The effects of a community-based pulmonary rehabilitation programme on exercise tolerance and quality of life: a randomized controlled trial

The molecules B7.1 and B7.2 deliver costimulatory signals of critical importance to naive T cells, and may thus be involved in abrogation of oral tolerance in IBD. Functional disparity apparently exists among antigen-presenting cells in vivo. We wanted to examine if differential B7 expression occurs on mucosal macrophage subsets. Cryosections of bowel specimens from patients with IBD and normal controls were subjected to immunofluorescence and immunoperoxidase staining. In normal mucosa, selective subepithelial accumulation of B7.2+ cells was found. In inflamed IBD mucosa, however, subsets appeared consisting of both B7.2(hi) and B7.1(hi) cells as well as CD14(hi) macrophages. Notably, outside lymphoid aggregates the prominent fraction of recently recruited CD14(hi) macrophages comprised most (approximately 80%) of the B7.1(hi) cells, whereas most (approximately 70%) B7.2(hi) cells were identified as resident mucosal macrophages (CD14(lo) or CD14-). Differential expression of B7.1 and B7.2 on two functionally different subsets of intestinal macrophages implies separate immunoregulatory roles for the two molecules. This finding is in keeping with recent experimental data demonstrating that monocyte-derived cells are crucial for immune responses at mucosal surfaces. Preferential B7.1 up-regulation might be critical in breaking the immunological tolerance to luminal antigens in IBD, but it cannot be excluded that it is a secondary pathogenic event.     

Characterisation of Saccharomyces cerevisiae ARO8 and ARO9 genes encoding aromatic aminotransferases I and II reveals a new aminotransferase subfamily

It is known that lpr mice develop systemic lymphadenopathy and lupus erythematosus-like autoimmune disease that are associated with the accumulation of CD4- CD8- (double-negative; DN) CD3+ B220+ abnormal T cells as well as normal mature CD4+ or CD8+ single-positive (SP) CD3+ T cells. In order to clarify the role of B cells in the lymphoproliferation and autoimmunity of lpr mice, we created B-cell-deficient C57BL/6 (B6) lpr mice (B6lpr/lpr microMT/microMT) by crossing B6lpr/lpr mice with B6 microMT/microMT mice in which the B-cell development was arrested at pre-B stage owing to a targeted disruption of the immunoglobulin mu heavy-chain gene locus. In the B-cell-deficient B6-lpr mice, both lymphadenopathy and splenomegaly were markedly suppressed. Although the accumulation of both CD3+ B220- SP normal T cells and CD3+ B220+ DN abnormal T cells was inhibited in the B-cell-deficient lpr mice, the decrease in numbers of CD3+ B220- SP normal T cells occurred more strikingly than that of the CD3+ B220+ DN abnormal T cells. Glomerulonephritis did not develop in the B-cell-deficient lpr mice over 40 weeks. The present results indicate that the B cells thus play a crucial role in the extensive proliferation of normal CD3+ B220- mature SP T cells rather than the accumulation of abnormal DN T cells.     

Characteristic T helper 2 T cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humoral autoimmunity

Autoimmune lymphoproliferative syndrome (ALPS) is marked by massive lymphadenopathy, hepatosplenomegaly, autoimmunity and the presence of increased numbers of circulating and tissue TCR-alpha beta, CD4- CD8- T cells. The underlying defect is that of decreased T cell and B cell apoptosis, due in most, but not all, cases to heterozygous mutations of the Fas gene and corresponding defective Fas signaling function. Here we measure in vivo and in vitro cytokine secretion in ALPS to shed light on the relation of apoptosis defects to the development of autoimmunity. In in vivo studies, ALPS patients manifested greatly increased circulating levels of IL-10 (> 100-fold), compared with both healthy individuals and various disease controls; in contrast, their levels of IL-1 beta, IL-4, and IFN-gamma were normal and their levels of IL-2 and TNF-alpha were marginally increased. In parallel in vitro studies, ALPS patients CD4+ DR+ T cells stimulated either with anti-CD3/CD28 or anti-CD2/CD28 produced increased amounts of IL-4 and IL-5 (10 to 20-fold) and decreased amounts of IFN-gamma (4-fold) as compared with those of control CD4+ DR+ T cells. In contrast, ALPS patients' CD4-/CD8- T cells produced very low amounts of cytokines. Finally, ALPS patients' peripheral monocytes/macrophages produced decreased amounts of IL-12 (30-fold) and increased amounts of IL-10 (5-fold). In conclusion, ALPS is marked by the presence of DR+ T cells that exhibit a skewed Th2 cytokine response upon various forms of stimulation. This cytokine response, in the presence of increased circulating IL-10 levels, is likely to define the cytokine milieu that accounts for the humoral autoimmune features of ALPS and, perhaps, of other humoral autoimmune states.     

Expression of adhesion molecules and HLA-DR by macrophages and dendritic cells in aphthoid lesions of Crohn's disease: an immunocytochemical study

The phenotypes and ultrastructure of macrophages and dendritic cells in aphthoid lesions of the colon were immunocytochemically observed in patients with Crohn's disease. Biopsy specimens were endoscopically obtained from both aphthoid and advanced lesions in Crohn's disease patients. Biopsy specimens obtained from patients with infectious colitis and from normal individuals served as controls. Aphthoid lesions contained densely aggregated CD68+ macrophages, which were surrounded by numerous ID-1+ dendritic cells. In the normal controls and infectious colitis patients, however, a few scattered CD68+ macrophages and ID-1+ dendritic cells were noted beneath the surface epithelium. CD3+ lymphocytes were significantly increased in both aphthoid and advanced lesions of Crohn's disease, but the CD4/CD8 ratio was similar in all groups studied. The double immunoperoxidase staining method revealed that both CD68+ macrophages and ID-1+ dendritic cells in the aphthoid lesions simultaneously expressed ICAM-1 and HLA-DR antigens. Electronmicroscopic observation revealed that CD68+ macrophages had numerous vesicles and lysosomal granules and few projections, and that ID-1+ dendritic cells had appreciable cytoplasmic protrusions with a few vacuoles. These findings suggested that the colonic mucosa in Crohn's disease contained two types of macrophage/dendritic cells in the same lineage that expressed intercellular adhesion molecules and class-II MHC antigens. It also appeared that the aphthoid lesions of Crohn's disease featured an increase in macrophages and dendritic cells consistent with immunological activation.     

Involvement of Fas-mediated apoptosis in the inhibitory effects of interferon-alpha in chronic myelogenous leukemia

Interferon-alpha (IFN-alpha) is an established treatment for chronic myelogenous leukemia (CML) in chronic phase, but the mechanism of its antileukemic activity is not clear. One possible mechanism of action might include the induction of apoptosis, and especially Fas-mediated cell killing may play an important role in the elimination of malignant cells. We investigated Fas receptor (Fas-R) expression and the consequences of Fas-R triggering in CML patients. Using two-color flow cytometry, we found a significantly higher number of Fas-R-expressing CD34+ cells in the bone marrow (BM) of CML patients compared with normal subjects. We have previously shown that IFN-gamma induces Fas-R expression on CD34+ cells; in this study, we investigated whether IFN-alpha induces Fas-R expression on CML progenitor cells. Dose-dependent induction of Fas-R expression was observed after IFN-alpha stimulation of CD34+ cells from CML BM. In methylcellulose culture, IFN-alpha alone at a therapeutic concentration showed only marginal antiproliferative effects on both normal and CML BM progenitors. In contrast, a Fas-R agonist, the anti-CD95 monoclonal antibody CH11, inhibited colony formation from normal progenitors, and the inhibition was even stronger on CML progenitors. When CML BM cells were cultured in the presence of IFN-alpha, Fas-R-mediated inhibition of colony growth was potentiated in a dose-dependent fashion, consistent with IFN-alpha induction of Fas-R expression. This functional effect did not require the presence of accessory cells, since similar results were obtained with purified CD34+ cells. In suspension cultures, we demonstrated that suppression of CML hematopoiesis by IFN-alpha and Fas-R agonist was exerted through Fas-R-mediated induction of apoptosis. Our findings suggest that the Fas-R/Fas-ligand system might be involved in the immunologic regulation of CML progenitor growth and that its effect can be amplified by IFN-alpha.     

Age-related changes of B-cell immune function in patients with subacute myelo-optico-neuropathy (SMON)

Several kinds of immunological abnormalities have been found more frequently in patients with subacute myelo-optico-neuropathy (SMON). To investigate whether the B-cell immune system is implicated in aging in patients with SMON, we examined serum levels of immunoglobulin including IgG, IgM, and IgA, and the number of CD20+ cells (B lymphocytes) and CD20+ CD23+ cells (activated B lymphocytes) using flow cytometry, and compared them with those in age-matched controls. We also investigated whether the number of HLA-DR+ cells was correlated with those of CD20+ cells, CD20+ CD23+ cells, or HLA-DR+CD3+ cells (activated T lymphocytes) in patients with SMON. Serum levels of IgG, IgM and IgA were decreased with aging both in the patients with SMON and in the controls, and no significant difference was found between the two groups. Although the patients with SMON tended to show higher levels of CD20+ and CD20+ CD23+ cells than the age-matched controls, there were no significant differences between the two groups. The number of HLA-DR+ cells was correlated not with that of CD20+ cells or CD20+ CD23+ cells, but with that of HLA-DR+CD3+ cells. In patients with SMON, it is likely that the B-cell immune system is mainly implicated in the effect of aging, but it is unlikely that other factors than aging are associated with the B-cell immune system. The increase in the number of HLA-DR+ cells associated with aging in patients with SMON reflects the increase in the number of activated T lymphocytes, and is not correlated with the changes of B lymphocytes.     

Increased expression of costimulatory molecules on peripheral blood monocytes in patients with Crohn's disease

BACKGROUND: Activation of T lymphocytes and monocytes/macrophages has been implicated in the pathogenesis of Crohn's disease (CD). Costimulatory molecules play important roles in optimal T-cell activation. METHODS: With flow cytometric analysis we have investigated the expression of the costimulatory molecules B7-1 (CD80), B7-2 (CD86), and CD18 and the intercellular adhesion molecule-1 (ICAM-1) on peripheral blood monocytes and the expression of the activation markers HLA-DR and IL-2R (CD25) on peripheral blood T lymphocytes from 31 CD patients, 17 ulcerative colitis (UC) patients, and 10 healthy controls. RESULTS: In CD patients the percentage of activated T cells (CD3+ HLA-DR+ and CD3+ IL-2R+) was significantly increased compared with those of controls and UC patients (P < 0.05). Most monocytes from all three groups expressed B7-2, CD18, and ICAM-1 molecules (all > 79%), but only a few positive cells expressed B7-1 molecules (< 5%). No significant differences were detected in the percentage positivity of all costimulatory molecules tested among CD, UC, and controls. The mean fluorescence intensity (MFI) of B7-1 in all three groups was very weak and not significantly different. However, in CD patients there was a significantly increased MFI of B7-2, CD18, and ICAM-1 molecules compared with UC and controls (P < 0.05). On the other hand, both the percentage positivity and MFI of HLA-DR molecules on monocytes of UC patients were significantly lower than those of CD patients and controls (P < 0.05). CONCLUSIONS: Expression of the costimulatory molecules B7-2, CD18, and ICAM-1 on peripheral blood monocytes of CD patients is increased. In CD patients activation of peripheral T lymphocytes may correlate with increased expression of these costimulatory molecules on peripheral blood monocytes.     

Successful immunotherapy of the highly metastatic murine ESb lymphoma with sensitized CD8+ T cells and IFN-alpha/beta

Daily IFN-alpha/beta therapy was totally ineffective in inhibiting the development of visceral metastases in DBA/2 mice injected i.v. with the ESb lymphoma regardless of the number of tumor cells injected. The finding that IFN-alpha/beta therapy increased the survival time of ESb-immunized mice rechallenged with ESb cells suggested that cooperation between the immune system and IFN-alpha/beta was important. Adoptive transfer of Esb-immune spleen cells (but not normal cells) together with IFN-alpha/beta treatment did inhibit the development of ESb metastases in immunocompetent DBA/2 mice. Either treatment alone was ineffective. The anti-metastatic effect was specific for the ESb lymphoma as spleen cells from ESb-immunized mice together with IFN-alpha/beta treatment did not inhibit the development of metastases in mice challenged with IFN-alpha/beta-resistant 3C18 FLC. Depletion of CD8+ T cells (but not CD4+ T cells or B lymphocytes) prior to transfer eliminated the protective effect of ESb-immune splenocytes in IFN-alpha/beta-treated mice. As few as 1 x 10(6) ESb-immune spleen cells highly enriched for CD8+ cells increased the survival time of IFN-alpha/beta-treated ESb-challenged DBA/2 mice. The combined therapy of ESb-specific immune cells and IFN-alpha/beta resulted in long-term immunity to this tumor.     

Costimulatory molecules in ocular cicatricial pemphigoid

PURPOSE: To examine normal and inflamed conjunctiva from patients with ocular cicatricial pemphigoid (OCP) for the presence of costimulatory molecule CD28 and its ligands B7-1 (CD80) and B7-2 (CD86). METHODS: Conjunctival biopsy specimens from 12 patients with OCP and from five healthy persons undergoing cataract surgery were analyzed by light microscopy and immunohistochemical examination with monoclonal antibody probes for CD28, B7-1, and B7-2 molecules and for mononuclear cell subtypes. RESULTS: Epithelium of OCP conjunctiva showed more Langerhans' cells, B7-1-positive (+) cells, and B7-2 expression (ratio of B7-2-positive cells to antigen-presenting cells). In the substantia propria, OCP specimens showed significantly increased numbers of T cells (CD3 +), macrophages (CD68+), CD28+ cells, B7-2+ cells (CD86+), Langerhans' cells (CD1a), and B7-1+ cells (CD80). Most of the B7-2+ cells, macrophages, and Langerhans' cells were located subepithelially. B7-2 expression was significantly higher in OCP conjunctival substantia propria compared with normal conjunctiva. CONCLUSIONS: The results of this study indicate that the expression of the costimulatory molecule B7-2 is upregulated in conjunctiva of patients with active OCP. This increased subepithelial B7-2 expression may contribute to the sustained immune activation in OCP conjunctiva.     

Clinical and pharmacokinetic observations on fluconazole in the management of cryptococcal meningitis

Natural killer (NK) cell activity, the autologous mixed lymphocyte reaction (AMLR) and proportions of T cell subpopulations (CD3+/CD4+ and CD3+/CD8+) and NK cells (CD16+) were studied in 21 patients with bilateral primary breast cancer (BBC), 10 patients with single-breast cancer (SBC) and 20 healthy controls. All patients studied had no evidence of disease and had been off radiotherapy and/or chemotherapy for at least 1 year. Ten patients with BBC were also treated with tamoxifen. Patients with SBC had NK cell activity, AMLR responses and T cell subpopulations that were comparable to those of normal controls. In patients with BBC, a significant (P < 0.01) increase in NK activity compared to that in normal controls (42 +/- 13% versus 21 +/- 10%, effector-to-target cell ratio, 25:1) and a significant (P < 0.05) decrease in CD4+ T cell proportions (30 +/- 15% versus 49 +/- 13%) and absolute numbers (472 +/- 82/mm3 versus 953 +/- 131/mm3) were found. However, the proliferative response of BBC patients' T lymphocytes in AMLR was in the range of the normal controls. Lymphocytes derived from 10 BBC patients treated with tamoxifen exhibited NK cell activity that was comparable to that of normal controls and patients with SBC, and was significantly (P < 0.01) reduced compared to the pretreatment period. BBC patients who received tamoxifen also show a reduction in the proportion of CD4+ T cells and in AMLR proliferative responses, which decreased compared to levels in normal controls. Taken together, these results indicate that long-term tamoxifen treatment modulates immune responses in BBC patients.     

Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a costimulatory signal that up-regulates IL-4 synthesis

Although there is good evidence that the induction of IL-4 synthesis in CD4+ T lymphocytes is favored by Ag presentation by B cells and not macrophages, the precise molecular signals provided by B cells to T cells that enhance IL-4 synthesis are not clear. To examine this issue, we established an APC-independent system to activate highly purified T cells and induce cytokine synthesis, using immobilized mAbs against several T cell surface molecules, including CD3, CD28, and the CD40 ligand (CD40L). The counter-receptors for all three of these molecules are expressed on B cells, and include CD40, which is expressed primarily on B cells, but also on dendritic cells and thymic epithelium. We found that IL-4 synthesis was greatly enhanced by triggering of CD40L on the T cell surface in conjunction with ligation of CD3/TCR and CD28, whereas ligation of CD3/TCR and CD28 in the absence of CD40L triggering resulted in little or no IL-4 synthesis. CD40L costimulation greatly enhanced IL-4 synthesis both in T cells from normal nonallergic adult subjects as well as in naive T cells from cord blood. Furthermore, we demonstrated that IL-4 synthesis was optimally enhanced when the strength of the CD3/TCR signal was limiting, while IL-4 synthesis was inhibited when CD3/TCR stimulation was maximal. These studies confirm that IL-4 synthesis can be induced in normal T lymphocytes in the absence of exogenous IL-4, and demonstrate that CD40L costimulation is of fundamental importance in regulation of IL-4 production. In addition, these findings provide a mechanism by which B cells preferentially enhance IL-4 synthesis in T cells at low Ag concentrations.     

Flow cytometric analyses of the specific activation of peripheral blood mononuclear cells from healthy donors after in vitro stimulation with a fermented mistletoe extract and mistletoe lectins

Immunostimulatory properties of mistletoe extracts derived from Viscum album L. (VAL) are well described, demonstrating activation especially of T, T-helper cells and monocytes/macrophages. In order to characterise in detail the communication between different cell populations, we studied mistletoe-induced expression of co-stimulatory signals and their ligands by flow cytometry. Peripheral blood mononuclear cells (PBMC) from 15 healthy controls were incubated for 7 days with a fermented VAL extract. VAL significantly upregulated the expression of the co-stimulatory molecule B7.1 (CD80) on monocytes/macrophages, but not B7.2 (CD86). No significant changes in the expression of either molecules on B cells could be found, suggesting that only monocytes/macrophages act as antigen presenting cells (APCs) in this in vitro system. Purified mistletoe lectins, components of most VAL extracts were also analysed, but did not induce similar responses of monocytes/macrophages. The receptor for B7 molecules, CD28, but not CTLA-4 (CD152), was also found to be significantly enhanced on CD4+ cells after VAL simulation. There was no evidence for activation of a B cell response via the CD40/CD40L pathway. Our data support the concept that stimulation by VAL extracts induces a specific T-helper cell reaction with monocytes/macrophages acting as APCs and purified lectins do not exert the same effects.     

Absence of bcl-2 expression by activated CD45RO+ T lymphocytes in acute infectious mononucleosis supporting their susceptibility to programmed cell death

bcl-2 proto-oncogene encodes an inner mitochondrial membrane protein that blocks programmed cell death (apoptosis). There is now increasing evidence that regulation of bcl-2 expression is a determinant of life or death in normal lymphocytes. We have recently described that activated (CD45RO+) CD4+ and CD8+ T cells in acute infectious mononucleosis (IM) undergo apoptotic cell death on culturing, indicating an activation-driven cell death of mature T cells. In this work, we examine bcl-2 expression by activated T cells in acute IM using a flow-cytometric analysis with an anti-bcl-2 monoclonal antibody (MoAb). It was consistently observed that most T cells from acute IM patients displayed only much less bcl-2, while normal T cells expressed bcl-2 relatively strongly. Multicolor analysis showed that bcl-2-lacking T cells in acute IM were restricted to the CD45RO+ (activated) populations of CD4+, as well as CD8+ T cells. In contrast, the relatively intense levels of bcl-2 were expressed in both CD45RO+ and CD45RO- T-cell populations from normal subjects. This marked difference in bcl-2 expression of CD45RO+ T cells between acute IM and normal controls was also confirmed by Western blot analysis. Activated (CD45RO+) T cells with low bcl-2 expression, but not bcl-2-expressing CD45RO- T cells, in acute IM patients were found to die easily when cultured without added growth factors. However, in normal individuals, both CD45RO+ and CD45RO- T cells were relatively stable on culturing. These findings suggest that lack of bcl-2 expression by activated (CD45RO+) T cells in acute IM might be associated with their susceptibility to programmed cell death.     

An analysis of lymphocyte subsets in the regional lymph nodes of patients with papillary thyroid carcinoma

Lymphocyte subsets in the lymph nodes regional to papillary thyroid carcinoma were determined using flow cytometry to ascertain the differences in local immunological responses between elderly and young patients. Lymph nodes from age-matched patients with benign thyroid tumors were used as controls. No significant alterations in lymphocyte subsets were observed in the lymph nodes from the young patients regardless of whether metastasis was present, whereas those from the elderly patients showed significant decreases in pan T cell (CD2+, CD3+) and cytotoxic T cell (CD8+, CD8+CD11b-) populations, and a significant increase in B cells (CD19+) compared with those from both the young patients and the age-matched controls. These results indicate that local immunological alterations occur in elderly patients with papillary thyroid carcinoma, and we believe that immunological changes are one of the clinical characteristics of this tumor.     

The induction of in vivo proliferation of long-lived CD44hi CD8+ T cells after the injection of tumor cells expressing IFN-alpha1 into syngeneic mice

The tumorigenicity of transplantable tumor cells in mice is reduced by transduction with cytokine genes, including IFN-alpha and interleukin (IL) 12. Although T cells are considered important in tumor rejection, the mechanism by which genetically modified tumor cells stimulate the immune system has not been examined. In this study, the in vivo proliferation of T-cell subsets in mice transplanted with cytokine-producing syngeneic tumor cells was assessed by administering the DNA precursor bromodeoxyuridine. The injection of viable cells producing IFN-alpha or IL-12 caused a marked proliferation of CD8+ T lymphocytes in both the spleen and lymph nodes. Proliferation was most prominent among memory-phenotype CD44hi CD8+ T cells. In contrast, proliferation of CD8+ T cells did not occur in mice injected with control cells or with cells expressing IL-4, granulocyte colony-stimulating factor, or IFN-gamma. Pulse-chase studies in mice injected with IFN-alpha-producing cells showed that a proportion of proliferating CD8+ T cells survived for at least 70 days, suggesting that long-lived memory cells are induced using such an approach. In summary, these results, together with previous studies on the host immune reactivity triggered by the injection of tumor cells expressing IFN-alpha, represent a strong rationale for considering IFN-alpha as a powerful T-cell adjuvant for the generation of more effective cancer vaccines.     

CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells

Thymectomy of susceptible strains of mice on day 3 of life results in a spectrum of organ-specific autoimmunity that can be prevented by reconstitution of the thymectomized animals early in life with normal adult lymphocytes. The effectors and suppressors of autoimmunity in this model have been convincingly shown to be CD4+ T cells. It has been demonstrated recently that the regulatory CD4+ T cells that prevent disease coexpress CD25. We have further characterized the population of CD4+CD25+ immunoregulatory cells and demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells. Furthermore, the CD4+CD25+ T cells appear to be members of a unique lineage of regulatory T cells, as the induction of CD25 expression on a monospecific population of T cells derived from TCR transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, the TCR transgenic SCID mice were highly susceptible to autoimmune disease induced by the cloned line of autoantigen-specific effectors, while normal mice were relatively resistant. The capacity of the cloned line to transfer disease to nu/nu recipients could be inhibited by normal spleen cell populations containing CD4+CD25+ cells and by purified CD4+CD25+ cells. Although the target Ag(s) and mechanism of action of the CD4+CD25+ T cells remain to be determined, it is likely that they also play an important role in modulating other autoimmune diseases that are mediated by activation of "ignorant" self-reactive T cells present in the normal peripheral lymphocyte pool.     

Effects of type I/type II interferons and transforming growth factor-beta on B-cell differentiation and proliferation. Definition of costimulation and cytokine requirements for immunoglobulin synthesis and expression

In this report, we sought to determine the role of selected type I interferons [interferon-alpha (IFN-alpha) and interferon-tau (IFN-tau)], IFN-gamma and transforming growth factor-beta (TGF-beta) in the regulation of bovine antibody responses. B cells were stimulated via CD40 in the presence or absence of B-cell receptor (BCR) cross-linking. IFN-alpha enhanced IgM, IgG2 and IgA responses but did not enhance IgG1 responses. BCR signalling alone was more effective at inducing IgG2 responses with IFN-alpha than dual cross-linking with CD40. Recombinant ovine IFN-tau was less effective at inducing IgG2 responses when compared with IFN-alpha, though IgA responses were similar in magnitude following BCR cross-linking. At higher concentrations, IFN-tau enhanced IgA responses greater than twofold over the levels observed with IFN-alpha. Previous studies have shown that addition of IFN-gamma to BCR or pokeweed mitogen-activated bovine B cells stimulates IgG2 production. However, following CD40 stimulation alone, IFN-gamma was relatively ineffective at stimulating high-rate synthesis of any non-IgM isotype. Dual cross-linking via CD40 and the BCR resulted in decreased synthesis of IgM with a concomitant increase in IgA and similar levels of IgG2 production to those obtained via the BCR alone. We also assessed the effects of endogenous and exogenous TGF-beta on immunoglobulin synthesis by bovine B cells. Exogenous TGF-beta stimulates both IgG2 and IgA production following CD40 and BCR cross-linking in the presence of IL-2. Blocking endogenous TGF-beta did not inhibit the up-regulation of IgG2 or IgA by interferons.     

Is epsilon-aminocaproic acid as effective as aprotinin in reducing bleeding with cardiac surgery?: a meta-analysis

Infection of BALB/c mice with Trypanosoma cruzi resulted in up-regulated expression of Fas and Fas ligand (FasL) mRNA by splenic CD4+ T cells, activation-induced CD4+ T cell death (AICD), and in Fas: FasL-mediated cytotoxicity. When CD4+ T cells from infected mice were co-cultured with T. cruzi-infected macrophages, onset of AICD exacerbated parasite replication. CD4+ T cells from T. cruzi-infected FasL-deficient BALB gld/gld mice had no detectable AICD in vitro and their activation with anti-TCR did not exacerbate T. cruzi replication in macrophages. However, infection of BALB gld/gld mice with T. cruzi resulted in higher and more prolonged parasitemia, compared to wild-type mice. Secretion of Th2 cytokines IL-10 and IL-4 by CD4+ T cells from infected gld mice was markedly increased, compared to controls. In addition, in vivo injection of anti-IL-4 mAb, but not of an isotype control mAb, reduced parasitemia in both gld and wild-type mice. These results indicate that, besides controlling CD4+ T cell AICD and parasite replication in vitro, an intact Fas: FasL pathway also controls the host cytokine response to T. cruzi infection in vivo, being required to prevent an exacerbated Th2-type immune response to the parasite.     

Increased expression of the monocyte differentiation antigen CD14 in extrinsic allergic alveolitis

Expression of the CD14 antigen was studied on alveolar macrophages in extrinsic allergic alveolitis (EAA), using immunocytochemistry and cytometry. Compared to control donors, EAA patients had higher percentages of My4 positive cells (40 versus 22%), and the antigen density was fourfold higher (410 versus 92 channels). Levels of soluble CD14 (sCD14) in serum were found to be increased in EAA patients with an average of 4.6 +/- 1.5 micrograms.ml-1 compared to 3.2 +/- 0.7 micrograms.ml-1 in controls. Follow-up of patients with antigen avoidance revealed a concomitant decrease of CD14 staining of alveolar macrophages (AMs) and of sCD14 in serum, whilst allergen exposure induces both parameters. These data are consistent with the concept that antigen contact upregulates CD14 expression on AMs in EAA, followed by shedding and increase of sCD14 in serum.