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We have investigated whether intracellular signal transduction molecules can be used as immunohistological markers of normal and neoplastic human leucocytes in routine tissue sections. We obtained selective labelling of white cells for eight such molecules (the ‘linker’ molecules SLP-76 and BLNK, the Src family kinases Lyn, Fyn, Syk and Hck, and the phospholipases PLC- γ1 and PLC- γ2). Antibodies to SLP-76 and PLC- γ1 selectively labelled T cells, and antibodies to BLNK, Lyn, Fyn, Syk and PLC- γ2 labelled B cells (although Fyn immunostaining was restricted to mantle zone B cells). Antibodies to the Syk and Hck kinases labelled probable thymocyte precursors at the periphery of the thymic cortex. In addition to lymphoid cells, several other leucocyte types were immunostained (e.g. SLP-76, Lyn, Syk and Hck were found in megakaryocytes, myeloid cells and/or macrophages, and PLC- γ2 was detected in arterial endothelium). SLP-76 and PLC- γ1 were found in most T-cell lymphomas studied, and some B-cell lymphomas were also positive for PLC- γ1 (e.g. diffuse large cell and Burkitt's lymphoma). The five B cell-associated markers were found in most B-cell non-Hodgkin's lymphomas, although some diffuse large B-cell lymphomas were negative (e.g. for Lyn) and anti-Fyn tended not to stain small B-cell neoplasms. The observation that a range of leucocyte signalling molecules can be detected in routine biopsies offers new possibilities for studying normal and neoplastic human white cells in diagnostic tissue samples. [ABSTRACT FROM AUTHOR]

New short-lived strains of mice (SAM-P), which have been developed by Takeda et al. (1981), show a defective antibody response to T dependent (TD) antigen in vitro, as demonstrated in the accompanying paper (see page 419). In the present study, we investigated the cellular site of the defect, using a cell culture system. In this paper, it is demonstrated that T-helper (Th) cell activity for the antibody response to TD antigen is impaired, while other cellular immune responses, e.g. mixed leucocyte reaction, cytotoxic T-lymphocyte response, and delayed-type hypersensitivity reaction, are normal. These results suggest that the defect in T-helper subset is limited in helper function for the antibody response, and that the helper function for the cell-mediated immune responses is intact. These two functions of the T-helper subset are apparently regulated in a different manner. The SAM-P strains of mice may thus serve as an appropriate model for studying functional heterogeneity in T-helper/inducer cell subsets. [ABSTRACT FROM AUTHOR]

X-irradiated (250 rad), cyclophosphamide-treated or Atx A mice injected with syngeneic trinitrophenylated spleen cells (TNP-SC) and footpad challenged with syngeneic lymphoblasts generated delayed-type hypersensitivity (DTH) responses 24, 48 and 72 h after challenge. The syngeneic-DTH (syn-DTH) response was mediated by Lyt-1+ cells and suppressed with Lyt-1+2+3+, I-Jk+ cells. The suppressor cells were obtained from spleens or thymuses of normal syngeneic mice. Suppressor factor (SF) was extracted or released from Lyt-1+2+3+, I-Jk+ cells obtained from normal A mice (but not from X-irradiated A mice). The factor blocked the DTH responses of X-irradiated mice injected with syngeneic TNP-SC and challenged with syngeneic lymphoblasts when injected into the mice both at the induction phase and the elicitation phase of the DTH. The factor failed to abrogate allogeneic and xenogeneic DTH. However, allogeneic factor (derived from C57BL/6 mice) abolished the syn-DTH response of mice injected with syngeneic TNP-SC and challenged with syngeneic lymphoblasts. The SF was produced by Lyt-1+2+3+, I-Jk+ T cells or by thymocytes. The combined extracted product of Lyt-1+ and Lyt-2+ cells did not abrogate the syn-DTH response. Normal spleen cells depleted of phagocytes by a magnetic procedure also produced the SF. These findings indicate, therefore, that suppressive factor (or factors; see Discussion of the accompanying paper, Ref.17) controls the immunological autoreactivity against syngeneic TNP-SC. [ABSTRACT FROM AUTHOR]

As described in an accompanying paper, trinitrophenyl (TNP) modification of pork insulin (PI) at the A1 glycine position allows this molecule to stimulate a proliferative response in H-2b (B10) mice. We now show that this antigen stimulates low IgG responses in the same strain of mice. Our results show that T-cell help and proliferation may therefore be regulated independently. [ABSTRACT FROM AUTHOR]

MRL-lpr mice and their congenic counterparts MRL- + spontaneously develop an autoimmune disease that resembles systemic lupus erythematosus in humans. The two strains, although congenic, differ by a considerable number of disease parameters, reflecting the expression of the lpr autosomal recessive gene. One paradox that has developed out of the work utilizing the congenic mice is that the gene responsible for lymphoproliferation also appears to be responsible for the inability of T cells to respond to proliferative signals in vitro. In this paper we investigated a possible lpr gene-encoded macrophage defect in these mice. It was found, however, that both the MRL- + and MRL-lpr mice failed to divide in response to Con A, the lack of division correlating with an inability to secrete the growth promoter interleukin-2. In MRL- + mice and young MRL-lpr mice this non-responsiveness was corrected by the addition of normal CRA PEC. The defect could not be explained by a failure of M RL- + or M RL-lpr peritoneal exudate cells to quantitatively or qualitatively provide a source of interleukin-1 to Con A-activated T cells or by the possibility that the peritoneal exudate cells were blocked in their function by the presence of sera-derived autoantibodies and/or immune complexes on their membranes. We postulate that the inability of T cells to proliferate in MRL congenic mice can be explained by two defects: (i) the failure of antigen-presenting cells in MRL- + and MRL-lpr to provide the necessary signals to immunocompetent T cells, this defect not being associated with the lpr gene, and (ii) the lpr gene controlled outgrowth of a unique T-cell population that cannot respond in our assay system. [ABSTRACT FROM AUTHOR]

T-colony formation can be induced in PHA-stimulated peripheral blood mononuclear cells (PBM) from man, but not in PHA-stimulated purified T cells, the latter requiring the presence of factors produced by PHA-stimulated PBM and termed T-colony promoting activity (TCPA). In this paper, we demonstrate that interleukin-2 (IL-2), the growth hormone of T lymphocytes, controls T-colony formation. We show that: (i) IL-2 activity and TCPA produced by PHA-activated PBM are co-purified by gel filtration and chromatography on blue agarose, a procedure which yields a 850-fold IL-2 purification; (ii) recombinant IL-2, produced by genetically manipulated Eseherichia coli, can induce T-colony formation in PHA-stimulated purified T cells; (iii) Monoclonal antibody against the IL-2 receptor (anti-Tac antibody) completely inhibits the T-colony formation in PHA-stimulated PBM when directly added to the culture system. [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]

Linked Content This article is linked to Strik et al and Strik, D'Heans papers. To view these articles visit https://doi.org/10.1111/apt.13994 and https://doi.org/10.1111/apt.14071. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Duvvuri et al. (2010) Highly conserved cross-reactive CD4+ T-cell HA-epitopes of seasonal and the 2009 pandemic influenza viruses. Influenza and Other Respiratory Viruses 4(5), 249–258. Background The relatively mild nature of the 2009 influenza pandemic (nH1N1) highlights the overriding importance of pre-existing immune memory. The absence of cross-reactive antibodies to nH1N1 in most individuals suggests that such attenuation may be attributed to pre-existing cellular immune responses to epitopes shared between nH1N1 virus and previously circulating strains of inter-pandemic influenza A viruses. Results We sought to identify potential CD4+ T cell epitopes and predict the level of cross-reactivity of responding T cells. By performing large-scale major histocompatibility complex II analyses on Hemagglutinin (HA) proteins, we investigated the degree of T-cell cross-reactivity between seasonal influenza A (sH1N1, H3N2) from 1968 to 2009 and nH1N1 strains. Each epitope was examined against all the protein sequences that correspond to sH1N1, H3N2, and nH1N1. T-cell cross-reactivity was estimated to be 52%, and maximum conservancy was found between sH1N1 and nH1N1 with a significant correlation ( P < 0·05). Conclusions  Given the importance of cellular responses in kinetics of influenza infection in humans, our findings underscore the role of T-cell assays for understanding the inter-pandemic variability in severity and for planning treatment methods for emerging influenza viruses. [ABSTRACT FROM AUTHOR]

By substituting the heavy chain constant region of IgM and IgD with that of IgG, IgA or IgE, immunoglobulin class switching endows antibodies with novel effector functions that enhance the ability of the immune system to effectively clear invading pathogens. Plasmacytoid dendritic cells critically link innate immunity with adaptive immunity by producing massive amounts of type 1 IFN in response to viruses. We have recently found that type 1 IFN triggers class switching by inducing myeloid dendritic cells to upregulate the expression of BAFF and APRIL, two powerful B cell-activating molecules. In this paper, we propose that IFN-producing plasmacytoid dendritic cells modulate class switching by activating B cells through both T cell-dependent and T cell-independent pathways. A better understanding of these pathways may facilitate the development of novel antiviral vaccine strategies and aid in identifying new therapies for antibody-mediated autoimmune disorders, such as lupus. [ABSTRACT FROM AUTHOR]

Murine models of mucosal inflammation are frequently due to the inability of the mouse to mount a regulatory T cell response. To the extent that such responses arise from oral tolerance mechanisms, these models provide a unique way of studying oral tolerance. In this paper we focus on the regulatory cells generated in two of the most well-studied of such models, the cell-transfer model and the TNBS-colitis model. Our analysis leads to the view that regulatory cells generated by the oral tolerance seen in mucosal inflammation are, at least in part, cells that recognize self-antigens or antigens in the mucosal microflora whose effector function relies on the expression of TGF-β. [ABSTRACT FROM AUTHOR]

This paper describes the initial appearance and distribution of mature T and B cells in the developing immune tissues of the stripe-faced dunnart ( Sminthopsis macroura) based on the use of species cross-reactive antibodies to the lymphocyte cell surface markers CD3, CD5 and CD79b. At birth no mature T or B cells were detected in the liver or bone marrow using anti-CD3, anti-CD5 or anti-CD79b antibodies. T cells were detected in the thymus with anti-CD3 by day 12 and anti-CD5 by day 50 postpartum, and T cells in the spleen were detected by day 43 and day 80 postpartum using anti-CD3 and anti-CD5, respectively. B cells were observed in the dunnart spleen by 43 days after birth. CD3- and CD79b-positive cells were detected in the lymph nodes by 50 days and CD5 by day 15 after birth, and in the gut-associated lymphoid tissues by day 50 and anti-CD5 by day 57 postpartum. The development and distribution of T and B cells in the immune tissues of dunnart pouch young is similar to that described in other marsupial species. Low numbers or absence of mature lymphocytes in immune tissues of early pouch young dunnarts further support the proposition that young marsupials are reliant on non-specific defence strategies and/or maternal strategies for a significant period of their time of development in the pouch. [ABSTRACT FROM AUTHOR]

The CDC crossmatch test is being phased out in solid organ donor allocation, and standard luminex single antigen bead assays do not differentiate complement activating function of HLA antibodies. The current study investigated the LIFECODES C3d‐binding assay to determine if it could accurately predict actual T and B cell CDC results in a cohort of highly sensitised patients. Nineteen serum samples from different highly sensitised solid organ patients were crossmatched against cells from 62 unique donors, with 174 total T and B cell crossmatches performed. The sera also underwent SAB assay using OLI and LC platforms, and C3d‐binding assay. Complement activating ability of each unique HLA antibody specificity detected using SAB was assigned based on the actual CDC results, which was then used to determine the accuracy of the C3d‐binding assay. The C3d‐binding assay was found to be highly accurate, with sensitivity of 95%, specificity 89% and negative predictive value 97% for class I DSA and the T cell CDC crossmatch results. Furthermore, we found 100% accuracy for prediction of the complement activating function of HLA‐C antibodies. Negative predictive value of above 90% was also found for HLA class II DSA. C3d‐binding proved more accurate than virtual crossmatch alone to predict CDC results. This study confirms that the C3d‐binding assay predicts actual CDC crossmatch results accurately. In particular, the high negative predictive value of the C3d‐binding assay may be extremely useful to define HLA antibodies that do not activate complement in highly sensitised recipients. [ABSTRACT FROM AUTHOR]

Background Comparable T cell-containing and T cell-depleted culture systems for human IgE synthesis arc currently not available. Objective This has prompted us to develop peripheral blood mononuclear cell (PBMC) based culture systems for human IgE synthesis in the presence and absence of T cells. Methods In this paper we describe simplified conditions for in vitro synthesis of high levels of IgE by human peripheral blood B cells, both in T cell-containing cultures and in anti-CD40 stimulated T cell-depleted cultures. Results T cell-depleted cultures released approximately 20 times more IgE [range 4I0-2220ng/mL (mean 1270 ng/mL); based on six experiments using cells from three donors] than did T cell-containing cultures [range 23-105 ng/mL (mean 58ng/mL); based on 15 experiments using cells from three donors]. Reconstitution experiments were performed lo investigate the role of T cells on IgE synthesis. Adding T cells back to the anti-CD40 stimulated T cell-depleted cultures resulted in a dose-dependent inhibition of IgE production. In the absence of anti-CIMO low numbers of T cells stimulated, while high numbers suppressed, IgE production: the optimal ratio of T cells to non-T cells for maximal IgE production was found to be 1:1. At this ratio, irradiated (non-replicating) T cells supported a much greater IgE synthesis than did non-irradiated T cells. Conclusion The development of these systems provides directly comparable T cell-containing and T cell-depleted cultures for human IgE synthesis from peripheral blood, allowing further study of the role of T cells in IgE regulation. These systems will also be of use for determining whether potential modulators of IgE synthesis act on the T cells or on other cell types. [ABSTRACT FROM AUTHOR]

Interleukin-4 (IL-4) mediated locomotor responses by murine B cells in vitro were examined in this paper. The IL-4 induced migration was found to act directly on purified, splenic B cells, without involvement of secondary mediators. It appeared that only a subpopulation of B cells was able to respond in migration assays. Flowcytometric analysis showed that the migrating cells had the characteristics of naive B cells: I-Alo, J11dhi, IgDhi. They also displayed high expression of the adhesion molecule L-selectin and made predominantly IgM antibodies. This is contrary to what has previously been observed regarding motile responses to chemotactic factors by T cells, which mostly affect memory or activated T cells. However, this is in accordance with other studies indicating that IL-4 is a cytokine that exerts its effect mainly on resting B cells. [ABSTRACT FROM AUTHOR]

Brown Norway (BN) rats are poor responders to T-cell mitogens and alloantigens when compared to Lewis (LEW) rats. This is dependent partly upon a defect in IL-2 production. The TH2-mediated immune abnormalities observed in BN rats injected with mercuric chloride (HgCl2) are self-limited and it is probable that this regulation phase involves TH1-like cells. This paper reports on a study of the ability of lymph node cells (LNC) from normal BN and LEW rats and from HgCl2-injected BN rats to produce IL-2 and to proliferate when stimulated in vitro by Con A or alloantigens in mixed lymphocyte reaction (MLR), as well as to develop a cytotoxic T lymphocyte (CTL) response to alloantigens. This study will confirm that LNC from BN rats proliferate less than LNC from LEW rats, that the former produce less IL-2 than the latter, and that the proliferative response is restored partially after addition of IL-2. In addition, it is shown (1) that the CTL response is defective in normal BN rats when compared to that of normal LEW rats, and (2) that, after the second week of HgCl2, injections, the proliferative responses to Con A and alloantigens are improved as well as IL-2 production, and a complete restoration of CTL function is observed. These results show that normal BN rats are deficient in the induction of TH1-like cells and that, from the second week of HgCl2 injections, these TH1 functions improve. [ABSTRACT FROM AUTHOR]

Two main ideas have been put forward lo explain the unexpectedly low anti-hapten antibody titres which can result from pre-priming a mouse with carrier before hapten-carrier immunization. The first involves the interaction of a network of idiotype-specific suppressor T cells, the second instead arguing for the role of intrinsie B-cell anergy. This paper proposes that the data available can equally be interpreted as reflecting the suboptimal interaction between T and B cells at differing stages of maturity, provided that memory B cells can be divided into two subsets. Further, it is suggested that these considerations must be taken into account in the analysis of B-cell anergy in receptor transgenic mice. [ABSTRACT FROM AUTHOR]

We have developed a new assay for quantitative detection of all helper T cells that can induce normal B lymphocytes to proliferation and Ig secretion. To establish the optima] assay conditions, we have used cloned I helper cells of defined specificities that had previously been shown to activate normal B lymphocytes expressing the specific antigen(s) on direct cellular interactions. As shown in this paper, "irrelevant" B lymphocytes-that is, those that do not express either antigen or restriction elements recognized by the effector helper T cells-can also be induced in the presence of appropriate concentrations of pokeweed mitogen which are not mitogenic for the "target" B lymphocytes. 'Nonspecific" plaque-forming cell responses are of the same magnitude as those provided to specifically triggered targets and equal or better than those induced by lipopolysaecharide. The assay is highly sensitive and enables "semiquantitative' detection of less than 20-30 effector T cells per culture. Since effeetor helper T cells can be detected regardless of the clonal specificity, the assay appears useful for quantitative studies of various populations of T helper cells displaying mixed specificities and for the classification of cells with unknown functions. [ABSTRACT FROM AUTHOR]

This paper describes the results obtained using an indirect protein A plaque-forming-cell (PFC) assay applied to human peripheral blood lymphocytes (PBL) activated with pokeweed mitogen (PWM). A maximal-response was obtained after 6 days of culture with regard to the three major classes of immunoglobulin (Ig) investigated. No difference was found between females and males. T and B lymphocytes mixed in ratios varying from 1:8 to 8:1 and unfractionated cells were investigated. A maximal PFC response of isolated lymphocytes was found in cultures of 1:4 T/B reconstituted suspensions of untreated cells, whereas the maximal response of untreated B and 2000-rad-irradialed T lymphocytes was found in cultures with a 4:1 T/B ratio. The number of plaques developed in cultures of unfractionated cells exceeded the response of 4:1 T/B reconstituted untreated lymphocytes but was far below the number of PFC developed in cultures of untreated B and 2000-rad-irradiated T lymphocytes. Normal donors developed approximately 70 × 10³ PFC/106 cells. The viability was 85% alter the incubation period. No difference was found in the PFC response of cultures of separated, reconstituted T/B lymphocytes set up in autologous and allogeneic combinations. [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 thoracic duct or efferent prescapular duct was cannulated in four fetal calves aged 121-259 days post-conception. The duration of lymph flow ranged from 2 to 20 days and the mean flow rates sustained over these collection periods varied from 54 to 488 ml/hr. Lymphocyte output ranged from 44 × 106 cells/hr in thoracic duct lymph from a 121-day fetus to 3.9 × 108 cells/hr in efferent prescapular lymph from a 259-day fetus. The circulating lymphocyte pool in fetal calves of about 120 and 190 days gestational age was calculated to contain, respectively, 4 × 108 cells and 2 × 1010 cells. The proportion of lymphocytes bearing surface immunoglobulin detected in fetal lymph ranged from 2.1% to 8.7%. Recirculating lymphocytes from fetal calves produced strong proliferative responses when stimulated by T-cell mitogens but responded poorly to B-cell mitogens. Fetal lymphocytes also responded to stimulation by allogeneic cells and stimulated other cells to proliferate during mixed lymphocyte culture. When stimulated with Con A, fetal lymphocytes secreted IL-2 to a degree that was indistinguishable from the secretory behaviour of lymphocytes from adult animals. The results presented in this paper show that chronic lymphatic fistulae can be established successfully in fetal calves to give access to recirculating lymphocytes. This provides a new experimental approach for studying the development of the bovine immune system. [ABSTRACT FROM AUTHOR]

In this paper we present experiments that indicate that, in man, most T-celI subpopulations produce interleukin-2 (IL-2), but that the main cell subpopulation which produces it, both upon activation with phytohaemagglutinin or in autologous mixed lymphocyte cultures, is that of autologous rosette-forming (Tar) T4+ T cells. Conversely, the main IL-2-responding T-cell subpopulation is that composed of T cells depleted of Tar (T-Tar) that are T8+ IL-2 was also found to be more effectively produced by Tar cells that do not bind peanut agglutinin (PNA) than by those that do. The PNA T4+ Tar cells were also found to respond best to interleukin- I (IL-I). [ABSTRACT FROM AUTHOR]

The results presented in this paper demonstrate that a mouse IgM monoclonal antibody (T-80) recognizes an antigen on cells of the T-lymphocyte lineage of sheep. However, this antibody does not identify all T cells, as 10-20% of thymocytes and some peripheral-blood T cells are negative. T-80- thymocytes reside in the medulla. The majority of cortical thymocytes are T-80+ and classified as dull cells on the basis of antigen density per cell as measured by flow microfluorometry. In contrast, T-80+ cells in the periphery can be categorized into two populations, i.e., dull cells and bright cells. Suggestive evidence was obtained that bright T-80+ cells are fast recirculating T cells, whereas dull ceils are sessile or less easily mobilizable T cells in the periphery. In foetal environment, over 90% of thymocytes and approximately 5% of spleen cells are T-80+ at 54 days of gestation (gestation period = 150 days), which may indicate that T-cell emigration from the thymus commences well before mid-gestation in sheep. [ABSTRACT FROM AUTHOR]

In this paper we describe the first in vitro response to the liver alloantigen F. The anti-F response serves as a valuable model for autoimmune phenomena since priming appropriate strains of mice (responders) with allogeneic but not syngeneic type F leads to autoantibody production. The in vitro system is based on the proliferation of T cells, from mice primed in vivo with F, when coincubated with splenic adherent cells (SAC) prepulsed with F in vivo. The system displays two important correlates of the in vivo antibody response to F:1.T cells from mice primed with syngeneic F do not proliferate when incubated with SAC prepulsed with syngeneic F and 2. Mice that do not make antibody responses to allo F in vivo (DBA/2) do not show in vitro proliferative responses. These findings indicate that the proliferative assay is a good in vitro model for the F response. [ABSTRACT FROM AUTHOR]

Examines various types of T lymphocyte functions in the spleens of mice infected four days previously with Friend virus (FV) in order to analyze its effect on the antibody response. Finding that infection does not reduce the percentage of T lymphocytes in the spleen, nor the ability to respond to phytohemagglutinin (PHA); Results suggesting that FV does not affect spleen T lymphocyte proliferation or helper function; Conclusion that the immune defect resides in the B lymphocytes.

Sera from mice with large tumours from a variety of tissue types and sources have been shown to contain substances capable of suppressing the proliferative response of normal mouse lymphocytes to concanavalin A (Con A), bacterial endotoxin (LPS) and allogeneic cells. The present paper deals with studies on the nature of these inhibitory materials using mainly a methylcholanthreneinduced rhabdomyosarcoma in DBA/2J mice. It was found that a material responsible for inhibition of the Con A response eluted with immunoglobulins on Sephadex G-150 and eluted with monomeric immunoglobulin on Sephadex G-200. The component of tumour-bearer serum responsible for the suppression of the LPS response of normal lymphocytes eluted from Sephadex G-150 with the α and β globulins and albumin (molecular weight < 150,000). The immunoglobulin-containing serum fraction from tumour-bearing animals inhibited the mixed lymphocyte response, Con A response, and specific immune response to purified protein derivative (PPD) in allogeneic cell systems. It also inhibited the in vitro primary response of mouse cells to sheep red blood cells, and, to a lesser extent, the response to a T cell-independent antigen (DNP-dextran). The inhibitory activity continued to elute with monomeric IgG on Sephadex G-200 when columns were run in 1640 medium and adjusted to pH 2.5, indicating that an acid dissociable complex was not responsible for inhibitory activity. Inhibitor activity could be removed by absorption on immunoadsorbents containing goat anti-mouse immunoglobulin, and could be recovered by acid elution from the adsorbent. Inhibitor activity was not removed by immunoadsorption on columns prepared with antisera to chicken immunoglobulin. [ABSTRACT FROM AUTHOR]

A receptor which binds secretory lgA (sIgA) is expressed on human T cells from patients with systemic lupus erythematosus, rheumatoid arthritis, Behcet's syndrome and IgA nephropathy and on normal T cells following phytohaemagglutinin (PHA) stimulation. The specificity of this receptor was initially probed with a panel of normal serum immunoglobulins in competitive inhibition assays with sIgA using two-colour immunofluorescence. While the receptor showed the strongest affinity for igAl (IC5010-6 M), IgD which has a similarly glycosylated hinge region to IgAl, also bound to the receptor (IC50 10-5 M). IgA2, which lacks the 'O'-glycosylated hinge region, did not significantly inhibit the binding at these concentrations suggesting that the IgA determinants for this receptor might be the oligosaccharides present in the hinge region of IgAl. IgAl has up to 10 'O'-linked oligosaccharides and four N-linked oligosaccharides per molecule. In order to probe the role of the 'O'-linked hinge sugars in the binding event, a sugar library was prepared from IgAl by a procedure designed to release 'O'-linked oligosaccharides preferentially, and to retain them in the natural closed ring formation. The sugars were released by hydrazinolysis at 65° and the resulting oligosaccharide library analysed by high voltage paper electrophoresis (HVE) and P4 gel permeation chromatography. Competitive inhibition studies demonstrated that both the library and the individual 'O'-linked sugars associated with IgA1 were implicated in the binding of IgAl to this receptor (IC50 between 1 × 10-5 M and 6 × 10-s M). Within this range the individual sugars showed small differences in their affinity for the receptor in the following order: Galβ3GalNAc = NeuNAc2α3(6)Galβ3GalNAc > NeuNAc2α3(6)Galβ3[NeuNAc2α6]GalNAc ≥ GalNAc. [ABSTRACT FROM AUTHOR]

The non-obese diabetic (NOD) mouse is a model for the study of insulin-dependent diabetes mellitus (IDDM). Recently transgenic NOD mice have been derived (NOD-E) that express the major histocompatibility complex (MHC) class III-E molecule. NOD-E do not become diabetic and show negligible pancreatic insulins. The possibility pertained that NOD-E mice are protected from disease by a process of T-cell deletion or anergy. This paper describes our attempts to discover whether this was so, by comparing NOD and NOD-E mouse T-cell receptor Vβ usage. Splenocytes and lymph node cells were therefore tested for their ability to proliferate iii response to monoclonal anti-Vβ antibodies. We were unable to show any consistent differences between NOD and NOD-E responses to the panel of antibodies used. Previously proposed Vβ were shown to be unlikely candidates for deletion or anergy. T cells present at low frequency (Vβ5+) in both NOD and NOD-E mice were shown to be as capable of expansion in response to antigenic stimulation as were more frequently expressed Vβ. Our data therefore do not support deletion or anergy as mechanisms which could account for the observed disease protection in NOD-E mice. [ABSTRACT FROM AUTHOR]

This paper describes a T-cell targeting strategy based on the use of an antigen-monoclonal antibody heteroconjugate. A rat anti-idiotypic monoclonal antibody specific for a murine B-cell lymphoma was conjugated to the purified protein derivative (PPD) of tuberculin. This construct selectively delivered up to 4.5 &times 104 molecules of PPD onto each tumour cell. Targeted PPD was internalized for endosomal processing and was presented in association with the I-A class II restriction element to PPD-reactive T-helper (Th) cells. Activated Th cells were demonstrated to proliferate and secrete significant levels of tumour necrosis factor (TNF). Such lymphokine secretion was observed at a PPD concentration as low as 1 ng/mI. Despite the secretion of TNF, the S-cell lymphoma was found to be resistant to autonomous Th-mediated cytotoxicity. Targeted Th cells did, however, activate tumourcidal macrophages that subsequently mediated significant tumour cytostasis. Based on this observation, it is proposed that the targeting system described may be exploited as the basis for a future immunotherapeutic strategy. [ABSTRACT FROM AUTHOR]

Lectins can be used to detect changes in cell-surface glycosylation. In this paper we examine the lectin-binding characteristics of murine T cells as measured by flow cytometry. A large panel of labelled lectins was used to stain naive, activated and resting murine T cells. Some lectins did not detectably bind any T cells, some bound to all T cells and some bound to only a subset of splenic T cells. Three lectins which preferentially bind to previously activated T cells were identified: Bandeiraea simplicifolia BS-I, Bauhinia purpurea and Lycopersicon esculentum. In addition, two lectins were found to bind preferentially to activated T cells; Glycine max and Triticum vulgaris. Finally, no differences were found in the ability of a large panel of lectins to bind to Th1 and Th2 clones. Lectin binding may be a powerful tool for distinguishing naive, activated and memory T cells. [ABSTRACT FROM AUTHOR]

In a representative cohort of immunocompromised young people, we observed marked differences in humoral and cellular responses to a standard two-dose mRNA vaccination regime between disease categories. In conclusion, although immunocompromised young people display attenuated humoral and cellular responses to vaccination in general, there are marked differences in vaccine responses between disease subgroups, not completely explained by immunosuppression used. First, given the heterogeneity in vaccine responses, some patient groups who qualify for an additional primary vaccination dose, for example JIA patients, may not benefit significantly, resulting in suboptimal use of vaccines and vaccination capacity. [Extracted from the article]

Glucocorticoid-induced TNF receptor-related (GITR) can act as a costimulatory receptor, representing a potential target for safely enhancing immunotherapy efficacy. GITR is triggered by a GITR ligand or an agonist antibody and activates CD8+ and CD4+ effector T cells, reducing tumor-infiltrating Treg numbers and resulting in activation of immune responses and tumor cell destruction by effector T cells. GITR is an attractive target for immunotherapy, especially in combination therapy with immune checkpoint inhibitors, as is being explored in clinical trials. Using H2L2 transgenic mice encoding the human immunoglobulin variable region and hybridoma technology, we generated a panel of fully human antibodies that showed excellent specific affinity and strong activation of human T cells. After conversion to fully human antibodies and engineering modification, we obtained an anti-GITR antibody hab019e2 with enhanced antitumor activity in a B-hGITR MC38 mouse model compared to Tab9H6V3, an anti-GITR antibody that activates T cells and inhibits Treg suppression from XenoMouse. As a fully human antibody with its posttranslational modification hot spot removed, the hab019e2 antibody exerted more potent therapeutic effects, and may have potential as a novel and developable antibody targeting GITR for follow-up drug studies. [ABSTRACT FROM AUTHOR]

Problem: Endometriosis (EM) is a chronic immunoinflammatory disease associated with an abnormal immunotolerant microenvironment. Myeloid‐derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that play a major role in immunosuppression in cancer, inflammation and other diseases. This paper aims to elucidate whether or not MDSCs are involved in regulating this microenvironment in EM and how this regulation occurs. Method of Study: Immunochemistry (IHC) and qPCR were conducted to measure CD11b and ARG1 expression in the ectopic endometrium samples from EM patients. CCL25 levels in EM PF and the expression of CCR9 on M‐MDSCs were measured by ELISA. M‐MDSC migration was determined towards rhCCL25, α‐CCR9, α‐CCL25 and EM PF through in vitro chemotaxis assay. CD33+CD14+CD11b+HLA‐DR‐ M‐MDSCs isolated from EM PBMCs were added to CD8+ T cells stimulated with α‐CD3/α‐CD28 antibody. After 72 hours of co‐culture, proliferation was measured to rate the immunosuppressive function of M‐MDSCs. Finally, levels of IL‐10, GM‐CSF and arginase activity in the cultured supernatants were detected. Results: IHC and qPCR results revealed higher CD11b and ARG1 expression in EM endometrium than normal endometrium. MDSCs accumulated in the EM microenvironment, in which M‐MDSCs were the predominant type. CD33+CD14+CD11b+HLA‐DR− M‐MDSCs expressed high CCR9 levels and were recruited through CCL25. M‐MDSCs from EM PBMCs inhibited proliferation and activity in autologous T cells. rhCCL25 promoted IL‐10 and GM‐CSF secretion and arginase enzymatic activity in CD33+CD14+CD11b+HLA‐DR− M‐MDSCs. Conclusion: CD33+CD14+CD11b+HLA‐DR− M‐MDSCs recruited and activated by CCR9/CCL25 play a crucial role in the pathogenic progression of endometriosis, thus providing a potential target for EM treatment. [ABSTRACT FROM AUTHOR]

Acute‐phase neutralizing antibody (NAb) passive immunization in simian immunodeficiency virus (SIV)‐infected rhesus macaques (Macaca mulatta) can confer stringent viremia control with T‐cell augmentation. In one NAb‐infused SIV partial controller, we identify chronic‐phase Nef‐specific CD107a+ CD4+ T‐cell response maintenance, implicating that NAb infusion modulates long‐term T‐cell responses even within viremic control. [ABSTRACT FROM AUTHOR]

Background: Characterising the clinical and immunological impact of daily cat exposure in cat‐allergic subjects with asthma who live with cats (WC) and those who do not (WoC) may provide understanding of the drivers of the allergic response. Methods: Clinical and immunological characteristics (skin prick test, spirometry, symptom assessments, immunological markers) were compared between asthmatic subjects WC (n = 10) and WoC (n = 9). Results: WC subjects had greater use of long‐acting beta agonists (p <.05) and high‐potency corticosteroids. No differences were observed in lung function, nasal and ocular symptoms, or asthma control between the groups. Cat dander‐ and Fel d 1‐specific IgG4 concentrations were higher in WC than WoC subjects (both p <.05). Total IgE and cat dander‐, Fel d 1‐ and Fel d 7‐specific IgE concentrations were similar, but Fel d 4‐sIgE was higher in WC subjects (p <.05) versus WoC. Basophil sensitivity to cat dander extract and Fel d 1 was lower in WC versus WoC subjects (p <.05) and correlated with higher IgG4 concentrations (r = 0.63; p =.009). Fel d 1‐specific CD4+ T‐cell responses polarised toward Th2A responses in WC versus WoC subjects; Fel d 1‐specific IgE correlated with surface expression of CRTH2 and CD200R (both p ≤.05). Conclusion: Immunological differences observed in WC versus WoC did not reflect clinical tolerance with natural cat exposure. The ability to live with a cat despite allergy could be driven by higher preventative medication use. This study may support design of novel therapeutics for allergy management. [ABSTRACT FROM AUTHOR]

Fibroblasts are the major resident cells which inhabit the periodontal tissues. As such, they are crucial for maintaining the connective tissues which support and anchor the tooth Little is known of their origins, synthesis of regulatory cytokines and growth factors in health and disease, and importance in soft tissue regeneration. An emerging concept is that fibroblasts are not homogeneous, but instead consist of subsets of cells which can regulate hone marrow-derived cells such as T lymphocytes. Fibroblasts can be separated into subsets on the basis of morphology, size and expression of intermediate filaments as well as collagen subtypes. Differential surface marker expression has also been a key feature to distinguish fibroblast subsets from many tissues. Antigens such as Thy-1, class II MHC, and Clq are among those surface proteins which have been employed successfully to separate fibroblasts Importantly. these fibroblast subsets are not only antigenically diverse, but also possess distinct functions. Thy 1- pulmonary fibroblasts can display class II MHC antigens, synthesize IL-1 and can activate T lymphocytes, whereas the Thy 1+ subset is devoid of these functions. Recently, fibroblasts from the human orbit have also been shown to be separable on the basis of Thy 1 surface marker expression. Fibroblasts derived from human gingiva and periodontal ligament also appear to be composed of subsets with a heritable pattern of surface markers which will permit their separation into functional subpopulations. This paper will review findings of fibroblast heterogeneity in periodontal and other tissues. Evidence Will be presented for the use of surface markers to delineate functional subsets. The ability to discriminate subsets of fibroblasts will aid in studies of periodontal disease pathogenesis and wound healing. [ABSTRACT FROM AUTHOR]

CD2 is expressed on murine B cells, probably as a result of a chromosomal translocation event during speciation. There are no activating antibodies to mouse CD2, but when activated non-specifically, only T cells up-regulate their expression of CD2. We investigated the expression and function of CD2 on B cells using mice transgenic for human CD2 under the control of a modified version of the autologous promoter/enhancer that included the immunoglobulin enhancer. This construction directs expression of human CD2 to the B cell compartment as well as to the T cell compartment. In this paper, we confirm that activating pairs of anti-CD2 monoclonal antibodies are mitogenic for mouse T cells transgenic for human CD2. In contrast, mouse B cells that express similar amounts of human CD2 are not stimulated to proliferate by equivalent doses of these antibodies. We were also unable to show any functional consequence for these B cells as a result of CD2 ligation. [ABSTRACT FROM AUTHOR]

Unfractionated and T-cell depleted human peripheral blood lymphocytes (PBL) were cultured in vitro in the presence of pokeweed mitogen (PWM) and Staphylococcus aureus strain Cowan I (StaCw). After 7 days of culture, the cells were assayed for cytoplasmic immunoglobulins (Cyto-Ig) by direct staining using fluorescein-labelled F(ab')2 fragments prepared from specific antisera against human IgG F(ab')2. The amount of immunoglobulin of the IgM and IgG class released into the cell-free supernatants was also measured by radioimmunoassay. In unfractionated PBL StaCw, like PWM, was able to induce a significant increase of either the number of Cyto-Ig containing cells or the amount of IgM And IgG secreted into the supernatant. In contrast, the amount of 1gM and IgG immunoglobulin released into the supernatant of T-cell depleted suspensions stimulated with PWM was significantly reduced in comparison with that of Unfractionated populations, whereas it was unchanged in T-cell depleted vs unfractionated suspensions stimulated with StaCw. The addition of a few I lymphocytes restored the ability of T-call depleted suspensions to produce Ig in the presence of PWM, whereas despite addition of high numbers of T cells no further augmentation of the Ig production induced by StaCw on T-cell depleted suspensions was observed. Cultures of umbilical cord blood lymphocytes (UCBL) stimulated with PWM did not generate Ig-producing cells, whereas UCBL stimulated with StaCw showed significant production of Ig of both 1gM and lgG classes. The results indicate that T lymphocytes are probably not involved either with stimulation or with the suppression of Ig production induced by StaCw. [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]

This study addresses itself to the problem of antibody formation in vitro by mouse splenic B lymphocytes enriched for reactivity to the hapten NIP by the hapten-gelatine binding and melting technique of Haas and Layton (1975). Small numbers of NIP-gelatine-bound B cells were placed in micro- cultures either by bulk dispensing of dilute cell suspensions, or by micromanipulation under direct microscopic visualization. Antibody formation was induced by the T cell-independent hapten-protein conjugate NIP-polymerized flagellin, using 104 thymus cells per microlitre as 'filler' cells. The frequency of precursors of NIP-specific antibody- forming cells among bound cells was about 2.2 × 10-2 (one cell in forty-five) by both statistical and direct evaluation, after adjustment for a background frequency of 6-10 × 10-8 precursors in the thymus filler cells. Single clones commenced antibody secretion asynchronously, as shown by the fact that the incidence of positive cultures continued to rise over the whole three days of culture, and that very small clones of one to four plaque-forming cells (PFC) were still found on day 3. The mean PFC number per positive culture rose from 1.2 at day 1 to 4.7 at day 2 and about 20 at day 3. Negative feedback, presumably mediated by antigen-antibody complexes, was shown to be a powerful effect in microcultures containing bound cells. It was evident with 250 cells per well (five clones) and the effect was progressive, such that with 10⊃ bound cells per well, plaque numbers were 40-50 per cent of their potential optimum; with 104, 10 per cent, and 105, 1 per cent. With routine techniques of harvesting of cultured cells, a failure to disperse PFC uniformly into single cells was noted. Groups of two or more large cells of very similar morphology were frequently observed at the centre of haemolytic plaques. Micromanipulation studies revealed that essentially all large cells at the centre of plaques were PFC. It was found that a routine plaque count underestimated the true PFC number per culture by a factor of 2. In the absence of negative feedback, the system is capable of generating one PFC per two input B lymphocytes. This is by far the most efficient plaque- generating system yet described, and contrasts with a yield of one PFC per 104 input cells in most typical tissue culture systems. Reasons for believing that both the culture and the enrichment systems can be further improved are discussed, and the potential of the method for understanding the cell and molecular biology of lymphocyte triggering is described. [ABSTRACT FROM AUTHOR]

The pathophysiology of atopic dermatitis (AD) is highly complex and understanding of disease endotypes may improve disease management. Immunoglobulins E (IgE) against human skin epitopes (IgE autoantibodies) are thought to play a role in disease progression and prolongation. These antibodies have been described in patients with severe and chronic AD, suggesting a progression from allergic inflammation to severe autoimmune processes against the skin. This review provides a summary of the current knowledge and gaps on IgE autoreactivity and self-reactive T cells in children and adults with AD based on a systematic search. Currently, the clinical relevance and the pathomechanism of IgE autoantibodies in AD needs to be further investigated. Additionally, it is unknown whether the presence of IgE autoantibodies in patients with AD is an epiphenomenon or a disease endotype. However, increased knowledge on the clinical relevance and the pathophysiologic role of IgE autoantibodies and self-reactive T cells in AD can have consequences for diagnosis and treatment. Responses to the current available treatments can be used for better understanding of the pathways and may shed new lights on the treatment options for patients with AD and autoreactivity against skin epitopes. To conclude, IgE autoantibodies and self-reactive T cells can contribute to the pathophysiology of AD based on the body of evidence in literature. However, many questions remain open. Future studies on autoreactivity in AD should especially focus on the clinical relevance, the contribution to the disease progression and chronicity on cellular level, the onset and therapeutic strategies. [ABSTRACT FROM AUTHOR]

The duration of protection after hepatitis B vaccination is not exactly known. This phase IV study evaluated antibody persistence and immune memory 20‐30 years after adult immunization with recombinant hepatitis B vaccine (HBsAg vaccine, Engerix‐B) in routine clinical practice. Men and women 40‐60 years old, with documented evidence of vaccination with three or four HBsAg vaccine doses 20‐30 years earlier and without subsequent booster, were enrolled and received HBsAg vaccine as challenge dose. HBsAg‐specific antibodies (anti‐HBs) and frequencies of HBsAg‐specific circulating memory B cells and CD4+ T cells expressing combinations of activation markers (CD40L, IL2, IFNγ, TNFα) were measured prechallenge, 7 and 30 days postchallenge. Of 101 participants in the according‐to‐protocol cohort for immunogenicity, 90.1% had anti‐HBs concentrations ≥ 10 mIU/mL prechallenge administration; 84.2% and 100% mounted an anamnestic response 7 and 30 days postchallenge, respectively. HBsAg‐specific memory B and CD4+ T cells expressing at least two activation markers were low prechallenge and increased markedly postchallenge. These results suggest sustained immune memory and long‐term protection 20‐30 years after a complete primary HBsAg vaccination course during adulthood, in line with current recommendations that a booster is not needed in fully vaccinated immunocompetent adults. [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]

In our view, Melvin Cohn (Scand J Immunol. 2018;87:e12640) has set out the logical guidelines towards a resolution of the very real enigma of the selectability of vertebrate germline Ig V repertoires under the current evolutionary paradigm. . ." A somatically derived repertoire scrambles this (germline VL + VH) substrate so that its specificities are lost, making it un-selectable in the germline. Consequently, evolution faced an incompatibility." It is argued here in Reply that a reverse transcriptase-based soma-to-germline process (S->G) targeting germline V segment arrays goes some considerable way to resolving fundamental contradictions on the origin, maintenance and then real-time adaptive diversification of these limited sets of V segments encoded within various V repertoire arrays. [ABSTRACT FROM AUTHOR]

Abstract: Background: Profilins are dominant pan‐allergens known to cause cross‐sensitization, leading to clinical symptoms such as pollen‐food syndrome. This study aimed to determine the T‐cell response to Phl p 12 in profilin‐sensitized patients, by measuring the prevalence, strength and cross‐reactivity to clinically relevant profilins. Methods: The release of Phl p allergens from pollen was determined by mass spectrometry and immunochemistry. T‐cell responses, epitope mapping and cross‐reactivity to profilins (Phl p 12, Ole e 2, Bet v 2 and Mal d 4) were measured in vitro using PBMCs from 26 Spanish grass‐allergic donors IgE‐sensitized to profilin. Cross‐reactivity was addressed in vivo using 2 different mouse strains (BALB/c and C3H). Results: Phl p 12 and Phl p 1 are released from pollen simultaneously and in similar amounts. Both T‐cell response frequency (17/26 donors) and strength were comparable between Phl p 12 and Phl p 1. T‐cell cross‐reactivity to other profilins correlated with overall sequence homology, and 2 immunodominant epitope regions of Phl p 12 were identified. Data from mice immunized with Phl p 12 showed that cross‐reactivity to Bet v 2 was mediated by conserved epitopes and further influenced by additional genetic factors, likely to be MHC II. Conclusion: The strength, prevalence and cross‐reactivity of T‐cell responses towards Phl p 12 are comparable to the major allergen Phl p 1, which supports the hypothesis that T cells to Phl p 12 can play an important role in development of allergic symptoms, such as those associated with pollen‐food syndrome. [ABSTRACT FROM AUTHOR]

The article explores A 58-year-old woman presented with a new onset of generalized weakness and a 6 months history of frequent falls. Her vitals were stable, and cardiovascular, pulmonary, and abdominal examinations were unremarkable. Her mentation was intact with apparently normal cognition. A neurological examination revealed normal cranial nerve function, bilateral quadriceps weakness (sitting-rising test).

The article offers information on a study concerning induction of human leucocyte antigen (HLA)-B restricted T cells possessing cytotoxic and suppressive functions against haematopoietic progenitor cells from a patient with severe aplastic anaemia. Topics discussed include treatment of acquired aplastic anaemia (AA) with antithymocyte globulin and ciclosporin (CsA), bone marrow (BM) hypoplasia and pancytopenia, and immune pressure of autoreactive cytotoxic T lymphocytes.

Background Although specific immunotherapy is the only aetiological treatment for allergic disorders, the underlying mechanisms are not fully understood. Specific immunotherapy induces changes in lymphocyte Th subsets from Th2 to Th1/Treg. Whether differences in immunological patterns underlie patient response to immunotherapy has not yet been established. Objectives We studied the immunological changes occurring during a 1-year period of Dermatophagoides pteronyssinus ( DP) immunotherapy and their relation with clinical outcome. Methods We included 34 patients with DP allergy who received subcutaneous specific immunotherapy ( SCIT) for 1 year. Following treatment, patients were classified as responders or non-responders. Fourteen allergic subjects who did not receive SCIT were included as controls. Peripheral blood was obtained at 0, 1, 3, 6 and 12 months and cultured with nDer p 1. Phenotypic changes, cytokine production and basophil response were analysed by flow cytometry; transcription factors were measured by mRNA quantification. Serum immunoglobulin levels were also measured. Results After 1 year of SCIT, 82% of cases showed improved symptoms (responders). Although increases in sIgG4 were observed, BAT reactivity was not modified in these patients. Increases in T- BET/ FOXP3 as well as nDer p 1-specific Th1/Treg frequencies were also observed, along with a decrease in Th2, Th9 and Th17. These changes corresponded to changes in cytokine levels. Conclusion Patients who respond well to DP- SCIT show immunological differences compared to non-responders. In responders, basal differences include a lower frequency of Th1 and higher frequencies of Th2, Th9 and Th17 cells. After 1 year of treatment, an increased production of sIgG4 was observed in responders, along with a change in Th2 response towards Th1/Treg. [ABSTRACT FROM AUTHOR]

This study examined specific antibody and T-cell responses associated with experimental malaria infection or malaria vaccination, in malaria-naive human volunteers within phase I/ IIa vaccine trials, with a view to investigating inter-relationships between these types of response. Malaria infection was via five bites of Plasmodium falciparum-infected mosquitoes, with individuals reaching patent infection by 11-12 days, having harboured four or five blood-stage cycles before drug clearance. Infection elicited a robust antibody response against merozoite surface protein-119, correlating with parasite load. Classical class switching was seen from an early Ig M to an Ig G1-dominant response of increasing affinity. Malaria-specific T-cell responses were detected in the form of interferon- γ and interleukin-4 ( IL-4) ELIspot, but their magnitude did not correlate with the magnitude of antibody or its avidity, or with parasite load. Different individuals who were immunized with a virosome vaccine comprising influenza antigens combined with P. falciparum antigens, demonstrated pre-existing interferon- γ, IL-2 and IL-5 ELIspot responses against the influenza antigens, and showed boosting of anti-influenza T-cell responses only for IL-5. The large Ig G1-dominated anti-parasite responses showed limited correlation with T-cell responses for magnitude or avidity, both parameters being only negatively correlated for IL-5 secretion versus anti-apical membrane antigen-1 antibody titres. Overall, these findings suggest that cognate T-cell responses across a range of magnitudes contribute towards driving potentially effective antibody responses in infection-induced and vaccine-induced immunity against malaria, and their existence during immunization is beneficial, but magnitudes are mostly not inter-related. [ABSTRACT FROM AUTHOR]