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The article presents a list of forthcoming papers on immunology. Some of the papers include Cross-Linking of Neutrophil CD11b Results in Rapid Cell Surface Expression of Molecules Required for Antigen Presentation and T-Cell Activation," "Various Members of the Toll-Like Receptor Family Contribute to the Innate Immune Response of Human Epidermal Keratinocytes," "Identification and Characterisation of a Functional, Alternatively Spliced TLR7 and Genomic Disruption of TLR8 in Chickens," and "Introduction of Human Papillomavirus Type 16-Specific Immunologic Responses in a Normal and an HPV Infected Populations."

The article lists several papers related to immune system that are to be published in the December 2004 issue of the journal "Immunology." Some of the papers are "Phenotypic and Functional Heterogeneity of Porcine Blood Monocytes and Its Relation With Maturation," by Sonia Chamorro, Concepcion Revilla, Belen Alvarez, Fernando Alonso, Angel Ezquerra, Javier Dominguez; "Influence of Pathological Progression on the Balance Between Cellular and Humoral Immune Responses in Bovine Tuberculosis," Michael Welsh, Rodat Cunningham, David Corbett, R. Martyn Girvin, James McNair, Robin Skuce, David Bryson, John Pollock.

Myeloid-derived suppressor cells (MDSC) are important to the tumour microenvironment as they actively suppress the immune system and promote tumour progression and metastasis. These cells block T-cell activation in the tumour microenvironment, preventing anti-tumour immune activity. The ability of a treatment to alter the suppressive function of these cells and promote an immune response is essential to enhancing overall therapeutic efficacy. Interleukin-12 (IL-12) has the potential not only to promote anti-tumour immune responses but also to block the activity of cells capable of immune suppression. This paper identifies a novel role for IL-12 as a modulator of MDSC activity, with implications for IL-12 as a therapeutic agent. Treatment with IL-12 was found to alter the suppressive function of MDSC by fundamentally altering the cells. Interleukin-12-treated MDSC exhibited up-regulation of surface markers indicative of mature cells as well as decreases in nitric oxide synthase and interferon-γ mRNA both in vitro and in vivo. Treatment with IL-12 was also found to have significant therapeutic benefit by decreasing the percentage of MDSC in the tumour microenvironment and increasing the percentage of active CD8 T cells. Treatment with IL-12 resulted in an increase in overall survival accompanied by a reduction in metastasis. The findings in this paper identify IL-12 as a modulator of immune suppression with significant potential as a therapeutic agent for metastatic breast cancer. [ABSTRACT FROM AUTHOR]

Our earlier observations indicate that adoptive transfer of spleen cells obtained from dengue type 2 virus (DV)-primed mice suppressed DV antigen-specific antibody secretion as detected by Jerne PFC technique. Findings of this paper indicate that the suppression was produced by non-glass-adherent cells, macrophage-depleted (by carbonyl iron) cells and by T lymphocytes of the spleen but not by the glass-adherent cells and B lymphocytes. The activity of these cells is dependent upon production of prostaglandin as shown by abrogation of their suppressor activity by pre-treatment of cells by indomethacin or aspirin which are known to block synthesis of prostaglandins. [ABSTRACT FROM AUTHOR]

The method described in the previous paper was used to induce secondary responses in spleen cells from CBA/H mice, pre-primed with lymphocytic choriomeningitis (LCM) virus by culturing them with LCM-infected peritoneal cells. The cytolytic effector cells thus generated have been characterized. Effector cells were sensitive to treatment with anti-θ ascitic fluid and complement. Separation procedures based on rosetting of certain categories of lymphocytes with sheep red cells through an isopaque-Ficoll gradient indicated that effector cells lacked surface immunoglobulin and generally did not bear Fc receptors. Cytolytic activity was restricted by the H-2 gene complex. Killing had single-hit characteristics. All these results suggested that the cells from memory cultures mediating cytolysis were T cells. There was evidence for two T cell subsets, a major subpopulation directed against antigens on infected targets and a minor one directed against antigens on uninfected, H-2-compatible targets. Specificity was present at the infected cell: memory responder and killer:target levels between LCM virus (an arenavirus) and ectromelia virus (a poxvirus). [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]

In the previous paper we showed that the immune response to sheep red cells (SRBC) was degenerate; serum antibodies showed increasing loss of specificity, signalled by cross-reactions with horse RBC (HRBC), with time after immunization and with hyperimmunization. In the present report we have analysed the role T cells may play in this process. To do this we studied the antibodies made by mice deprived of T cells by irradiation as well as those made by normal mice immunized with SRBC in distilled water, which was shown to depress the DNA synthetic response of T cells. In both instances the mice with fewer responding T cells made less antibody which could agglutinate HRBC than did the appropriate controls. This was true even when no difference in anti-SRBC titre was apparent. In addition we showed that the antibody made by mice with reduced numbers of T cells was less effective at passive suppression of the immune response to SRBC than was similarly titred (against SRBC) antibody made by normal mice. Thus, certain sub-populations of antibodies, normally made in response to SRBC, immunization, are particularly thymus dependent. We have discussed why we think they are those of particularly high affinity. [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]

In a companion article to this study,1 the successful programming of a JAWSII dendritic cell ( DC) line's antigen uptake and processing was demonstrated based on pre-treatment of DCs with a specific 'cocktail' of select chemokines. Chemokine pre-treatment modulated cytokine production before and after DC maturation [by lipopolysaccharide (LPS)]. After DC maturation, it induced an antigen uptake and processing capacity at levels 36% and 82% higher than in immature DCs, respectively. Such programming proffers a potential new approach to enhance vaccine efficiency. Unfortunately, simply enhancing antigen uptake does not guarantee the desired activation and proliferation of lymphocytes, e.g. CD4+ T cells. In this study, phenotype changes and antigen presentation capacity of chemokine pre-treated murine bone marrow-derived DCs were examined in long-term co-culture with antigen-specific CD4+ T cells to quantify how chemokine pre-treatment may impact the adaptive immune response. When a model antigen, ovalbumin ( OVA), was added after intentional LPS maturation of chemokine-treated DCs, OVA-biased CD4+ T-cell proliferation was initiated from ~ 100% more undivided naive T cells as compared to DCs treated only with LPS. Secretion of the cytokines interferon-γ, interleukin-1β, interleukin-2 and interleukin-10 in the CD4+ T cell : DC co-culture (with or without chemokine pre-treatment) were essentially the same. Chemokine programming of DCs with a 7 : 3 ratio of CCL3 : CCL19 followed by LPS treatment maintained partial immature phenotypes of DCs, as indicated by surface marker ( CD80 and CD86) expression over time. Results here and in our companion paper suggest that chemokine programming of DCs may provide a novel immunotherapy strategy to obviate the natural endocytosis limit of DC antigen uptake, thus potentially increasing DC-based vaccine efficiency. [ABSTRACT FROM AUTHOR]

Natural killer ( NK) cells provide an immediate first line of defence against viral infections. Memory responses, maintained by CD4+ T cells, require exposure to viral antigen and provide long-term protection against future infections. It is known that NK cells can promote the development of the adaptive response through cytokine production and cross-talk with antigen-presenting cells. In this paper however, we summarize a series of recent publications, in mouse models and for the first time in man, with the unifying message that rapid viral antigen control by the innate immune system limits antigen exposure to CD4+ cells thereby abrogating the development of a memory response. We discuss the significant implication of these studies on viral treatment strategies and immunization models. [ABSTRACT FROM AUTHOR]

Summary: The cre‐loxP system has been revolutionary in the field of immunology. The technology enables genetic deletion in mice with unprecedented precision. It is therefore now widely used to investigate gene functions in animal models of disease, and in fundamental studies of the immune response. This widespread adoption of cre‐loxP technology has allowed a thorough investigation of its strengths and weaknesses. Here we highlight an important paper which not only describes potential problems with the commonly‐used screening procedures used when identifying offspring of the correct genotype, but also describes how this screening can be improved to ensure that the right animals are produced. [ABSTRACT FROM AUTHOR]

A DNA vaccine based on the heat-shock protein 65 Mycobacterium leprae gene (pHSP65) presented a prophylactic and therapeutic effect in an experimental model of tuberculosis. In this paper, we addressed the question of which protective mechanisms are activated in Mycobacterium tuberculosis-infected mice after immune therapy with pHSP65. We evaluated activation of the cellular immune response in the lungs of infected mice 30 days after infection (initiation of immune therapy) and in those of uninfected mice. After 70 days (end of immune therapy), the immune responses of infected untreated mice, infected pHSP65-treated mice and infected pCDNA3-treated mice were also evaluated. Our results show that the most significant effect of pHSP65 was the stimulation of CD8+ lung cell activation, interferon-γ recovery and reduction of lung injury. There was also partial restoration of the production of tumour necrosis factor-α. Treatment with pcDNA3 vector also induced an immune stimulatory effect. However, only infected pHSP65-treated mice were able to produce significant levels of interferon-γ and to restrict the growth of bacilli. [ABSTRACT FROM AUTHOR]

Discusses the 'Immunology' paper by Smith et al. and its contribution to understanding at which point in the immune response to antigen the critical decision making between an active versus a tolerogenic response may take place. Induction of oral tolerance initially to provoke the activation of T cells; Possible role of the antigen-presenting cells present in the intestine in determining the T-cell response to antigen.

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]

We demonstrated the efficacy of a long- term cultured cytotoxic T-lymphocyte line, CTLL-D4, on tumour growth inhibition using athymic nude mice as recipients. CTLL-D4, specific for a unique surface determinant on a radiation-induced leukaemia RL♂1 of BALB/c origin, was obtained from the limiting dilution culture of MLTC cells performed between spleen cells of a CS6F1-nu/ + mouse immunized in vivo and RL♂1 stimulator cells, and cultured for several months in the absence of added TCGF as described in our preceding paper (Kuribayashi, 1985). The specific inhibition of tumour growth by CTLL-D4 was demonstrated both in Winn-type neutralization assay and in systemic transfer experiments. A subcutaneous inoculation of the mixture of CTLL-D4 and RL♂1 cells resulted in the complete inhibition of tumour growth, even at the effector to tumour cell ratio of 1 : 1, whereas non-cytolytic D4f, which was self-Ia antigen(s)-reactive, composed entirely of Lyt-l + 23- T cells and derived originally from CTLL-D4 but completely lost its cytotoxic activity during culture with the irradiated syngeneic feeder cells alone, had no inhibitory effect at all. In the adoptive transfer studies, the subcutaneously established tumours were rejected by the single i.v. transfer of 2 × 107 CTLL-D4 cells into CB6F1-nu/nu mice. However, D4f was ineffective again in this systemic transfer system. When the effect of CTLL-D4 cells on tumour rejection in vivo was compared to that of non-cultured spleen cells hyperimmunized with RL♂1 cells, the former exhibited more rapid rejection in nude mice after i.v. transfer than the latter did, suggesting that CTLL-D4 cells also attack the tumour cells much more effectively as effectors in vivo. Thus, it is conceivable that CTLs are mainly involved in tumour rejection in this adoptive transfer system using RL♂ 1 tumour cells and athymic nude mice. [ABSTRACT FROM AUTHOR]

CBA/N mice harbour an X-linked B cell defect which is transmitted by CBA/N female mice to their hybrid male progeny. These mice mount normal responses to thymus-dependent (TD) and some thymus-independent (TI-1) antigens, while the response to TI-2 antigens is absent. Hapten-specific plaque-forming cell (PFC) responses to TD antigens can be blockaded by concomitant exposure of these mice to TI-2 antigens bearing the same hapten. This paper investigates in defective mice the blockade of their response to TNP3-LPS (trinitrophenylated lipopolysaccharide, a TI-1 antigen), imposed by DNP59-Ficoll (dinitrophenylated Ficoll, a TI-2 antigen). The effectiveness of the blocking agent, DNP59-Ficoll, differed in various inbred mouse strains: CBA/N × C3H/HeN F1 male > CBA/N female > CBA/N · C3H/HeN F1 female. The role of T cells in the observed hapten-specific blockade phenomenon was investigated using athymic CBA/N nude mice and a B cell tolerogen. Our findings indicate that T cell participation is not essential for the blockade of CBA/N PFC responses and they suggest that direct blockade of TI- and TD-responsive B cell populations is likely to occur. [ABSTRACT FROM AUTHOR]

A series of immunoassays have recently been elaborated in which the red cell is used as a label or marker of interacting antibody, often antiimmunoglobulin (anti-Ig). This paper considers and investigates quantifiably, the different variables which affect the sensitivity of direct and indirect antiglobulin rosetting reactions (DARR and IARR) and of reverse passive haemagglutination (RPH). Sensitivity is governed by the surface properties and amount of antibody on the indicator red cell and, in detection of cell-bound antigen, by the antigen density. By varying the antibody:Ig ratio on the red cell using affinity purified anti-Ig, cells with more than 1:32-64 antibody: Ig showed similar sensitivity in detection of lymphocyte sIg in DARR and IARR tests and of serum Ig by RPH. Using these indicator cells coupled with different Ab: Ig ratios to detect lymphocytes sensitized with different levels of anti-Ig in a model IARR test, it was clear that studying cells with a high density of determinants on the lymphocyte surface it is not necessary to have 'strong' antiimmunoglobulin on the indicator cell, but increasingly sparse determinants require increasingly strong anti-Ig on the red cell to detect all positively reacting cells. Red cells of different species afford carriers of varying sensitivity in all three reactions—DARR, IARR and RPH. Preliminary trypsin treatment may greatly further enhance the sensitivity of some species red blood cells (e.g. bovine and sheep), but leaves others (e.g. pig and donkey) unchanged. Use of 125I-labelled Ig and anti-Ig showed that the increased sensitivity of trypsinized bovine and sheep RBC is not due to increased uptake of Ig during chromic chloride linkage or of antibody in agglutinations. [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]

This paper describes the induction of delayed-type hypersensitivity (DH) in the mouse and guinea-pig to haptenated liposomes. The tripeptide- enlarged hapten 3-(p-azobenzenearsonate)-N-acetyl- L-tyrosylglycylglycine (A) was coupled to phosphatidylethanolamine (PE) and incorporated into liposomal membranes (A PE-liposomes). In mice DH was measured as footpad swelling and in guinea pigs by skin testing. To induce hapten A-specific DH in mice with A-PE- liposomes the application of the cationic, surface- active lipid, dimethyl dioctadecyl ammonium bromide (DDA) was necessary. The use of Freund's complete adjuvant (FCA) did not result in the induction of DH to hapten A. In guinea-pigs, however, FCA and DDA had equally good adjuvant properties in the induction of DH. The time course of the DH and the optimal time interval between immunization and elicitation were determined for the mouse system. Also, the effect of dose and epitope density was studied in that system. Cyclophosphamide treatment, before immunizing mice with A-PE-liposomes and DDA, resulted in greatly impaired DH, probably caused by the short lifetime of the integrity of liposomes after intracutaneous administration to mice. The results make it very likely that presentation of hapten A in a liposomal or micellar structure is required to induce a cellular immune response to this hapten in mice. [ABSTRACT FROM AUTHOR]

Bovine peripheral blood monocytes were isolated from bully coats of ACD-anticoagulated whole blood. Cells cultivated on plastic surfaces for 20 h were judged to be 95% thonocytes based on non- specificesterase-l staining, uptakeoflatexparticlesand surface receptor characteristics. Bovine monocytes were maintained up to 80 days in vitro in Dulbecco's modified Eagle medium with 15% horse serum and 15% foetal bovine serum. Several morphological and physiological features of bovine monocytes were examined during the course of culture. Cell size and cytoplasmic spreading, granulation and vacuolization increased progressively. Multinucleated giant cells pre- dominated during the latter stages of in vitro culture A high percentage of bovine monocytes possessed C3 and IgU Fc receptors, whereas 1gM Fc and sheep erythrocyte receptors were not detected. Phagocytosis was mediated by the IgG receptor, but not by the C3 receptor. Peroxidase activity declined in a linear fashion, with cells essentially negative after 8 days of culture. Total cell protein and acid phosphatase increased during cultivation. Lysozyme activity was undetectable in both lysates and supernatants of bovine monocyte. These findings are consistent with the concept of maturation of mononuclear phagocytes. The procedures for isolation and cultivation described in this paper will provide methodology for detailed study of bovine mononuclear phagocytes. [ABSTRACT FROM AUTHOR]

This paper describes a rather simple coupling method for tripeptide enlarged haptens to phosphatidylethanolamine (PE) and the incorporation of these conjugates into liposomal model membranes (haptenated liposomes). These haptenated liposomes evoke a hapten-specific humoral immune response in mice. The magnitude of the response as measured by the appearance of direct plaque forming cells in the spleen is dependent on the route of immunization and the dose and epitope density of the hapten-PE derivatives. It was not possible to evoke an IgG response after either primary or secondary immunization with haptenated liposomes (as measured by the production of indirect plaques or mercaptoethanol-resistant antibody). These data, in addition to the observations that mice depleted of, or deficient in thymus-derived (T) lymphocytes respond to haptenated liposomes, indicate that these haptenated liposomes are T-cell independent antigens. [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]

The experiments described in this paper extend the observations of previous work in vitro demonstrating a decrease in the frequency of antigenreactive units specific for horse RBC in spleen cells from mice primed with KLH. It was observed that the addition of lymphoid cells having T-cell function reconstituted the anti-HRBC response to normal values. Significant enhancement of the response beyond the normal values could be evoked using two dissimilar methods, (i) addition of allogeneic thymus cells, and (ii) restimulation in vitro with the priming antigen. The latter type enhancement was elicited by the addition of small doses of KLH to cultures of spleen cells from mice recently primed with KLH, including cultures otherwise demonstrating antigen-induced suppression. The stimulus required to enhance the response to HRBC in these cultures was specific for the priming antigen, KLH. These results are discussed in the light of current theories of 'antigenic competition' and specific heterologous enhancement. [ABSTRACT FROM AUTHOR]

We have previously reported an experimental autoimmune model induced by the local infection of Listeria monocytogenes. The unilateral inoculation of virulent Listeria into a testis of a normal mouse induced a delayed-type hypersensitivity response against testicular antigen and caused autoimmune orchitis in the contralateral testis. The orchitis was transferred to naive mice by T cells from the intratesticularly infected mice. In this paper, we demonstrated that avirulent Listeria, which lacks the expression of listeriolysin O, failed to induce any anti-testicular responses or contralateral orchitis even when it was inoculated at a high dose into the testis. Furthermore, the intraperitoneal inoculation of virulent Listeria with testicular antigen induced the antitesticular responses and orchitis although intraperitoneal inoculation of testicular antigen with avitulent Listeria failed to induce them. The difference between virulent and avirulent Listeria in the induction of anti-testicular responses was supposed to be dependent on the difference in macrophage activation by the two bacterial strains because, first, the anti-testicular responses were elicited in normal mice when macrophages from virulent Listeria-infected mice were intraperitoneally transferred with testicular antigen although no viable bacteria were detected from the macrophages, and secondly, in contrast, the intraperitoneal co-inoculation of macrophages from avirulent Listeria-infected mice and testicular antigen failed to elicit any antitesticular responses. Finally, we found that the virulent Listeria-induced macrophages expressed a higher level of CD80 (BT-1) and CD86 (B7-2) molecules than did the avirulent Listeria-induced macrophages and naive peritoneal macrophages. These results thus suggest that virulent Listeria activates macrophages to induce autoreactive T cells while avirulent Listeria does not. The up-regulation of B7 molecules by virulent Listeria infection is a candidate of the mechanism for the activation of autoreactive T cells. [ABSTRACT FROM AUTHOR]

Invariant chain (Ii) plays an important role in major histocompatibility complex (MHC) class II antigen processing and presentation and is constitutively synthesized in B lymphocytes, in macrophages, dendritic cells and in some epithelial cells. It has been shown that interferon-γ, tumour necrosis factor-α and interleukin-4 co-regulate Ii and MHC class II expression in various cell types. We describe here a novel regulation of Ii expression in macrophages. Treatment of the premature monocytic cell lines WEHI 265.1, M1 and WEHI-3B with recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) strongly enhances Ii expression while class II expression is not induced. In contrast, GM-CSF did not enhance Ii in mature macrophage cell lines. The increase of Ii expression m WEHI 265.1 cella takes several days. This long induction time, and a difference in activity between GM-CSF-conditioned medium and GM-CSF, together suggest that GM-CSF stimulates WEHI 265.1 cells to secrete a factor that modulates Ii expression. These results may imply a class II-independent function of Ii, which we discuss in this paper. [ABSTRACT FROM AUTHOR]

The serum glycoprotein α2-macroglobulin can be converted into a potent macrophage-activating factor that promotes the Fcγ receptor-mediated phagocytosis of macrophages, through modification of the sugar moiety with liposome-treated B-cell glycosidase(s). This paper discusses the activation mechanism of B-cell membranous glycosidase by liposomes using mouse splenic B cells. B-cell membranous β-galactosidase and βN-acetylglucosaminidase were significantly activated by liposome treatment, and this process can be regulated by trypsin-sensitive protein. To clarify the contribution of trypsin-sensitive protein to enzyme activities, the B-cell surface antigen receptor was studied. With the addition of a Fab′ fragment of anti-mouse IgM but not IgD antibody, the activation of both glycosidases induced by liposomes was significantly inhibited and was essentially the same as that of saline-treated glycosidase activities. Consequently, interactions of liposomes with cell-surface IgM may cause B-cell membranous glycosidase activation. A significant decrease in membrane fluidity, particularly near the membrane surface rather than deep within the membrane, was observed in liposome-treated B cells using electron spin resonance. Liposomes would thus appear to interact with B cells via cell-surface IgM, with a consequent decrease in membrane fluidity, as well as the activation of B-cell membranous glycosidases, causing α2-macroglobulin to be converted into a macrophage activating factor. [ABSTRACT FROM AUTHOR]

This paper investigates major histocompatibility complex (MHC) regulation of the class of the immune response given in vitro and in vivo following immunization of the congenic BALB/k (H-2k) and BALB/c (H-2d) mice with the hapten trinitrophenyl (TNP). TNP-immune lymph node cells from BALB/k mice produced high levels of interferon-γ (IFN-γ), interleukin-5 (IL-5) and IL-2 when stimulated with TNP-antigen-presenting cells (APC) in vitro, while TNP-immune lymph node cells from BALB/c mice produced very low levels of these cytokines. No significant difference was found in antigen-specific production of IL-3, IL-4 and tumour necrosis factor-α (TNF-α). There was a strong correlation between the pattern of cytokine production in vitro and the secondary antibody production in vivo. Sera from BALB/k mice had anti-TNP IgG2a, IgG2b and IgG3 levels threefold greater, and anti-TNP IgA levels eightfold greater, than BALB/c mice. The level of specific IgG1 and IgE was only marginally raised in BALB/k mice. In contrast to these strain differences in cytokine and antibody production, there was no difference in two measures of cellular immunity: contact sensitivity in vivo and antigen-specific lymphocyte response in vitro. Our results suggest that there is a good correlation between the production of cytokines in vitro and antibody response in vivo, but not with measures of cellular immunity. Moreover, this MHC control of the class of the immune response to TNP does not fit into the T-helper type-1 (Th1)-Th2 paradigm. [ABSTRACT FROM AUTHOR]

Nerve growth factor (NGF) was originally considered as a trophic factor for peripheral sympathetic and sensory neurones; however, recent reports indicate that NGF may induce proliferation of immune and hacmatopoietic cells. Histochemical studies conducted in human spleen and lymph nodes have suggested the presence of NGF receptor (NGF-R) immunoreactive elements in secondary follicles; however the nature. of the cells bearing the NGF-R in lymphoid tissue has not been determined. In this paper we report the results of an immunohistochemical study conducted on mucosa associated lymphoid tissue. Using a specific monoclonal antibody to human NGF-R (mAb 20.4) we observed an NGF-R-immunoreactive population in all secondary lymphoid follicles examined. Double immunostaining revealed that this population was composed of follicular dendritic cells (FDC); lymphoid cells within the germinal centres did not appear to be 204 immunoreactive. Cell suspensions from tonsillar follicles also contained NGF-R immunopositive dendritic cells which were enriched by a 20.4 labelled magnetic bead procedure, revealing cells with the morphological characteristics of FDC. Mononuclear cells from human peripheral blood did not contain any NGF-R-immunoreactive elements using our techniques. [ABSTRACT FROM AUTHOR]

Evidence from in vitro studies indicates that immunoglobulin A (IgA) responses are highly T dependent, yet investigations of the requirement for cognate help For IgA responses in tiro have not previously been undertaken. Experiments reported in this paper employ hapten-carrier immunization of individual Peyer's patches (PP), the site of generation of IgA antibody-containing cells (ACC) responding to lumenal antigenic challenge in the intestine, to determine the requirements for T-cell and B-cell priming under normal physiological conditions in vivo. These experiments demonstrate that both hapten-specific B-cell priming and carrier-specific T-cell priming in PP are required for an IgA-specific anti-hapten ACC response in the intestinal lamina propria to subsequent lumenal challenge with hapten-carrier conjugate. These results confirm that IgA B-cell induction in PP requires cognate T-cell help. An IgA ACC response can also be obtained when hapten and carrier priming occur in different PP, providing functional significance for our previous observations that PP-derived T-helper cells are able to migrate between PP after priming. [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]

This paper describes a method for simultaneous measurement of the accumulation of plasma protein and erythrocytes in skin reactions of hypersensitivity to bovine γ-globulin (BGG) and tuberculin PPD in the guinea-pig. The procedure consists in giving 125I-labelled plasma albumin and 51Cr-labelled autologous erythrocytes together by intravenous injection into guinea-pigs bearing skin lesions of allergic inflammation at different times and for different periods during the development of the skin reactions. Isotope accumulation in excised skin reactions is measured by scintillation counting at different stages during the evolution of hypersensitivity responses. Skin reactions of combined anaphylactic and Arthus hypersensitivity to BGG were characterized by pronounced increased vascular permeability principally in the first hour. In established 24-hour hypersensitivity reactions to both antigens (BGG and PPD) there was continuing accumulation of both plasma albumin and erythrocytes. During the development of the tuberculin reaction, an intermediate phase of isotope accumulation occurred between 6 and 9 hours after skin testing; serum transfer studies showed that this intermediate peak was not attributable to circulating antibody alone. These isotope tracer techniques were also applied to study vascular permeability in systemically transferred reactions of delayed hypersensitivity and in the vascular response to the intradermal injection of an inflammatory factor generated by antigen-activation of sensitized lymphocytes. It was concluded that isotope tracing provided objective and sensitive methods for analyzing microvascular responses in allergic inflammation. [ABSTRACT FROM AUTHOR]

Although induced immunological tolerance of histocompatibility antigens is generally considered to be specific, cases of concomitant third-party unresponsiveness may occur. The present paper describes one case in point. Antigenic overlap between original and third-party donor, as well as runt disease have been excluded as possible explanations for the observed lack of specificity. It is hypothesized that an innate inability, of the host to respond to the relevant third-party antigen(s), or the ability of certain antigens to induce tolerance of themselves as well as of distinct but related antigens, may be responsible for the phenomenon. [ABSTRACT FROM AUTHOR]

In this study we show that glycosylation is relevant for immune recognition of therapeutic antibodies, and that defined glycan structures can modulate immunogenicity. Concerns regarding immunogenicity arise from the high heterogeneity in glycosylation that is difficult to control and can deviate from human glycosylation if produced in non‐human cell lines. While non‐human glycosylation is thought to cause hypersensitivity reactions and immunogenicity, less is known about effects of Fc‐associated glycan structures on immune cell responses. We postulated that glycosylation influences antigen recognition and subsequently humoral responses to therapeutic antibodies by modulating 1) recognition and uptake by dendritic cells (DCs), and 2) antigen routing, processing and presentation. Here, we compared different glycosylation variants of the antibody rituximab (RTX) in in vitro assays using human DCs and T cells as well as in in vivo studies. We found that human DCs bind and internalize unmodified RTX stronger compared to its aglycosylated form suggesting that glycosylation mediates uptake after recognition by glycan‐specific receptors. Furthermore, we show that DC‐uptake of RTX increases or decreases if glycosylation is selectively modified to recognize activating (by mannosylation) or inhibitory lectin receptors (by sialylation). Moreover, glycosylation seems to influence antigen presentation by DCs because specific glycovariants tend to induce either stronger or weaker T cell activation. Finally, we demonstrate that antibody glycosylation impacts anti‐drug antibody (ADA) responses to RTX in vivo. Hence, defined glycan structures can modulate immune recognition and alter ADA responses. Glyco‐engineering may help to decrease clinical immunogenicity and ADA‐associated adverse events such as hypersensitivity reactions. [ABSTRACT FROM AUTHOR]

Double‐negative (DN) T cells are present at relatively low frequencies in human peripheral blood, and are characterized as expressing the alpha‐beta or gamma‐delta T‐cell receptor (TCR), but not the CD4 nor the CD8 co‐receptors. Despite their low frequencies, these cells are potent producers of cytokines and, thus, are key orchestrators of immune responses. DN T cells were initially associated with induction of peripheral immunological tolerance and immunomodulatory activities related to disease prevention. However, other studies demonstrated that these cells can also display effector functions associated with pathology development. This apparent contradiction highlighted the heterogeneity of the DN T‐cell population. Here, we review phenotypic and functional characteristics of DN T cells, emphasizing their role in human diseases. The need for developing biomarkers to facilitate the translation of studies from animal models to humans will also be discussed. Finally, we will examine DN T cells as promising therapeutic targets to prevent or inhibit human disease development. [ABSTRACT FROM AUTHOR]

Killer cell immunoglobulin‐like receptors (KIRs) are important receptors for regulating the killing of virus‐infected or cancer cells of natural killer (NK) cells. KIR2DS2 can recognize peptides derived from hepatitis C virus (HCV) or global flaviviruses (such as dengue and Zika) presented by HLA‐C*0102 to activate NK cells, and has shown promising results when used for cancer immunotherapy. Here, we present the complex structure of KIR2DS2 with HLA‐C*0102 at a resolution of 2·5Å. Our structure reveals that KIR2DS2 can bind with HLA‐C*0102 and HLA‐A*1101 in two different directions. Moreover, Tyr45 (in activating receptor KIR2DS2) and Phe45 (in inhibitory KIRs) distinguish the two different binding models and binding affinity between activating KIRs and inhibitory KIRs. The conserved 'AT' motif of the peptide mediates recognition and determines the peptide specificity of recognition. These structural characteristics shed light on how KIRs activate NK cells and can provide a molecular basis for immunotherapy by NK cells. [ABSTRACT FROM AUTHOR]

Monocytes play a crucial role in maintaining homeostasis and mediating a successful innate immune response. They also act as central players in diverse pathological conditions, thus making them an attractive therapeutic target. Within the bone marrow, monocytes arise from a committed precursor termed Common Monocyte Progenitor (cMoP). However, molecular mechanisms that regulate the differentiation of cMoP to various monocytic subsets remain unclear. Herein, we purified murine myeloid precursors for deep poly‐A‐enriched RNA sequencing to understand the role of alternative splicing in the development and differentiation of monocytes under homeostasis. Our analyses revealed intron retention to be the major alternative splicing mechanism involved in the monocyte differentiation cascade, especially in the differentiation of Ly6Chi monocytes to Ly6Clo monocytes. Furthermore, we found that the intron retention of key genes involved in the differentiation of murine Ly6Chi to Ly6Clo monocytes was also conserved in humans. Our data highlight the unique role of intron retention in the regulation of the monocytic differentiation pathway. [ABSTRACT FROM AUTHOR]

Accurate assessment of SARS‐CoV‐2 immunity is critical in evaluating vaccine efficacy and devising public health policies. Whilst the exact nature of effective immunity remains incompletely defined, SARS‐CoV‐2‐specific T‐cell responses are a critical feature that will likely form a key correlate of protection against COVID‐19. Here, we developed and optimized a high‐throughput whole blood‐based assay to determine the T‐cell response associated with prior SARS‐CoV‐2 infection and/or vaccination amongst 231 healthy donors and 68 cancer patients. Following overnight in vitro stimulation with SARS‐CoV‐2‐specific peptides, blood plasma samples were analysed for TH1‐type cytokines. Highly significant differential IFN‐γ+/IL‐2+ SARS‐CoV‐2‐specific T‐cell responses were seen amongst previously infected COVID‐19‐positive healthy donors in comparison with unknown / naïve individuals (p < 0·0001). IFN‐γ production was more effective at identifying asymptomatic donors, demonstrating higher sensitivity (96·0% vs. 83·3%) but lower specificity (84·4% vs. 92·5%) than measurement of IL‐2. A single COVID‐19 vaccine dose induced IFN‐γ and/or IL‐2 SARS‐CoV‐2‐specific T‐cell responses in 116 of 128 (90·6%) healthy donors, reducing significantly to 27 of 56 (48·2%) when measured in cancer patients (p < 0·0001). A second dose was sufficient to boost T‐cell responses in the majority (90·6%) of cancer patients, albeit IFN‐γ+ responses were still significantly lower overall than those induced in healthy donors (p = 0·034). Three‐month post‐vaccination T‐cell responses also declined at a faster rate in cancer patients. Overall, this cost‐effective standardizable test ensures accurate and comparable assessments of SARS‐CoV‐2‐specific T‐cell responses amenable to widespread population immunity testing, and identifies individuals at greater need of booster vaccinations. [ABSTRACT FROM AUTHOR]

Summary: Immunologists are sometimes guilty of describing the innate immune response as 'non‐specific'. What we really mean is that the pattern recognition receptors of innate immune cells are not able to recombine and mutate to bind the spectacular range of molecular patterns that can be recognised by B and T cells. So, while it may be accurate to describe the innate immune response as less specific than adaptive immunity, even this belies the emerging complexity of the receptors and receptor complexes that control inflammatory responses. This complexity is necessary to recognise danger, and therefore successfully initiate proportionate inflammatory responses to cellular damage or against potential pathogens. [ABSTRACT FROM AUTHOR]

Summary: Inflammation and immune dysfunction have been increasingly recognized as crucial mechanisms in atherogenesis. Modifications in cell lipid metabolism, plasma dyslipidaemia and particularly low high‐density lipoprotein (HDL) levels occur both in atherosclerosis and in autoimmune rheumatic diseases (which are strongly associated with an increased risk of atherosclerosis), suggesting the presence of a crucial link. HDL, the plasma lipoprotein responsible for reverse cholesterol transport, is known for its several protective effects in the context of atherosclerosis. Among these, HDL immunomodulatory effects are possibly the less understood. Through the efflux of cholesterol from plasma cell membranes with the consequent disruption of lipid rafts and the interaction with the cholesterol transporters present in the plasma membrane, HDL affects both the innate and adaptive immune responses. Animal and human studies have demonstrated a predominance of HDL anti‐inflammatory effects, despite some pro‐inflammatory actions having also been reported. The HDL role on the modulation of the immune response is further suggested by the detection of low levels together with a dysfunctional HDL in patients with autoimmune diseases. Here, we review the current knowledge of the immune mechanisms of atherosclerosis and the modulatory effects HDL may have on them. [ABSTRACT FROM AUTHOR]

Regulated or programmed cell death plays a critical role in the development and tissue organization and function. In addition, it is intrinsically connected with immunity and host defence. An increasing cellular and molecular findings cause a change in the concept of cell death, revealing an expanding network of regulated cell death modalities and their biochemical programmes. Likewise, recent evidences demonstrate the interconnection between cell death pathways and how they are involved in different immune mechanisms. This work provides an overview of the main cell death programmes and their implication in innate immunity not only as an immunogenic/inflammatory process, but also as an active defence strategy during immune response and at the same time as a regulatory mechanism. [ABSTRACT FROM AUTHOR]

Summary: Upon activation, naïve CD4+ T helper (Th) cells differentiate into distinct Th effector cell lineages depending on the local cytokine environment. However, these polarized Th cells can also adapt their function and phenotype depending on the changing cytokine environment, demonstrating functional plasticity. Here, Th17 cells, which play a critical role in host protection from extracellular pathogens and in autoimmune disorders, are of particular interest. While being able to shift phenotype within their lineage, Th17 cells can also acquire characteristics of Th1, Th2, T follicular helper (Tfh) or regulatory T cells. Th17 cell identity is determined by a spectrum of extracellular signals, including cytokines, which are critical orchestrators of cellular immune responses. Cytokine induces changes in epigenetic, transcriptional, translational and metabolomic parameters. How these signals are integrated to determine Th17 plasticity is not well defined, yet this is a crucial point of investigation as it represents a potential target to treat autoimmune and inflammatory diseases. The goal of this review was to discuss how cytokines regulate intracellular networks, focusing on the regulation of lineage‐specific transcription factors, chromatin remodelling and metabolism, to control human Th17 cell plasticity. We discuss the importance of Th17 plasticity in autoimmunity and cancer and present current strategies and challenges in targeting pathogenic Th17 cells with cytokine‐based approaches, considering human genetic variants associated with altered Th17 differentiation. Finally, we discuss how modulating Th17 plasticity rather than targeting the Th17 lineage as a whole might preserve its essential immune function while purging its adverse effects. [ABSTRACT FROM AUTHOR]

In this paper we describe the effect of depletion of splenic macrophages on the uptake, and immune response against, different formulations of rabies virus antigen. Splenic macrophages were removed by intravenous injection with clodronate liposomes. β-propiolacton inactivated rabies virus (RV-BPL) and immune-stimulating complexes (iscom) containing these antigens were given to macrophage-depleted and control mice. In the absence of phagocytic cells in the spleen, antigen is still trapped in the red pulp and to a lesser extent in the peri-arteriolar lymphocyte sheaths (PALS) for both antigen formulations. The localization pattern in the main area of immune response induction, namely the follicles, was unaltered after macrophage depletion. Functionally, the depletion of splenic and liver macrophages had no influence on the induction of specific antibody responses in both RV-BPL or RV-iscom immunized mice, even though the latter presentation form was clearly associated with specific localization in the marginal metallophillic macrophages. In RV-BPL immunized mice, macrophage depletion had no influence on proliferative T-cell responses. However, macrophage-depleted mice that were immunized with RV-iscom showed a significant decrease in proliferative T-cell responses. These results confirm existing ideas on the spleen as a physical filter rather than an induction site for humoral responses and shed new light on the efficient role of iscoms as antigen-presenting moieties in relation to their specific in vivo localization patterns and partial macrophage dependency. [ABSTRACT FROM AUTHOR]

Summary: Human cytomegalovirus (HCMV) is a ubiquitous pathogen that is potentially pathogenic in immunosuppressed individuals and pregnant females during primary infection. The HCMV envelope glycoprotein B (gB) facilitates viral entry into all cell types and induces a potent immune response. AD‐2 epitope is a highly conserved linear neutralizing epitope of gB and a critical target for antibodies; however, only 50% of sero‐positive individuals make IgG antibodies to this site and IgA responses have not been fully investigated. This study aimed to compare IgG and IgA responses against gB and the AD‐2 epitope in naturally exposed individuals and those receiving a recombinant gB/MF59 adjuvant vaccine. Thus, vaccination of sero‐positive individuals improved pre‐existing gB‐specific IgA and IgG levels and induced de novo gB‐specific IgA and IgG responses in sero‐negative recipients. Pre‐existing AD‐2 IgG and IgA responses were boosted with vaccination, but de novo AD‐2 responses were not detected. Naturally exposed individuals had dominant IgG responses towards gB and AD‐2 compared with weaker and variable IgA responses, although a significant IgA binding response to AD‐2 was observed within human breastmilk samples. All antibodies binding AD‐2 contained kappa light chains, whereas balanced kappa/lambda light chain usage was found for those binding to gB. V region‐matched AD‐2‐specific recombinant IgG and IgA bound both to gB and to AD‐2 and neutralized HCMV infection in vitro. Overall, these results indicate that although human IgG responses dominate, IgA class antibodies against AD‐2 are a significant component of human milk, which may function to protect neonates from HCMV. [ABSTRACT FROM AUTHOR]

Summary: Class II human leucocyte antigen (HLA) proteins are involved in the immune response by presenting pathogen‐derived peptides to CD4+ T lymphocytes. At the molecular level, they are constituted by α/β‐heterodimers on the surface of professional antigen‐presenting cells. Here, we report that the acceptor variant (rs8084) in the HLA‐DRA gene mediates the transcription of an alternative version of the α‐chain lacking 25 amino acids in its extracellular domain. Molecular dynamics simulations suggest this isoform undergoes structural refolding which in turn affects its stability and cellular trafficking. The short HLA‐DRA isoform cannot reach the cell surface, although it is still able to bind the corresponding β‐chain. Conversely, it remains entrapped within the endoplasmic reticulum where it is targeted for degradation. Furthermore, we demonstrate that the short isoform can be transported to the cell membrane via interactions with the peptide‐binding site of canonical HLA heterodimers. Altogether, our findings indicate that short HLA‐DRA functions as a novel intact antigen for class II HLA molecules. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex (MHC) restrictions in the secondary antibody response in vitro to the soluble protein antigen trinitrophenyl keyhole limpet haemocyanin (TNP-KLH) were investigated in this study. Experimental conditions were employed which ensured that co-operation between KLH-primed T cells and TNP-primed B cells was possible only through linked recognition of carrier and haptenic determinants. Under such conditions co-operation between T and B cells appears to be MHC-restricted.

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]

Anti-picrylsuppressor factor was prepared in the standard way, i.e. by culturing lymphoid cells from mice injected with picrysulphonic acid and then painted with picryl chloride and taking the supernatant fluid. It was assessed by its ability to depress the passive transfer of contact sensitivity by immune cells incubated in it. The factor can be specifically absorbed by picryl (but not oxazolone) albumin sepharose beads and can be specifically eluted by picryl (but not oxazolone) ϵ-aminocaproic acid and by picryl-ϵ-N-lysine. These findings emphasise the role of the hapten epitope in the binding of a specific T cell product. The factor can also be absorbed by Concanavalin A sepharose and can be eluted by an appropriate sugar such as ɑ-methylmannoside, but not by an inappropriate sugar such as lactose. It was possible to undertake two sequential affinity chromatography steps—first absorption with picryl albumin sepharose and elution with picryl-ϵ-N-lysine followed immediately by absorption by Con A sepharose and elution with α-methylmannoside. The availability of sequential affinity chromatography provides a simple approach to the purification of specific T suppressor factor. [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]