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A fraction with lymphokine properties was isolated from supernatant medium of the continuous cultured human lymphoblast cell line, 1788. Culture medium containing 2% human serum was used for cell growth in order to minimize antigenicity of supernatant fractions isolated from the medium. The culture medium was passed through an Amicon XM-100 membrane, concentrated over a PM-10 membrane, lyophilized, and reconstituted to a final concentration of approximately 40:1. Studies in vivo and in vitro showed that the active fraction contained skin reactive factor (when injected intradermally into guinea pigs and humans), lymphotoxin, migration inhibition factor, chemotactic factor, and macrophage activation factor. This same preparation, when injected intralesionally into cutaneous tumors, induced an inflammatory reaction followed by tumor regression. The fraction confined between membranes of pore size 10,000-100,000 daltons was active in promoting tumor regression, while the fraction less than 10,000 daltons was inactive. Patients with skin lesions from metastatic carcinoma of the breast and other malignancies were studied, and 16 out of 30 treated lesions were judged to have undergone either complete or greater than 50% regression. Of these, 8 were biopsied before and after lymphokine injection, and 6 out of 9 were negative for tumor cells. Additional studies in vitro with material fractionated on Sephadex G-200 indicated that the macrophage-activating component binds to alpha-2 macroglobulin in the culture medium.

Since it was first identified, thymosin alpha 1 (Tα1) has been characterized to have pleiotropic effects on several pathological conditions, in particular as a modulator of immune response and inflammation. Several properties exerted by Tα1 may be attributable to a direct action on lymphoid cells. Tα1 has been shown to exert an immune modulatory activity on both T cell and natural killer cell maturation and to have an effect on functions of mature lymphocytes, including stimulating cytokine production and cytotoxic T lymphocyte-mediated cytotoxic responses. In previous studies we have shown that Tα1 increases the expression of major histocompatibility complex class I surface molecules in murine and human tumor cell lines and in primary cultures of human macrophages. In the present paper, we describe preliminary data indicating that Tα1 is also capable of increasing the expression of tumor antigens in both experimental and human tumor cell lines. This effect, which is exerted at the level of the target tumor cells, represents an additional factor increasing the antitumor activity of Tα1. [ABSTRACT FROM AUTHOR]

The ability of B cells to negatively regulate cellular immune responses and inflammation has only recently been described. Hallmark papers from a number of distinguished laboratories have identified phenotypically diverse B-cell subsets with regulatory functions during distinct autoimmune diseases, including IL-10-producing B cells, CD5+ B-1a cells, CD1d+ marginal zone B cells, and transitional-2-marginal zone precursor B cells. Most recently, a numerically rare and phenotypically unique CD1dhiCD5+CD19hi subset of regulatory B cells has been identified in the spleens of both normal and autoimmune mice. CD1dhiCD5+ B cells with the capacity to produce IL-10 have been named B10 cells as they produce IL-10 exclusively and are the predominant B-cell source of IL-10. Remarkably, B10 cells are potent negative regulators of inflammation and autoimmunity in mouse models of disease in vivo. Herein, our current understanding of B10-cell development and function is reviewed in the context of previous studies that have identified and characterized regulatory B cells, emerging evidence for B10-cell regulation of tumor immunity, and the likelihood that B10 cells exist in humans. [ABSTRACT FROM AUTHOR]

Type 1 diabetes mellitus (T1DM) is a typical autoimmune disease and results from the destruction of insulin-producing β cells of the pancreas. It develops in the presence of genetic susceptibility, even though more than 85% of patients with T1DM do not have a close relative with the disorder. The etiology of T1DM is complex, and both genetic and environmental factors play important roles. A permissive genetic background is required for the development of the islet autoimmune process. The strongest genetic association idengified is that with HLA class II genes located on the short arm of chromosome 6. It is well known that both HLA DRB1*04-DQA1*0301-DQB1*0302 (DR4-DQ8) and DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) are positively, and DRB1*15-DQA1*0102-DQB1*0602 is negatively, associated with T1DM. However, only a minority of the subjects carrying the high-risk haplotypes/genotypes develops the disease, which suggests that additional genes play a crucial role in conferring either protection or susceptibility to T1DM. Major histocompatibility complex (MHC) class I chain–related A (MICA) is located in a candidate susceptibility region and activates natural killer (NK) cells, T cells and γδ CD8 T cells by its receptor NKG2D. The polymorphism of the MICA gene is associated with T1DM in different populations as demonstrated in several papers published in the last 7 years. [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]

The intestinal immune system responds to ingested antigens in a variety of ways, ranging from tolerance to full immunity. How T cells are instructed to make these differential responses is still unclear. Dendritic cells (DCs) sample enteric antigens in the lamina propria and Peyer's patches, and transport them within the patch or to mesenteric nodes where they are presented to lymphocytes. It is probable that DCs also transmit information that influences the outcome of T cell activation, but the nature of this information and the factors in the intestine that regulate DC behavior and properties are far from clear. We have developed a model in the rat that permits analysis of DCs actually in the process of migration from the intestine to mesenteric nodes. In this paper we will review those aspects of our research that relate to antigen uptake and discuss these in the context of other experimental systems. [ABSTRACT FROM AUTHOR]

In this paper some recent and partly preliminary results on anti-idiotypic immunity against clonal B cells in human monoclonal gammopathies are summarized. B cell lines producing antibodies to idiotypic determinants on autologous monoclonal immunoglobulin could be propagated after activation with Epstein-Barr virus of peripheral blood lymphocytes from patients with MGUS and MM clinical stage I but not from untreated persons with advanced MM. Blood T lymphocytes from patients with MGUS and Waldenström's macroglobulinemia were activated to DNA synthesis and production of interleukins by the autologous M protein. In another series of experiments T cell clones raised from patients with MM clinical stage I and MGUS bound F(ab')2 fragments of the autologous M protein and were stimulated to DNA synthesis by the idiotope-bearing protein. Control experiments demonstrated the specificity for idiotypic determinants. Ten of eleven clones were CD4-/CD8+. Finally, using a panel of 8 mAbs to alpha/beta V region epitopes, we noted a clonal expansion of CD4+ and CD8+ T cells in MGUS and MM patients.

Inflammation is a central feature of stable chronic obstructive pulmonary disease (COPD) and involves both activation of structural cells of the airways and the lungs and the activation and/or recruitment of infiltrating inflammatory cells. This results in enhanced expression of many pro-inflammatory proteins and reduced expression of some anti-inflammatory mediators. An altered protein expression is generally associated with concomitant changes in gene expression profiles in a cell-specific manner. Increased understanding of the role of transcription factors and of the signaling pathways leading to their activation in stable COPD will provide new targets to enable the development of potential anti-inflammatory drugs. Several new compounds targeting these pathways and/or transcription factors are now in development for the treatment of stable COPD. Furthermore, glucocorticoids drugs already in clinical use act through their own transcription factor, the glucocorticoid receptor, to control the expression of inflammatory and anti-inflammatory genes. [ABSTRACT FROM AUTHOR]

Here, the effects of neurointermediate (NIL), anterior (AL), and total hypophysectomy (HYPOX) on ileal mucosa cells and gut-associated lymphoid tissue (GALT) are reported. Compared with the sham-operated (SHAM) rats, the villi height and goblet cells numbers were significantly decreased in all groups. Lamina propria area decreased in AL and HYPOX, but not in NIL animals. CD8+ but not CD4+ lymphocytes decreased in the HYPOX and NIL groups. Paneth cells did not change, while IgA cells, IgM cells, and secretory IgA were significantly decreased in all groups. NIL but not AL animals lost significant numbers of IgA cells and secretory IgA. In summary, pituitary hormones exert lobe-specific regulatory effects on the gut and on GALT. [ABSTRACT FROM AUTHOR]

Lymphocyte homing to the secondary lymphoid organs is pivotal for proper immune responses. Studies using sulfotransferase-deficient mice showed that 6-sulfo sialyl Lewis X (6-sulfo sLex), a major ligand for L-selectin that is expressed on the high endothelial venules (HEVs), plays critical roles in lymphocyte homing to the peripheral lymph nodes. More recent studies revealed that 6-sulfo sLex is essential for the homing of CD4+CD25− conventional T cells to the nasal-associated lymphoid tissues (NALT) and is involved in nasal allergy. Further studies revealed that the homing of the CD4+CD25+ regulatory T cells to the NALT is dependent not only on the L-selectin-sulfated glycan interaction but also on P-selectin glycoprotein ligand-1 and CD44. These findings suggest that different carbohydrate-dependent homing mechanisms are utilized for different lymphocyte subsets. Recent studies indicated that the L-selectin-sulfated glycan interaction is also important for lymphocyte homing in chronic inflammation. In this review, the functions of the sulfated glycans in lymphocyte homing in physiological and pathological conditions are discussed. [ABSTRACT FROM AUTHOR]

Primary immunodeficiencies (PID) encompass more than 250 disease entities, including phagocytic disorders, complement deficiencies, T cell defects, and antibody deficiencies. While differing in clinical severity, early diagnosis and treatment is of considerable importance for all forms of PID to prevent organ damage and life-threatening infections. During the past few years, neonatal screening assays have been developed to detect diseases hallmarked by the absence of T or B lymphocytes, classically seen in severe combined immunodeficiencies (SCID) and X-linked agammaglobulinemia (XLA). As described in this review, a reduction or lack of T and B cells in newborns is also frequently found in several other forms of PID, requiring supplemental investigation and involving the development of additional technical platforms in order to help classify abnormal screening results. [ABSTRACT FROM AUTHOR]

The generation of antibody responses and B cell memory can only take place following multiple steps of differentiation. Key molecular processes during precursor B cell differentiation in bone marrow generate unique antibodies. These antibodies are further optimized via molecular modifications during immune responses in peripheral lymphoid organs. Multiple checkpoints ensure proper differentiation of precursor and mature B lymphocytes. Many of these checkpoints have been found disrupted in patients with a primary immunodeficiency. Based on studies in these patients and in mouse models, new insights have been generated in B cell differentiation and antibody responses. Still, in many patients with impaired antibody formation, it remains unclear how B cells are affected. In this perspective, we present 11 critical processes in B cell differentiation. We discuss how defects in these processes can result in impaired checkpoint selection and how they can be visualized in healthy subjects and patients with immunodeficiency or other immunological disease. [ABSTRACT FROM AUTHOR]

Receptor editing is the process of ongoing antibody gene rearrangement in a lymphocyte that already has a functional antigen receptor. The expression of a functional antigen receptor will normally terminate further rearrangement (allelic exclusion). However, lymphocytes with autoreactive receptors have a chance at escaping negative regulation by 'editing' the specificities of their receptors with additional antibody gene rearrangements. As such, editing complicates the Clonal Selection Hypothesis because edited cells are not simply endowed for life with a single, invariant antigen receptor. Furthermore, if the initial immunoglobulin gene is not inactivated during the editing process, allelic exclusion is violated and the B cell can exhibit two specificities. Here, we describe the discovery of editing, the pathways of receptor editing at the heavy (H) and light (L) chain loci, and current evidence regarding how and where editing happens and what effects it has on the antibody repertoire. [ABSTRACT FROM AUTHOR]

In response to infection or effective vaccination, naive antigen-specific CD8+ T cells undergo a dramatic highly orchestrated activation process. Initial encounter with an appropriately activated antigen-presenting cell leads to blastogenesis and an exponential increase in antigen-specific CD8+ T cell numbers. Simultaneously, a dynamic differentiation process occurs, resulting in formation of both primary effector and long-lived memory cells. Current findings have emphasized the heterogeneity of effector and memory cell populations with the description of multiple cellular subsets based on phenotype, function, and anatomic location. Yet, only recently have we begun to dissect the underlying factors mediating the temporal control of the development of distinct effector and memory CD8+ T cell sublineages. In this review we will focus on the requirements for mounting an effective CD8+ T cell response and highlight the elements regulating the differentiation of effector and memory subsets. [ABSTRACT FROM AUTHOR]

This manuscript reviews current evidence suggesting that aging of the immune system (immunosenescence) may be closely related to chronic stress and stress factors. Healthy aging has been associated with emotional distress in parallel to increased cortisol to dehydroepiandrosterone (DHEA) ratio. The impaired DHEA secretion together with the increase of cortisol results in an enhanced exposure of lymphoid cells to deleterious glucocorticoid actions. The lack of appropriated growth hormone signaling during immunosenescence is also discussed. It follows that altered neuroendocrine functions could be underlying several immunosenescence features. Indeed, changes in both innate and adaptive immune responses during aging are also similarly reported during chronic glucocorticoid exposure. In addition, chronically stressed elderly subjects may be particularly at risk of stress-related pathology because of further alterations in both neuroendocrine and immune systems. The accelerated senescent features induced by chronic stress include higher oxidative stress, reduced telomere length, chronic glucocorticoid exposure, thymic involution, changes in cellular trafficking, reduced cell-mediated immunity, steroid resistance, and chronic low-grade inflammation. These senescent features are related to increased morbidity and mortality among chronically stressed elderly people. Overall, these data suggest that chronic stress leads to premature aging of key allostatic systems involved in the adaptation of the organisms to environmental changes. Stress management and psychosocial support may thus promote a better quality of life for elderly people and at the same time reduce hospitalization costs. [ABSTRACT FROM AUTHOR]

Coccidioidomycosis is a recognized opportunistic infection in those with HIV-1 infection. The major risk factor is immunodeficiency, particularly when the peripheral blood CD4 T lymphocyte count is below 250/μL. There are many manifestations of coccidioidomycosis during HIV-1 infection, including diffuse, reticulonodular pneumonia, focal primary pneumonia, and disease disseminated beyond the thoracic cavity. Diagnosis is based on serology, culture and histopathologic identification. Two therapeutic modalities are currently available, the polyene antifungal amphotericin B and the triazole antifungals. Of the latter, the most experience is with the triazoles fluconazole and itraconazole. There are increasing data regarding drug interactions between triazoles and antiretroviral agents. The duration of treatment of coccidioidomycosis in those with HIV-1 infection is not established and in many patients it is either prolonged or life-long. Adherence to antiretroviral therapy is important in preventing recurrence. [ABSTRACT FROM AUTHOR]

Asthma, a chronic inflammatory disease of the airways, is greatly influenced by psychosocial factors and stress. This review looks at clinical studies that have shown strong associations between psychological stress and asthma to identify potential mechanisms for these interactions. Furthermore, we review animal studies involving stress and airway inflammation or airway hyperresponsiveness, and discuss possible mechanisms of stress action in asthma. In conclusion, further research, both in humans and in animal models, into the mechanisms of stress-induced changes in asthma exacerbation are required to help better understand the complex makeup of asthma and assist in the development of therapies directed at the interplay between the nervous system and airway inflammation. [ABSTRACT FROM AUTHOR]

Animal models for abdominal aortic aneurysms (AAAs), immunogenetical and pathophysiological studies support the importance of immune-mediated processes in the pathogenesis of AAA disease. Neutrophils, natural killer (NK) cells, monocytes/macrophages, and proinflammatory cytokines are involved in the complex and dynamic tissue remodeling of the AAA vessel wall. Our group showed an increased prevalence of circulating interferon-γ (IFN-γ) producing CD28− T cells especially in smaller AAAs, thus supporting the concept of a T cell-mediated pathophysiology of AAAs, especially during the early development of AAAs. Further research should now assess the possible benefit of anti-inflammatory therapeutic approaches in AAA patients, especially with small AAAs. [ABSTRACT FROM AUTHOR]

The intestinal immune system includes several organized structures, such as Peyer's patches, isolated lymphoid follicles (ILFs), cryptopatches (CPs) as well as mesenteric lymph nodes (MLNs) that constitute an extensive network with other nonorganized parts, such as intraepithelial and lamina propria lymphocytes. CPs are small clusters of lymphoid cells with an immature lymphocyte phenotype and dendritic cells. Initial observations in transfer experiments suggested that the immature lymphocytes are T cell precursors and CPs are a potential site of extrathymic intraepithelial lymphocyte (IEL) differentiation. This feature has recently been challenged particularly by the observation that CP cells express the orphan receptor RORγt and are phenotypically indistinguishable from lymphoid tissue-inducer (LTi) cells, suggesting that CP cells are the adult counterpart of fetal LTi cells. In addition, the chemokine receptor CCR6 is specifically expressed by precursor cells within CPs and its deletion inhibits the development of ILFs. Therefore, it is likely that ILFs derive from CPs under the control of CCR6 under inflammatory conditions and might constitute a valuable target for anti-inflammatory therapies. [ABSTRACT FROM AUTHOR]

Recent studies on “nonthermal” effects of mobile phone radiofrequency (RF) suggest that RF can interact with cellular functions and molecular pathways. To study the possible RF effects on human lymphocyte activation, we analyzed CD25, CD95, CD28 molecules in unstimulated and stimulated CD4+ e CD8+ T cells in vitro. Peripheral blood mononuclear cells (PBMCs) from young and elderly donors were exposed or sham-exposed to RF (1,800 MHz, Specific Absorption Rate 2 W/kg) with or without mitogenic stimulation. No significant changes in the percentage of these cell subsets were found between exposed and sham-exposed lymphocytes in both young and elderly donors. Nevertheless, after RF exposure we observed a slight, but significant, downregulation of CD95 expression in stimulated CD4+ T lymphocytes from elderly, but not from young donors. This age-related result is noteworthy given the importance of a such molecule in regulation of the immune response. [ABSTRACT FROM AUTHOR]

The questions of whether mucosal tolerance and IgA immunity are mutually exclusive or can coexist and whether they represent priming of the local immune system through the same or different activation pathways are addressed. Two strategies were attempted: the first using cholera toxin (CT) or the enzymatically inactive receptor-binding B subunit of CT (CTB), and the second using CTA1-DD or an enzymatically inactive mutant thereof, CTA1R7K-DD. The CTA1-DD adjuvant is a fusion protein composed of the ADP-ribosylating part of CT, CTA1, and DD, which is derived from Staphylococcus areus protein A and targets the molecule to B cells. Here, we provide compelling evidence that delivery of antigen in the absence of ADP ribosylation can promote tolerance, whereas ADP-ribosyltransferase activity induces IgA immunity and prevents tolerance. By linking antigen to the ADP-ribosylating enzymes we could show that CT, although potentially binding to all nucleated cells, in fact, bound preferentially to dendritic cells (DCs) in vivo. On the other hand, DD-bound antigen was distinctly targeted to B cells and probably also to follicular dendritic cells (FDCs) in vivo. Interestingly, the CT and CTA1-DD adjuvants gave equally enhancing effects on mucosal and systemic responses, but appeared to target different APCs in vivo. CT- or CTB-conjugated antigen accumulated in mucosal and systemic DCs. Whereas only CT promoted an active IgA response, CTB induced tolerance to the conjugated antigen. Following intravenous injection of CT-conjugated antigen, DCs in the marginal zone (MZ) of the spleen were selectively targeted. Interestingly, CTB delivered antigen to the same MZ DCs, but failed to induce maturation and upregulation of costimulatory molecules in these cells. Thus, ADP-ribosylation was necessary for a strong enhancing effect of immune responses following CT/CTBdependent delivery of antigen to the MZ DCs. Moreover, using CTA1-DD, antigen was targeted to the B cell follicle and FDC in the spleen after intravenous injection. Only active CTA1-DD, but not the inactive mutant CTA1R7K-DD, provided enhancing effects on immune responses. By contrast, antigen delivered by the CTA1R7K-DD stimulated specific tolerance in adoptively transferred T cell receptor transgenic CD4+ T cells. Whether targeting of B cells suffices for tolerance induction or requires participation of DCs remains to be investigated. With CT we found that enzyme-dependent modulation of DCs affects migration, maturation, and differentiation of DCs, which resulted in CD4+ T cell help for IgA B cell development. On the contrary, antigen presentation in the absence of ADP-ribosylating enzyme, as seen with CTB or CTA1R7K-DD, appears to expand specific T cells to a similar extent as enzymatically active CT or CTA1-DD, but fails to recruit help for germinal center (GC) formation and the necessary expansion of activated B cells. Also, the CD4+ T cells that are primed in a suboptimal, tolerogenic, fashion do not migrate to the B cell follicle to provide T cell help. Thus, ADP-ribosylating enzymes may be used to selectively control the induction of an active IgA response or promote the development of tolerance. In particular, on the targeted APC, modulation of the expression of costimulatory molecules, CD80, CD86, CD83, and B7RP-1, plays an important role in the effect of the ADP-ribosylating CTA1-based adjuvants on the development of tolerance or active IgA immunity. For example, the expression of CD86 in vivo was a prominent feature of the enzymatically active CT or CTA1-DD adjuvants. By contrast, CD80 expression appeared not to be important in CTA1-augmented APCs for an adjuvant function. [ABSTRACT FROM AUTHOR]

Neurotransmitters are stimulatory as well as inhibitory regulators of cell migration. Angiotensin is such an inhibitory regulator of the SDF-1-induced migration of cytotoxic T lymphocytes, as we have investigated by timelapse videomicroscopy and computer-assisted cell tracking. For angiotensin II, the most effective form of angiotensin for the inhibition of migration, two G protein-coupled receptors are known, which both downregulate the activity of the adenylyl cyclase via activation of inhibitory G proteins. This downregulation of the enzymatic activity is a key signaling event for the inhibition of T lymphocyte and tumor cell migration, while stimulatory neurotransmitters—for example, norepinephrine—cause an activation of the adenylyl cyclase. Similar to angiotensin, the SDF-1-induced migration of cytotoxic T lymphocytes was inhibited by DAMGO, a specific agonist for the mu-opioid receptor, which is coupled to inhibitory G proteins, too. More interestingly, DAMGO downregulated the met-enkephalin-induced migration of MDA-MB-468 breast carcinoma cells. Met-enkephalin binds to the delta-opioid receptor and, with lower affinity, to the mu-opioid receptor. Since the delta-opioid receptor also activates inhibitory G proteins, the promigratory effect of met-enkephalin is caused by an intracellular signaling distinct from the engagement of each opioid receptor alone. In summary, the dual control of the adenylyl cyclase functions as an integrator of stimulatory and inhibitory signals for T lymphocyte and tumor cell migration, which are delivered by neurotransmitters and other signal substances that bind to G protein-coupled receptors. [ABSTRACT FROM AUTHOR]