evidence. Risk factors and investigation methods for ABTF were also summarized. Based on previous studies and our experience, novel approach to management of ABTF was described. Conclusion: Effective management of BTF is to explore causes of treatment failure. Antibodies against BoNT/A complex could be one of many possibilities. Laboratory in vitro tests could be alternative tools to decrease adverse effect and rebooting immune responses in BTF patients. [ABSTRACT FROM AUTHOR]

The detection and semiquantitative measurement of circulating human leucocyte antigen (HLA)‐specific antibodies is essential for the management of patients before and after transplantation. In addition, the pretransplant cross‐match to assess the reactivity of recipient HLA antibody against donor lymphocytes has long been the gold standard to prevent hyperacute rejection. Whilst both of these tests assume that recipient HLA‐specific antibody is the only variable in the assessment of transplant risk, this is not the case. Transplant immunologists recognize that some HLA antigens are expressed at levels a magnitude lower than others (e.g., HLA‐C, HLA‐DQ), but within loci, and between different cell types there are many factors that influence HLA expression in both resting and activated cells. HLA is not usually expressed without the specific promoter proteins NLRC5, for HLA class I, and CIITA, for class II. The quantity of HLA protein production is then affected by factors including promoter region polymorphisms, alternative exon splice sites, methylation and microRNA‐directed degradation. Different loci are influenced by multiple combinations of these control mechanisms making prediction of HLA regulation difficult, but an ability to measure the cellular expression of each HLA antigen, in conjunction with knowledge of circulating HLA‐specific antibody, would lead to a more informed algorithm to assess transplant risk. [ABSTRACT FROM AUTHOR]

Summary: It is unclear whether γδ T cells are involved in humoral immunity against Plasmodium infection. Here, we show that B‐cell‐immunodeficient mice and γδ T‐cell‐deficient mice were incapable of protecting against Plasmodium berghei XAT parasites. γδ T‐cell‐deficient mice developed reduced levels of antigen‐specific antibodies during the late phase of infection. The numbers of follicular helper T cells and germinal centre B cells in γδ T‐cell‐deficient mice were lower than in wild‐type mice during the late phase of infection. Expression profiling of humoral immunity‐related cytokines in γδ T cells showed that interleukin‐21 (IL‐21) and interferon‐γ (IFN‐γ) are increased during the early stage of infection. Furthermore, blockade of IL‐21 and IFN‐γ signalling during the early stage of infection led to reduction in follicular helper T cells and germinal centre B cells. γδ T‐cell production of IL‐21 and IFN‐γ is crucial for the development and maintenance of follicular helper T cells and germinal centre B cells during the late phase of infection. Our data suggest that γδ T cells modulate humoral immunity against Plasmodium infection. γδ T cells produce interleukin‐21 (IL‐21) and interferon‐γ (IFN‐γ) during the early phase of Plasmodium infection. The γδ T‐cell‐produced IL‐21 and IFN‐γ elicit the development/maintenance of follicular helper T cells and germinal centre B cells during the late phase of Plasmodium infection. [ABSTRACT FROM AUTHOR]

Background and Purpose: IL-19 skews the immune response towards a Th2 type and appears to stimulate angiogenesis. In the current study, we tested if IL-19 treatment could reduce secondary injury and improve functional recovery after contusion spinal cord injury (SCI).Experimental Approach: Firstly, mice were given a moderate-severe thoracic SCI at the T9-10 level and expression of IL-19 and its receptor was measured in the injured spinal cord. Then SCI mice were treated with mouse recombinant IL-19 and its blocking antibody to investigate the therapeutic effect of IL-19.Key Results: Protein expression of IL-19 and its receptor IL-20R1 and IL-20R2 was up-regulated in the injured spinal cord of mice. IL-19 treatment promoted the recovery of locomotor function dose-dependently and reduced loss of motor neurons and microglial and glial activation following SCI. Treatment of SCI mice with IL-19 attenuated macrophage accumulation, reduced protein levels of TNF-α and CCL2 and promoted Th2 response and M2 macrophage activation in the injured region. Treatment of SCI mice with IL-19 promoted angiogenesis through up-regulating VEGF in the injured region. Treatment of SCI mice with IL-19 up-regulated HO-1 expression and decreased oxidative stress in the injured region. The beneficial effect of IL-19 was abolished by coadministration of the blocking antibody. Additionally, IL-19 deficiency in mice delayed the recovery of locomotor function following SCI.Conclusions and Implications: IL-19 treatment reduced secondary injuries and improved locomotor functional recovery after contusion SCI, through diverse mechanisms including immune cell polarization, angiogenesis and anti-oxidative responses. [ABSTRACT FROM AUTHOR]

Beside its key diagnostic value, the humoral immune response is thought to play a protective role in hantavirus pulmonary syndrome. However, little is known about the cell source of these antibodies during ongoing human infection. Herein we characterized B-cell subsets circulating in Andes-virus-infected patients. A notable potent plasmablast ( PB) response that increased 100-fold over the baseline levels was observed around 1 week after the onset of symptoms. These PB present a CD3neg CD19low CD20neg CD38hi CD27hi CD138+/− IgA+/− surface phenotype together with the presence of cytoplasmic functional immunoglobulins. They are large lymphocytes (lymphoblasts) morphologically coincident with the 'immunoblast-like' cells that have been previously described during blood cytology examinations of hantavirus-infected patients. Immunoreactivity analysis of white blood cell lysates suggests that some circulating PB are virus-specific but we also observed a significant increase of reactivity against virus-unrelated antigens, which suggests a possible bystander effect by polyclonal B-cell activation. The presence of this large and transient PB response raises the question as to whether these cells might have a protective or pathological role during the ongoing hantavirus pulmonary syndrome and suggest their practical application as a diagnostic/prognostic biomarker. [ABSTRACT FROM AUTHOR]

Time-shift experiments provide measures of the mean fitness of a population in environments of different points in time. Here, we show how to use this type of data to decompose mean fitness into (1) the effect of the environment in which the population is transplanted, (2) the effect of the genetic composition of the population and (3) 'temporal adaptation', which measures how the population fits the environment at that time. We derive analytical results for the pattern of 'temporal adaptation' and show that it is in general maximal in the recent past. The link between 'temporal adaptation' and 'local adaptation' is discussed, and we show when patterns of adaptation in time and space are expected to be similar. Finally, we illustrate the potential use of this approach using a data set measuring the adaptation of HIV to the immune response of several recently infected patients. [ABSTRACT FROM AUTHOR]

The enzyme activation-induced deaminase (AID) deaminates deoxycytidine at the immunoglobulin genes, thereby initiating antibody affinity maturation and isotype class switching during immune responses. In contrast, off-target DNA damage caused by AID is oncogenic. Central to balancing immunity and cancer is AID regulation, including the mechanisms determining AID protein levels. We describe a specific functional interaction between AID and the Hsp40 DnaJa1, which provides insight into the function of both proteins. Although both major cytoplasmic type I Hsp40s, DnaJa1 and DnaJa2, are induced upon B-cell activation and interact with AID in vitro, only DnaJa1 overexpression increases AID levels and biological activity in cell lines. Conversely, DnaJa1, but not DnaJa2, depletion reduces AID levels, stability and isotype switching. In vivo, DnaJa1-deficient mice display compromised response to immunization, AID protein and isotype switching levels being reduced by half. Moreover, DnaJa1 farnesylation is required to maintain, and farnesyltransferase inhibition reduces, AID protein levels in B cells. Thus, DnaJa1 is a limiting factor that plays a non-redundant role in the functional stabilization of AID. [ABSTRACT FROM AUTHOR]

In aging, immune responses are dramatically impaired, specifically the ability to produce protective antibodies. We previously showed that with age there is a B-cell intrinsic decrease in class switch recombination (CSR) because of a decrease in activation-induced cytidine deaminase (AID). One mechanism we have demonstrated for decreased AID includes increased mRNA degradation of the transcription factor E47, critical for AID transcription. Here, we show by means of a retroviral construct containing the DsRED reporter and the 3′UTR of E47 that the 3′UTR lowers mRNA expression, and particularly in B cells from old mice. This is the first demonstration that the E47 3′UTR directly regulates its degradation. The AID mRNA was not differentially regulated by degradation in aging. Therefore, we have here further established critical components for decreased AID with age. The major aim of this study was to establish conditions for the rescue of the intrinsic defect of aged B cells with retroviral addition of the coding region of E47 in splenic B cells to restore their ability to produce optimal AID and class switch to IgG. In this study, we show that young and old primary B cells overexpressing a stable E47 mRNA up-regulate E47, AID, and CSR and improve B-cell immune responses in senescent murine B cells. Our results provide a proof of principle for the rescue of intrinsic B-cell defects and the humoral immune response in senescence. [ABSTRACT FROM AUTHOR]

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Natural killer (NK) cells are key components of the innate anti-viral and anti-tumour immune responses. NK cell function is regulated by the interaction of killer cell immunoglobulin-like receptors (KIR) with human leucocyte antigen (HLA) class I molecules. In this study, we report on the generation of KIR-specific antibodies allowing for discrimination between activating and inhibitory KIR. For this purpose, BALB/c mice were immunized with human KIR2DS2 recombinant protein. The precise specificity of KIR2DS2-specific clones was determined on KIR-transfected BW cells and KIR-genotyped NK cells. When used in combination with EB6 (KIR2DL1/2DS1) or GL183 (KIR2DL2/2DL3/2DS2), two KIR-specific monoclonal antibodies (mAbs), 8C11 (specific for KIR2DL1/2DL2/2DL3/2DS2) and 1F12 (specific for KIR2DL3/2DS2), discriminated activating KIR2DS1 (8C11− EB6+) from inhibitory KIR2DL1 (8C11+ GL183−) and KIR2DL2 (1F12− GL183+), while excluding the main HLA-Cw-specific KIR. Using these mAbs, KIR2DS1 was shown to be expressed on the surface of NK cells from all individuals genotyped as KIR2DS1+ ( n = 23). Moreover, KIR2DS1 and KIR2DL1 were independently expressed on NK cells. We also determined the amino acid position recognized by the 8C11 and 1F12 mAbs, which revealed that some KIR2DL1 allele-encoded proteins are not recognized by 8C11. Because most available anti-KIR mAbs recognize both inhibitory and activating forms of KIR, these newly characterized antibodies should help assess the expression of activating and inhibitory KIR and their functional relevance to NK biology. [ABSTRACT FROM AUTHOR]

Receptors for the Fc region of immunoglobulin G (FcγRs) are expressed on a broad range of haematopoietic cell types and are responsible for regulating antibody production and linking the humoral and effector responses. In response to a number of stimuli, such as cytokine signals or inflammation, FcγR expression at the cell surface is dynamically regulated. On B cells, we observed what appeared to be a correlation between CD22 expression and FcγRIIb expression when the latter was varied in a number of models. Further investigation revealed that this was specific to a particular anti-CD22 monoclonal antibody, which appeared to require stabilization by interaction with FcγRIIb for optimal binding to CD22. Since alterations in the regulation of FcγR expression are important in controlling immune responses and have been associated with a number of immune-mediated disease states, we suggest that it might be prudent to confirm the expression of cell surface markers by two independent methods. Furthermore, because the efficacy of therapeutic antibodies may depend upon their interaction with FcγRs, our results are relevant to their design and assessment. [ABSTRACT FROM AUTHOR]

Background For protection against (re-)infection by influenza virus not only the magnitude of the immune response but also its quality in terms of antibody subclass and T helper profile is important. Information about the type of immune response elicited by vaccination is therefore urgently needed. Objectives The aim of the study was to evaluate in detail the immune response elicited by three current influenza vaccine formulations and to shed light on vaccine characteristics which determine this response. Methods Mice were immunized with whole inactivated virus (WIV), virosomes (VS) or subunit vaccine (SU). Following subsequent infection with live virus, serum antibody titers and Th cell responses were measured. The effects of the vaccines on cytokine production by conventional and plasmacytoid dendritic cells were investigated in vitro. Results and conclusions In Balb/c mice (Th2 prone) as well as in C57Bl/6 mice (Th1 prone), WIV induced consistently higher hemagglutination-inhibition titers and virus-neutralizing antibody titers than VS or SU. In contrast to VS and SU, WIV stimulated the production of the antibody subclasses IgG2a (Balb/c) and IgG2c (C57BL/6), considered to be particularly important for viral clearance, and activation of IFN-γ-producing T cells. Similar to live virus, WIV stimulated the production of proinflammatory cytokines by conventional dendritic cells and IFN-α by plasmacytoid cells, while VS and SU had little effect on cytokine synthesis by either cell type. We conclude that vaccination with WIV in contrast to VS or SU results in the desired Th1 response presumably by induction of type I interferon and other proinflammatory cytokines. [ABSTRACT FROM AUTHOR]

Synthetic anti-idiotypic antibodies represent a potentially valuable tool for the isolation and characterization of B cells that produce xenoantibodies. An anti-idiotypic antibody that binds to a subset of B cells producing antibodies encoded by the variable-region heavy chain 3 (VH3) germline genes DP35 [immunoglobulin variable-region heavy chain 3-11 (IGHV3-11)], DP-53 and DP-54 plus a small number of VH4 gene-encoded antibodies in humans has recently been identified. These germline progenitors also encode xenoantibodies in humans. We tested whether the small, clearly defined group of B cells identified with this anti-idiotypic antibody produce xenoantibodies in non-human primates mounting active immune responses to porcine xenografts. Peripheral blood B cells were sorted by flow cytometry on the basis of phenotype, and cDNA libraries were prepared from each of these sorted groups of cells. Immunoglobulin VH gene libraries were prepared from the sorted cells, and the VH genes expressed in each of the sorted groups were identified by nucleic acid sequencing. Our results indicate that xenoantibody-producing peripheral blood B cells, defined on the basis of binding to fluorescein isothiocyanate (FITC)-conjugated galactose α(1,3) galactose–bovine serum albumin (Gal-BSA) and the anti-idiotypic antibody 2G10, used the IGHV3-11 germline gene to encode xenoantibodies and were phenotypically CD11b+ (Mac-1+) and CD5–. This novel reagent may be used in numerous applications including definition of xenoantibody-producing B-cell subsets in humans and non-human primates and immunosuppression by depletion of B cells producing anti-Gal xenoantibodies. [ABSTRACT FROM AUTHOR]

The history of regulatory T cells goes back to the realisation that T cells could provide ‘help’ for antibody responses: the obverse of this is their ability to hold them in check. This brief personal overview follows the initial designation of T cells as ‘suppressor’ and the various hypotheses, some now disproved, put forward for their mechanism of action. We now cautiously label them T regulatory cells, but realise they do not control not all immune regulation. They probably operate through several mechanisms, and some of these are discussed. [ABSTRACT FROM AUTHOR]

CD4+ CD25+ T regulatory cells (Tregs) are classified as a subset of T cells whose role is the suppression and regulation of immune responses to self and non-self. Since their discovery in the early 1970s, the role of CD4+ CD25+ Tregs in both autoimmune and infectious disease has continued to expand. This review examines the recent advances on the role CD4+ CD25+ Tregs may be playing in various diseases regarding progression or protection. In addition, advances made in the purification and manipulation of CD4+ CD25+ Tregs using new cell markers, techniques and antibodies are discussed. Ultimately, an overall understanding of the exact mechanism which CD4+ CD25+ Tregs implement during disease progression will enhance our ability to manipulate CD4+ CD25+ Tregs in a clinically beneficial manner. [ABSTRACT FROM AUTHOR]

Deficiencies in immune responses against polysaccharides can have direct consequences for patients, and therefore, a better undestanding of these immune reactions is crucial We have studied the immune response against the polysaccharide dextran B512 (Dx). Administration of immunogenic doses of thymus-independent (TI) Dx reduces the immunoglobulin G1 response to later challenges with a thymus-dependent (TD) form of Dx. We investigated if this suppression is a general phenomenon caused not only by Dx but also by other TI antigens, and examined possible mechanisms contributing to this unresponsiveness. We show that clonal exhaustion is not involved in modulating subsequent responses, nor is signalling via FcγRIIB or other antibody mediated pathways. The reduced TD response is not an exclusive Dx phenomenon; it is also induced by TI antigen oxazolone (Ox). However, responses against the hapten dinitrophenyl (DNP) are not affected, indicating that the TI priming negative effect is not a general process. This may be explained by the restricted immune response to both Dx and Ox, in contrast to the unrestricted DNP response. Our conclusion from these experiments is that the underlying mechanism for the TI-induced reduction of latter TD responses is a property of the TI activation itself. [ABSTRACT FROM AUTHOR]