Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bispecific antibody (BsMAb) BIS-1 has been developed to redirect the cytolytic activity of cytotoxic T lymphocytes (CTL) to epithelial glycoprotein-2 (EGP-2) expressing tumour cells. Intravenous administration of BIS-1 F(ab')2 to carcinoma patients in a phase I/II clinical trial, caused immunomodulation as demonstrated by a rapid lymphopenia prior to a rise in plasma tumour necrosis factor-alpha and interferon-gamma levels. Yet, no lymphocyte accumulation in the tumour tissue and no anti-tumour effect could be observed. These data suggest a BsMAb-induced lymphocyte adhesion to blood vessel walls and/or generalized redistribution of the lymphocytes into tissues. In this study, we describe the effects of BIS-1 F(ab')2 binding to peripheral blood mononuclear cells (PBMC) on their capacity to interact with resting endothelial cells in vitro. Resting and pre-activated PBMC exhibited a significant increase in adhesive interaction with endothelial cells when preincubated with BIS-1 F(ab')2, followed by an increase in transendothelial migration (tem). Binding of BIS-1 F(ab')2 to PBMC affected the expression of a number of adhesion molecules involved in lymphocyte adhesion/migration. Furthermore, PBMC preincubated with BIS-1 F(ab')2 induced the expression of endothelial cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 during adhesion/tem. These phenomena were related to the CD3 recognizing antibody fragment of the BsMAb and dependent on lymphocyte-endothelial cell contact. Possibly, in patients, the BIS-1 F(ab')2 infusion induced lymphopenia is a result of generalized activation of endothelial cells, leading to the formation of a temporary sink for lymphocytes. This process may distract the lymphocytes from homing to the tumour cells, and hence prevent the occurrence of BIS-1 F(ab')2 - CTL-mediated tumour cell lysis.
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PMID:CD3 directed bispecific antibodies induce increased lymphocyte-endothelial cell interactions in vitro. 1064 7

To develop a T-cell-based therapy for carcinomas, the superantigen staphylococcal enterotoxin A (SEA) was supplied with tumor specificity by means of a recombinant fusion of the Fab fragment of the monoclonal antibody C242 recognizing human colorectal (CRC) and pancreatic carcinomas (PC). Using this Fab-SEA fusion protein (PNU-214565), potent cytotoxicity by activation of T cells can be obtained in the targeted area. Twenty-one patients with CRC and 3 with PC were treated with single, escalating doses of PNU-214565 to establish the maximum tolerated dose (MTD) and to define toxicities. The doses ranged from 0.01 ng/kg to 4.0 ng/kg with three patients at each dose level, except for the dose of 1.5 ng/kg with which six patients were treated because of dose-limiting toxicity. Adverse events (AE) were transient: 13 patients experienced mild to moderate fever. In one patient, a grade 3 fever was followed by a grade 2 hypotension. Other mild or moderate AEs were fatigue, nausea, vomiting, diarrhea, and abdominal pain. No significant hematological toxicity occurred. Immune activation was highly variable with strong activity in peripheral blood seen only in two patients at the dosage level 1.5 ng/kg. They showed pronounced elevations of interleukin-2 (IL-2), IL-6, tumor necrosis factor-alpha, and interferon-gamma, 3-5 hours after the start of infusion. In one patient, IL-2 and IL-6 increased substantially (2,925 U/mL and 32,000 U/mL) concomitantly with grade 3 fever and transient grade 2 neutropenia, grade 2 lymphopenia, and grade 2 monocytopenia. In conclusion, a single 3-hour infusion of PNU-214565 could be safely administered up to 4 ng/kg. MTD was not determined. Instead, a repeat-dose trial was initiated starting at 0.5 ng/kg, considered safe in this trial, with the objective of defining the MTD.
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PMID:Phase I study of single, escalating doses of a superantigen-antibody fusion protein (PNU-214565) in patients with advanced colorectal or pancreatic carcinoma. 1068 47

In vitro and in vivo, tryptophan degradation was found to be associated with T cell functional loss and tolerance induction. In systemic lupus erythematosus (SLE) besides the Th2-type cytokine interleukin-10, Th1-type cytokines including interferon-gamma (IFN-gamma) are expressed especially during exacerbation of the disease. IFN-gamma stimulates the enzyme indoleamine (2,3)-dioxygenase (IDO) converting tryptophan to the metabolite kynurenine which in macrophages is subsequently degraded to other, partly neurotoxic compounds like quinolinic acid, and finally to nicrotinamides. We measured kynurenine and tryptophan concentrations in the sera of 55 SLE patients. In these patients, the concentrations of tryptophan (median, interquartile range: 53.9, 45.7-64.1 microM) were lower (p < 0.0001), and the kynurenine concentrations (2.45, 1.75-3.40 microM) were increased (p < 0.0005) compared to healthy blood donors (70.0, 63.8-80.6; 1.80, 1.45-2.27 microM, respectively). Also the kynurenine per tryptophan quotients (K/T), which allow to estimate IDO activity, were significantly higher in patients than in normals (0.043, 0.033-0.062 vs. 0.027, 0.021-0.030; p < 0.0001), indicating enhanced IDO-induced tryptophan degradation in SLE. There was no significant relationship between tryptophan, kynurenine and the SLEDAI, and also the correlation of K/T with SLEDAI was rather weak (rs = 0.243, p < 0.05). Higher K/T was found in patients presenting with serositis (p = 0.01), decrease of complement (c3, c4; p < 0.01) and blood count change (anemia, leucopenia, lymphopenia; p = 0.032) than in patients without such disease manifestations. The significant correlation found between K/T and neopterin (rs = 0.808, p < 0.001), a marker of immune activation, points to a role of immune activation to be responsible for tryptophan degradation in SLE patients.
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PMID:Enhanced tryptophan degradation in systemic lupus erythematosus. 1083 18

Measles virus infection induces a profound immunosuppression. We analyzed in a time-dependent manner peripheral bloods of one to two-year-old children immunized with live attenuated measles vaccines, compared with age-matched measles patients, for immunosuppression. In contrast to transient severe lymphopenia with measles patients, primarily due to extensive apoptosis of a broad spectrum of uninfected lymphocytes, neither apoptosis nor lymphopenia occurred with measles vaccine recipients. Increase in number and activation of NK cells, which might compensate for the lymphopenia in measles patients, were not found with the vaccinees. While cell surface expression of apoptosis-related molecules such as TNF-related apoptosis-inducing ligand (TRAIL), TRAIL-receptors, CD95(Fas) and Fas-ligand, and plasma interferon-gamma were increased for measles patients, they remained unchanged after vaccination. Plasma interleukin (IL)-18, which is responsible for inducing apoptosis in several infectious diseases, was increased predominantly with measles patients, whereas the increase remained marginal with the vaccinees. IL-10 was elevated transiently in both measles patients and vaccinees. Decrease in plasma IL-12, which is often correlated with T cell suppression, was not found for both cases. Serum IgM and IgG antibodies to measles virus were induced at lower titers in the vaccinees than measles patients. These results indicate that in contrast to wild-type measles virus, live measles vaccines hardly provoked host cytokine responses that lead to apoptotic cytolysis of uninfected lymphocytes, lymphopenia and immunosuppression, and thereby induced weaker immune responses to the virus.
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PMID:Comparative analysis of host responses related to immunosuppression between measles patients and vaccine recipients with live attenuated measles vaccines. 1144 26

Morbilliviruses are highly contagious pathogens that cause some of the most devastating viral diseases of humans and animals, including measles virus (MV), canine distemper virus (CDV), and rinderpest virus (RPV). They replicate mainly in lymphoid organs throughout the body and cause severe immunosuppression accompanied with lymphopenia. We have recently shown that human, canine, and bovine signaling lymphocyte activation molecules (SLAMs; also known as CD150) act as cellular receptors for MV, CDV, and RPV, respectively. In these three morbilliviruses, all strains examined were shown to use SLAMs of their respective host species, and laboratory strains passaged on SLAM-negative cells were found to use, besides SLAM, alternative receptors, such as human CD46 for the Edmonston strain of MV. The use of SLAM as a receptor may be a property common to most, if not all, of the members of morbilliviruses. Human SLAM is a membrane glycoprotein selectively expressed on the cells of the immune system (immature thymocytes, activated lymphocytes, activated monocytes, and mature dendritic cells) and seems to mediate lymphocyte activation and to control interferon-gamma production. The destruction and/or impairment of infected SLAM-positive cells may be a mechanism for the immunosuppression induced by morbilliviruses, but other mechanisms may be also involved.
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PMID:The morbillivirus receptor SLAM (CD150). 1200 21

Rupture of follicular (epidermoid) cysts is believed to be the consequence of bacterial infection. We report a 24-year-old man with idiopathic CD4 lymphopenia and chronic Mycobacterium avium intracellulare infection who developed multiple, recurring painful abscesses over the distal extremities that increased in number and severity when systemic steroid and interferon-gamma treatment was instituted for interstitial lung disease. Cultures were consistently negative for microorganisms, but pathological examination revealed ruptured epidermoid cyst walls with human papillomavirus (HPV) viropathic changes (keratinocytes with perinuclear halos and abundant basophilic keratohyaline granules). Cutaneous examination showed numerous, widespread flat-topped papules and achromic macules over the extremities, head and neck. Nested polymerase chain reaction analysis for HPV DNA revealed that the abscess-related cyst walls harboured epidermodysplasia verruciformis (EV)-associated HPV types 20, 24, alb-7 (AY013872) and 80. His cutaneous lesions harboured HPV types 3, 8 and 80. Similar to past reports, our patient developed an EV-like eruption in the setting of immunodeficiency. In this instance, EV-associated HPV infection of the follicular infundibular epithelium or pre-existing cysts in the setting of immunodeficiency may have led to cystic growth, rupture and subsequent painful inflammation.
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PMID:Recurrent 'sterile' verrucous cyst abscesses and epidermodysplasia verruciformis-like eruption associated with idiopathic CD4 lymphopenia. 1451 Oct

To examine the effect of recombinant bovine interferon-gamma (rbIFN-gamma) on cattle persistently infected with bovine leukemia virus (BLV), BLV-infected cattle were inoculated intraperitoneally with IFN-gamma. All cattle were febrile after inoculation with IFN-gamma and then recovered within 48 h. Flow cytometric analysis showed that the numbers of CD4+ and CD8+ T cells were decreased for 2-3 days and then their numbers were recovered. The number of gammadelta T cells increased after the fever. In contrast, the number of IgM+ lymphocytes remained low for about 1 week. Moreover, the numbers of syncytia produced by peripheral blood lymphocytes decreased and remained low compared to that before IFN-gamma administration. These results suggest that IFN-gamma induces the up-regulation of gammadelta T cells, decreases the number of IgM+ lymphocytes and suppresses the growth of BLV in BLV-infected cattle in vivo.
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PMID:Increase in gammadelta T cells in the blood of cattle persistently infected with bovine leukemia virus following administration of recombinant bovine IFN-gamma. 1526 93

Decreased lymphocyte proliferation, lymphopenia, immunodepression, and opportunistic infections are common after major trauma. Early alimentation in these patients corrects lymphopenia, enhances immunity, and reduces the incidence of infections, but the underlying mechanisms are poorly understood. Tryptophan is essential for the production and function of rapidly proliferating cells such as lymphocytes. Tryptophan is enzymatically degraded by indoleamine 2,3-dioxygenase (IDO), whose activity is solely dependent on expression of interferon-gamma (IFN-gamma). Because increased expression of IFN-gamma has been reported in trauma patients, we investigated whether enhanced IDO-mediated tryptophan degradation is associated with lymphopenia and poor outcomes after major trauma. The incidence of bacteremic sepsis (BS), adult respiratory distress syndrome (ARDS), multiple organ dysfunction/failure syndromes (MODS/MOF), and death was prospectively documented in 22 trauma patients with a mean ISS of 24.9 +/- 2.2. Sequential blood samples were obtained from admission through postinjury day 10. Five patients developed BS, three of whom developed ARDS; two of the three ARDS patients developed MOF and died on day 10. Trauma patients had significantly lower tryptophan levels (days 1-10), higher kynurenine:tryptophan ratios (days 1-2), and fewer lymphocytes (days 1-4) than healthy volunteers (P < 0.05). Although patients with poor outcomes (i.e., BS, ARDS, MOF, and death) had significantly lower tryptophan levels and greater lymphopenia on several days after injury, the sample size was too small to draw any definitive conclusions. These data indicate that decreased plasma tryptophan levels and lymphopenia typically occur after major trauma. A concomitant increase in kynurenine suggests that the observed tryptophan deficiency is caused, in part, by IDO-mediated tryptophan degradation.
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PMID:Enhanced enzymatic degradation of tryptophan by indoleamine 2,3-dioxygenase contributes to the tryptophan-deficient state seen after major trauma. 1571 17

Interleukin-18 (IL-18) is a pleiotropic cytokine that enhances Th1 or Th2 immune response. We show a novel mechanism of gastric cancer cells that allows their immune escape utilizing IL-18. All 4 gastric cancer cell lines, but not colon lines, constitutively expressed IL-18 receptors and IL-18 dose-dependently enhanced their in vitro proliferation accompanied by nuclear factor kappaB activation. When IL-18-pretreated gastric cancer cells were cultured with cytokine-activated peripheral blood killer lymphocytes, the antitumor machineries, perforin or interferon-gamma production of killer lymphocytes decreased, resulting in a decreased susceptibility of cancer cells to killer lymphocytes. Furthermore, gastric cancer cells cultured with IL-18 showed an increased expression of a granzyme B inhibitor, protease inhibitor 9. IL-18 injections into severe combined immuno-deficient mice intraperitoneally inoculated with gastric cancer cells consistently decreased the mouse survival time. Our results indicate that gastric cancers exploit IL-18 to grow/invade and evade immunosurveillance in the hosts.
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PMID:Exploitation of interleukin-18 by gastric cancers for their growth and evasion of host immunity. 1604 75

The effect of various space allowances on the pituitary, adrenal and immune responses and on performance was investigated in 72 mature Holstein x Friesian beef bulls. The animals (weighing 403+/-3.5 kg) were blocked by weight and randomly assigned to two groups (familiar, F, and unfamiliar, UF) x three treatments (1.2, 2.7 and 4.2m(2) per bull; n=24 per space allowance), and housed for 83 days in 18 pens (n=4 per pen). Blood samples were collected on days -1, 0, 3, 14, 36 and 77 with respect to mixing and housing on day 0. The bulls were given exogenous adrenocorticotrophic hormone (ACTH) on day 3 and corticotrophin-releasing hormone (CRH) on days 14, 36 and 77. Basal plasma cortisol concentration was not affected (P>0.05) by mixing F and UF bulls. On day 3, basal cortisol was greater (P<0.05) in bulls housed at 1.2 than those at 2.7 and 4.2m(2) space allowances while no effect was observed in ACTH-induced plasma cortisol concentration among treatments. Following CRH administration, there was no effect (P>0.05) of treatment and treatment x time on plasma ACTH concentration. On day 14, interferon-gamma production was lower (P<0.05) in the bulls housed at 4.2 vs. 2.7 m(2) and was intermediate but not significantly different (P>0.05) for those housed at 1.2m(2). Animals housed at either space allowances had significant (P<0.05) neutrophilia, lymphopenia, eosinopenia and decreased haemoglobin on day 3 compared with day 0. The liveweight gain from days 0 to 83 was lower (P<0.05) in bulls housed at 1.2 compared with those at 2.7 and 4.2m(2). Housing bulls at 1.2m(2) space allowance had a detrimental effect on their growth and was associated with an acute rise in plasma cortisol concentration (on day 3) compared with those having space allowances of 2.7 and 4.2m(2)/bull.
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PMID:Pituitary, adrenal, immune and performance responses of mature Holstein x Friesian bulls housed on slatted floors at various space allowances. 1664 72


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