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Modification of in vitro and in vivo immune function by acute inflammatory cells.

The ability of adoptively transferred, syngeneic polymorphonuclear leukocyte-rich (PMNLr) inflammatory cells to influence lymphocyte-mediated cytotoxicity (LMC), complement-dependent cytotoxicity (CDC), and skin allograft survival was studied in a murine model. BALB/c mouse PMNLr, stimulated by i.p. injection of either glycogen (G/PMNLr) or thioglycollate (T/PMNLr), were transferred to other BALB/c mice at the time of primary or secondary immunization with a cellular alloantigen (C57BL/6 spleen cells) or after skin allografting (C57BL/6 tailskin). The metabolic activity of each PMNLr population was determined by measuring glucose utilization in the hexose monophosphate shunt. It appeared that metabolic activity of the T/PMNLr was significantly greater than that of the G/PMNLr. Our results indicate that, while the infusion of G/PMNLr tended to suppress the primary cell-mediated immune response and the secondary humoral immune response, the infusion of T/PMNLr stimulated both of these responses. Furthermore, i.p. infusion of mice with G/PMNLr at a time approximating grafting resulted in prolonged graft survival, but neither T/PMNLr nor syngeneic thymocytes effect graft survival. Our data demonstrate that both cellular and humoral immunity can be modified by acute inflammatory cells. The metabolic status of the acute inflammatory cells seems to be critical in determining their immunoregulatory potential.

Animals↗

1,25-Dihydroxyvitamin D3 as a natural regulator of human immune functions.

1,25-dihydroxyvitamin D3 (1,25-D3) modulates lymphocyte and macrophage functions in vitro. These effects are exerted through production of 1,25-D3 by antigen-presenting monocytes/macrophages (MO) and binding to vitamin D receptors expressed in MO and in activated, but not in resting T-lymphocytes. 1,25-D3 inhibits production of MO-derived cytokines such as interleukin-1 alpha, interleukin-6, and tumor necrosis factor alpha at the post-transcriptional level, most likely by reducing the half-life of specific mRNAs. The proliferation of T-cells and their release of cytokines such as IL-2 and interferon gamma are also suppressed by 1,25-D3, partly as a result of the reduced production of T-cell-activating cytokines (interleukin-1 alpha, tumor necrosis factor alpha), but also because of a direct effect on the T-cells. Although 1,25-D3 has no apparent effect on B-lymphocytes, the T-cell suppression indirectly inhibits antibody production by B-cells. The CD45R0+ subset of T-helper cells is relatively more sensitive than the CD45RA+ subset to the inhibitory effects of 1,25-D3. The CD45R0+ subset plays a key role in immune activation and in the pathogenesis of many autoimmune disease. 1,25-D3 acts as an important local regulator of T-cell functions and thus modulates several immunological effector functions. The actions of 1,25-D3 are distinct from those of commonly used immunosuppressants, and vitamin D3 analogs are therefore potentially useful as alternatives to conventional immunosuppressive therapies.

Calcitriol↗

Modulation of microglial form and immune function by factors released from goldfish optic nerves.

Activation of microglia is associated with neural damage and may aid repair of the CNS. To begin to investigate their role, microglia purified from mouse brain were grown in media conditioned (CM) by goldfish optic nerve (GFON), optic tectum (GFOT), vagal lobe, telencephalon and cerebellum, and medium conditioned by rat optic nerves (RON). Microglia maintained in GFON- or GFOT-CM assumed an ameboid morphology, whereas microglia grown in media conditioned by the other neural tissues produced long, crenellated processes that resembled the ramified microglial form. Microglia maintained in all types of CM functioned as antigen presenting cells in a MHC-restricted manner when tested on conalbumin-specific Thelper (Th) cells, except for microglia maintained in GFON- and GFOT-CM. These studies suggest that GFON, in contrast to RON, produces a substance(s) that affects microglial morphology and immune reactivity, and may promote the vigorous regeneration seen in GFON after damage.

Animals↗

Effect of acute nutritional deprivation on immune function in mice. I. Macrophages.

This study was designed to explore the effects of acute nutritional deprivation (starvation) on macrophage function in mice. In vivo macrophage activity was increased by starvation, as determined by multiplication of Listeria monocytogenes in both spleens and livers after intravenous injection. Similarly, in vitro studies revealed that the capacity of peritoneal macrophages to kill listeria was enhanced by starvation. This function was increased further by the addition of small concentrations of lipopolysaccharide (LPS; 10-100 ng/ml). The bactericidal activity of macrophages from starved mice, however, did not reach the levels observed with macrophages from BCG-infected mice. Furthermore, LPS did not appear to be an important second signal for macrophage activation in vivo, as LPS-unresponsive mice (C3H/HeJ and A/J) were protected by starvation. In contrast to these results we found that starved mice were not protected against Toxoplasma gondii infection and that macrophages from starved mice were unable to prevent multiplication of toxoplasma trophozoites in vitro. In toto, these experiments suggest that macrophage function is enhanced by starvation, but that this enhancement is not sufficient to fulfill all criteria for macrophage activation.

Animals↗

Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disease characterized by hypogammaglobulinemia and lack of antibody production. Numerous T cell defects have been described, including reduced gene expression and production of IL-2. Since some of the T cell defects could be explained by lack of IL-2, we have been investigating the effects of in vivo IL-2 treatment. Here, a long-acting form of IL-2, PEG-IL-2, was given for 12-18 months to 15 randomly chosen CVID subjects, in comparison to 39 CVID subjects who served as controls. After 6 to 12 months of treatment, T cell proliferative responses to mitogens and to IL-2 were significantly enhanced; proliferative responses to tetanus and candida antigens increased up to 50-fold. Four of eight subjects immunized with the neoantigen bacteriophage φX 174 displayed increased antibody responses after treatment. Treated subjects recorded reduced, but not overall statistically significant, days of bronchitis, diarrhea, and joint pain. These data indicate that IL-2 might serve as an adjuvant to therapy in some subjects with CVID, enhancing T cell functions and reversing T cell anergy in most.

Adolescent↗

Immune function in malignant cervical neoplasia: a multiparameter analysis.

Immunological assessment was carried out in 67 patients with various stages and histological grades of squamous cell carcinoma of the uterine cervix and compared with normal controls to discover whether any of these parameters could be used as an indicator of the patient's clinical status. The results show a gross impairment of the various lymphocyte subpopulations and anti-tumor immunity. This impairment was more pronounced in patients with high tumor load and having a histology of poorly differentiated squamous cell carcinomas. None of the parameters studied (total leukocyte numbers, lymphocyte subpopulations, leukocyte adherence inhibition test, natural killer cell activity, circulating immune complexes, and blocking effect of autologous serum) could be used as a clinical indicator, since no correlation could be noted between immune impairment and either the lymphocyte subpopulations or the circulating immune complexes.

Adult↗

Regulation of in vitro and in vivo immune functions by the cytosolic adaptor protein SKAP-HOM.

SKAP-HOM is a cytosolic adaptor protein representing a specific substrate for the Src family protein tyrosine kinase Fyn. Previously, several groups have provided experimental evidence that SKAP-HOM (most likely in cooperation with the cytosolic adaptor protein ADAP) is involved in regulating leukocyte adhesion. To further assess the physiological role of SKAP-HOM, we investigated the immune system of SKAP-HOM-deficient mice. Our data show that T-cell responses towards a variety of stimuli are unaffected in the absence of SKAP-HOM. Similarly, B-cell receptor (BCR)-mediated total tyrosine phosphorylation and phosphorylation of Erk, p38, and JNK, as well as immunoreceptor-mediated Ca(2+) responses, are normal in SKAP-HOM(-/-) animals. However, despite apparently normal membrane-proximal signaling events, BCR-mediated proliferation is strongly attenuated in the absence of SKAP-HOM(-/-). In addition, adhesion of activated B cells to fibronectin (a ligand for beta1 integrins) as well as to ICAM-1 (a ligand for beta2 integrins) is strongly reduced. In vivo, the loss of SKAP-HOM results in a less severe clinical course of experimental autoimmune encephalomyelitis following immunization of mice with the encephalitogenic peptide of MOG (myelin oligodendrocyte glycoprotein). This is accompanied by strongly reduced serum levels of MOG-specific antibodies and lower MOG-specific T-cell responses. In summary, our data suggest that SKAP-HOM is required for proper activation of the immune system, likely by regulating the cross-talk between immunoreceptors and integrins.

Adaptor Proteins, Signal Transducing↗

Abnormal immune function in vivo in a murine model of lysosomal storage disease.

Lysosomal storage diseases are a class of inborn errors of metabolism that lead to widespread disease in multiple tissues. The murine model of mucopolysaccharidosis type VII (MPS VII) closely parallels the human syndrome and has been extensively used to investigate the natural history and therapeutic strategies for lysosomal storage diseases in general. Here we demonstrate a previously undescribed immune defect in the MPS VII mouse. Although the normal populations of cells are present in lymph nodes of these mice, MPS VII mice show a blunted T cell proliferative response and decreased antibody production after immunization with antigens. One mechanism of this defect is ineffective processing of protein antigens, as responses to peptide antigens are normal. This phenotype is presumably caused by the lysosomal disorder, as the defect can be corrected in vivo by direct enzyme replacement therapy. These findings have implications for the use of this animal model, and may have clinical significance for other, more-common lysosomal storage diseases.

Animals↗

In vitro immune function after vaccination with an inactivated, gp120-depleted HIV-1 antigen with immunostimulatory oligodeoxynucleotides.

We examined the effect of a synthetic oligodeoxynucleotide containing unmethylated CpG immunostimulatory sequences (ISS) as an adjuvant for an HIV-1 immunogen (inactivated, gp120-depleted HIV-1 virus particles). The addition of the ISS to HIV-1 in incomplete Freund's adjuvant (IFA) was the optimal combination for the production of HIV-1-specific immune responses as measured by IFN-gamma (p=0.002) and IgG antibody production. Furthermore, the group that was immunized with HIV/IFA/ISS, as well as the group that received HIV-1 in complete Freund's adjuvant (CFA), stimulated significantly more RANTES (a beta-chemokine) (p=0.002) production from lymph node cells. These results suggest that the addition of CpG immunostimulatory sequences to HIV antigens in IFA may optimize HIV-1-specific immune responses and provides further rationale for the testing of ISS in combination with gp120-depleted whole-killed HIV-1 in IFA as a potential preventive or therapeutic HIV-1 vaccine.

AIDS Vaccines↗

Diet and immune function.

Adequate human nutrition is essential to maintain all normal physiological functions including defence of the self. Controversy exists about the precise constituents of diets optimal for all stages in the human life-span. Dietary composition may also need to be altered under such stressful conditions as infection or recovery from major surgery. Understanding how specific nutrients can alter immune responses may add to the quality of human lives by minimising the impact of disease morbidity and mortality. Dietary modification also offers hope of new therapeutic regimens for human diseases.

Aging↗

Effect of thymic hormone treatment on several immune functions of nude mice.

Studies of the effect of short-term, intense treatment with thymic hormone on mitogen response, cytotoxicity to EL-4 lymphoma and natural killer cell (NK) activity was investigated Balb/c nude mice (about 12-16-week-old) were treated 5 times per week for 3 weeks with: Facteur Thymic Serique (FTS) and Thymopentin (TP5, Thymopoietin 32-36) at 1 microgram and 10 ng; TM4 1 ng (an enzyme resistant variant of FTS); Thymosin Fraction V (TF5), 10 and 1 microgram; and 0.1 ml saline, and killed 2 days after the last treatment. The animals were monitored for changes in weight, hematocrit, peripheral blood lymphocyte (PBL) and spleen mitogen response. Additional groups of nude mice were immunized with 1 x 10(7) 5000 R irradiated EL-4 cells 10 days before sacrifice and tested for the presence of cytotoxic T-lymphocytes (CTL). The results show that weight and hematocrit were similar among the groups. Treatment with FTS significantly elevated the number of PBL. Spleen stimulation in mice treated with 1 microgram TP5 was depressed to mitogen concanavalin A (ConA) and lipopolysaccharide (LPS) stimulation. The phytohemagglutinin (PHA) response was not different among the treatment groups. The PBL mitogen response to ConA and LPS was generally increased over saline control in the hormone treated groups but was not statistically significant. The PHA response was only slightly elevated. No CTL was generated in nude mice in any of the groups. However, there was a statistically significant general depression of NK activity in all of the hormone treated animals compared with saline. The results indicate that the basic differentiation defect of the T-cells of nude mice cannot be restored to full functional activity by short-term treatment.

Aging↗

Altered cellular immune function in the atelectatic lung.

Pulmonary atelectasis is common and may predispose the lung to infection. We have previously shown that atelectasis impairs alveolar macrophage antibacterial function. This study examines the effect of atelectasis on the cytotoxic function of lymphocytes harvested from the bronchoalveolar space of atelectatic lung segments by bronchoalveolar lavage. Specifically, we studied natural killer and lectin-dependent cell-mediated cytotoxicity in peripheral blood and bronchoalveolar lavage lymphocytes from the atelectatic lower lobes and contralateral normal lobes in a group of 8 dogs. We observed a decline of natural killer and lectin-dependent cell-mediated cytotoxicity to 62.7% and 61.5%, respectively, of preatelectasis control values in the affected lung lobes (p less than 0.01). Simultaneous measurements of cytotoxic activity of bronchoalveolar lavage lymphocytes harvested from the unaffected contralateral normal lungs were comparable with control values. On the other hand, natural killer and lectin-dependent cell-mediated cytotoxicity activities in peripheral blood lymphocytes were significantly increased in animals having right lower lobe atelectasis (166.7% and 154.7% of pretreated normal control, respectively, p less than 0.01). Atelectasis was also associated with an influx of polymorphonuclear leukocytes into the bronchoalveolar compartment. These findings confirm the presence of natural killer cells and cytotoxic lymphocytes in the bronchoalveolar compartment and demonstrate an atelectasis-induced impairment of local bronchoalveolar lymphocyte function. Such a dysfunction of local lung cellular host defenses may render the atelectatic lung susceptible to infection.

Animals↗

The interactive effects of cocaine/gender on immune function in mice. An observation of in vivo acute cocaine exposure.

The present experiments used a mouse model including both sexes to study the impact of acute cocaine exposure on the function of four major immunocompetent cell types (T, B cells, NK, and macrophages). Cocaine hydrochloride, 5 mg or 40 mg/kg, was administrated by i.p. injection to C57BL/6 mice. Thymocytes and splenocytes were obtained 24 h after injection. Acute in vivo cocaine exposure inhibited the proliferation of T lymphocytes in response to Con-A in both thymocytes and splenocytes. However, the attenuated IL-2 production was only seen in thymocytes. These effects on T cells were greater in male mice than in female mice. The function of macrophages was also impaired by acute cocaine exposure; however, the impact was greater in female than in male mice. In conclusion, the effects of acute cocaine exposure altered the functions of immunocompetent cells and the effects varied with gender.

Animals↗

Idiopathic polyneuritis: serial studies of nerve and immune functions.

The clinical features of idiopathic polyneuritis in 22 patients admitted to the University of Kentucky Medical Center between July 1965 and June 1970 are described. Serial studies of peripheral nerve function in 12 patients followed to clinical recovery showed changes in nerve conduction velocity, distal motor latency, and/or muscle action potential amplitude. Six children and one adult, showing a change in all three parameters, exhibited a strong correlation between the degree of slowing and the shortness of their illness. Assessment of immune status, by quantitative measurement of cerebrospinal fluid immunoglobulin G(11 patients) and by the degree of lymphocyte transformation on exposure to specific brain protein and/or a homogenate of sciatic nerve (10 patients), bore no consistent relation to the severity or course of the illness. A double-blind trial of short-term, high dose adrenocorticotrophic hormone has yielded no valid evidence to date for or against the effectiveness of such therapy in this illness.

Action Potentials↗

The role of BAFF in immune function and implications for autoimmunity.

BAFF [B-cell activating factor belonging to the tumor necrosis factor (TNF) family] is a ligand that is required for peripheral B-cell survival and homeostasis. In addition to mediating B-cell survival, BAFF also regulates expression of certain B-cell-surface proteins, such as CD21/35. BAFF deficiency results in a reduced number of peripheral B cells and a diminished ability to mount robust humoral immune responses. Overexpression of BAFF has been linked to murine and human autoimmunity, and recent data provide clues as to how excess BAFF may allow the emergence of autoreactive B cells. In vivo animal testing with BAFF inhibitors has generated exciting data that support the pathway as a target for modulating B cells. The role of BAFF in B-cell biology, T-cell biology, and autoimmunity is discussed, as well as current efforts to develop BAFF inhibitors for clinical testing in autoimmune disorders.

Animals↗

The anatomical basis for the immune function of the gut.

The barrier function of the gut wall can be divided into different histotopographically defined lines of defence. These consist not only of lymphoid cells but also of goblet cells, entero-endocrine cells, macrophages and mast cells. Subsets of lymphoid cells are found preferentially within the epithelium (T suppressor) or in the lamina propria (T helper). Most plasma cells produce IgA. Peyer's patches are described in detail as typical organized lymphoid structures of the gut. In man, they are present well before birth and are found in large numbers even in old age. They are not only typical for the ileum but are also present in the duodenum and jejunum. The four compartments in Peyer's patches, i.e. follicle, corona, interfollicular area and the dome, are defined by the typical localization of lymphocyte subsets and by their different functions. Typical features of the epithelium of the dome are the lack of villi and goblet cells and the presence of specialized epithelial cells (M cells) which are important for the uptake of particulate antigen from the gut lumen. Precursor cells of IgA producing plasma cells leave the intestinal wall via the lymphatics and return preferentially to the gut mucosa, and this is summarized by the term gut-associated lymphoid tissue (GALT). Other organs with mucous membranes, such as mammary and salivary glands, bronchial and genital tract, are also included in this circulatory route and this is expressed by the term mucosa-associated lymphoid tissue (MALT). Mast cells in the gut mucosa can be classified as connective tissue or mucosa mast cells. These differ in their sensitivity to formaldehyde as a fixative, contain different granules and mediators, have different origins, and show major differences in the effectiveness of antiallergic compounds on the stabilizing of the cell membrane. Mucosa mast cells have also been demonstrated in the human gut. The histotopographical relationship of many cell types such as goblet and M cells in addition to cells of the immune system such as lymphoid cells, macrophages and mast cells, is essential in the understanding of the barrier function of the gut wall.

Animals↗