Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of treatment with a monoclonal antibody (R73 mAb) against T cell receptor alpha/beta (TCR-alpha/beta) on both established adjuvant arthritis (EAA) and established collagen-induced arthritis (ECIA) in rats have been investigated. Rats were treated with R73 mAb when arthritis reached a peak. Treatment with the anti-TCR-alpha/beta mAb markedly suppressed EAA, whereas ECIA was not affected by the mAb treatment. Histologically, R73 mAb-treated rats with EAA showed mild hyperplasia of synovial tissues, sparse infiltration of inflammatory cells, and minimal erosion of cartilage, whereas arthritic rats treated with PBS and an irrelevant control mAb against Giardia had marked hyperplasia of synovium with pannus, massive inflammatory cell infiltrate, and severe destruction of cartilage and subchondral bone. R73 mAb-treated rats with ECIA exhibited pronounced formation of pannus containing many inflammatory cells and marked cartilage and subchondral damage similar to those in arthritic rats that received the control treatments. Treatment with R73 mAb depleted markedly alpha/beta+ T cells in both peripheral blood and synovial tissues of rats with EAA and ECIA. R73 mAb treatment was associated with marked reduction in arthritogen-specific delayed-type hypersensitivity responses in both EAA and ECIA. The titers of antibodies against type II collagen produced in rats with ECIA were not affected by the mAb. Thus, alpha/beta+ T cells appear to have a central role in EAA, but not in chronic ECIA.
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PMID:Depletion of alpha/beta T cells by a monoclonal antibody against the alpha/beta T cell receptor suppresses established adjuvant arthritis, but not established collagen-induced arthritis in rats. 137 48

The development of autoimmune type I diabetes in the NOD mouse appears to be controlled by both genetic and environmental factors. This investigation was initiated to determine whether exogenous superantigens, as environmental factors, can influence the development of diabetes. Several staphylococcal enterotoxins (SE) (SEA, SEC1, SEC2, or SEC3), which are known superantigens, were injected i.v. into female NOD mice at 4 and 10 wk of age. At 32 wk of age, the incidence of diabetes in the SE-treated mice ranged from 6 to 12.5%; this was significantly lower than that of mice treated with PBS--64%. There was no significant difference in effectiveness among the various SE used. SE induced a modest decrease in T lymphocytes bearing specific V beta TCR 2 wk after injection, but this effect did not persist past 4 wk. To elucidate the mechanism of the SE effect, suppressor activity in SE-treated mice was evaluated. Splenocytes from SE-treated mice inhibited the transfer of diabetes by splenocytes from acutely diabetic NOD mice when injected into irradiated young NOD mice; only 10% became diabetic. In contrast, 83% of the mice receiving splenocytes from PBS-treated control mice became diabetic. Suppressor activity of splenocytes from SE-treated mice was diminished by the depletion of CD4+ T cells, but not by the depletion of CD8+ T cells, indicating that the suppressor cells belonged to the CD4+ T class of lymphocytes. On the basis of these observations, we conclude that exogenous superantigens activate CD4+ suppressor T cells, leading to the prevention of autoimmune type I diabetes in NOD mice.
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PMID:Prevention of autoimmune type I diabetes by CD4+ suppressor T cells in superantigen-treated non-obese diabetic mice. 840 8

T cell receptor (TCR/CD3) induced fluctuations in intracellular free ionizied calcium, [Ca2+]i, was analysed in the human T leukemia cell clone, Jurkat, cultured in the presence of the opioid methionine enkephalinamide (Met-Enk) in titrated concentrations (10[-7] to 10[-15] M) or saline (PBS). In the majority of individual experiments, the activation-induced fluctuations in [Ca2+]i were similar in cells cultured in the presence of Met-Enk and PBS, respectively. However, when all the experimental data from 101 separate TCR/CD3-activation experiments with Met-Enk were compared with the 67 separate control experiments, we found that a fraction (20-40%) of the individual sets of Met-Enk experiments responded significantly different when compared to PBS-controls. In this fraction of experiments the increase in [Ca2+]i after ligation of the TCR/CD3 complex was extremely slow compared to controls. Moreover, the levels of [Ca2+]i in this particular fraction were lower than control levels prior to ligation of the TCR/CD3 complex. The data support the idea that signal transduction in T cells can be influenced by endogenous opioid. The data therefore give credit to the evolving hypothesis of a functional relationship between the neuroendocrine system and the immune system.
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PMID:Effect of the opioid methionine enkephalinamide on signal transduction in human T-lymphocytes. 957 Mar 40

In in vivo tolerance induction, the dose of tolerogen injected is generally linearly correlated to the length of tolerance induced. Small, medium and large doses are related to no, partial and long-term tolerance, respectively. However, even with injection of substantially large doses of tolerogen, the length of tolerance induced varies over a wide range. Most of the recipients can still reject donor grafts. In this study, it is shown that the linear dose-response can be altered into an all or nothing response in a H-Y antigen-specific TCR transgenic (Tg) mouse model. In thymectomized female Tg mice, injection of 3, 30 and 100 x 10(6) male spleen cells was correlated to no, partial and massive deletion of Tg (alpha T beta T) CD8 cells, respectively. When the thymectomized Tg mice were injected with 9 x 10(6) T cell-enriched (T+) male cells, one half of the recipients showed no deletion of alpha T beta T cells, and in the other half massive deletion occurred. In complete correlation with deletion, all male skin grafts were rejected in the undeleted group as PBS-injected controls, whereas with massive deletion they were indefinitely tolerized. Thus, partial deletion and partial tolerance can be avoided. Injection of 18 x 10(6) male T+ cells induced long-term tolerance in all the recipients. The all or none T cell deletion and long-term tolerance induction has not only significant implications in understanding the mechanism of peripheral tolerance induction, but also in tolerance induction in transplantation, gene therapy and the prevention and treatment of autoimmune diseases.
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PMID:All or none peripheral tolerance induction in H-Y antigen-specific TCR transgenic mice. 977 95

Heat shock protein 65 (hsp65) and a derived peptide, p277, are autoantigens reported in IDDM. I.p. injection of hsp65 reduced diabetes incidence in NOD mice and administration of p277 cured already diabetic mice. Also, intrathymic (i.t.) administration of whole islets or GAD65 prevented diabetes in NOD mice. The aim of this study was to evaluate whether i.t. injection of mycobacterial hsp65 or p277 can prevent diabetes in NOD mice. Three-week-old NOD female mice were injected intrathymically with 50 microg of hsp65 (n=30), 5 microg of p277 (n=30), and PBS (n=29). Diabetes incidence was observed for the following 300 days. Pancreas was then used for histological and immunohistological evaluation. No significant differences in diabetes incidence were observed among the three groups of mice. Interestingly, hsp65-treated mice developed diabetes slightly faster at 177+/-6 days compared to 202+/-8 days (p=0.015) for the p277-treated group and 197+/-7 days (p=0.033) for controls. The insulitis score and average islet size did not differ significantly among the three groups of diabetic mice. Scattered TCR-gamma/delta positive cells were found in the pancreas of all groups of mice. In contrast, a huge infiltrate of TCR-gamma/delta positive cells was detected in four out of eight (50%) p277-diabetic NOD mice. Thus, our data show an earlier onset of diabetes in hsp65-treated mice and no improvement in the incidence with either hsp65 or p277, suggesting that hsp65 acts in a different way from what was reported with GAD65. Caution is advised in future vaccination studies as hsp65 poses a potential danger.
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PMID:Effect of intrathymic administration of mycobacterial heat shock protein 65 and peptide p277 on the development of diabetes in NOD mice: caution required in vaccination studies. 983 5

Thymic atrophy is an age-associated decline in commitment to the T cell lineage considered to be associated with defective TCR beta-chain rearrangement. Both IL-7 and stem cell factor (SCF) have dominant roles at this stage of triple negative (TN) thymocyte development. Because there is no age-associated decrease in the number of CD44(+)CD25(-)CD3(-)CD4(-)CD8(-) cells, this study investigated whether alterations in apoptosis within the TN pathway accounted for diminishing thymocyte numbers with age. Here we show significant age-associated increases in apoptotic TN thymocytes, specifically within CD44(+)CD25(+) and CD44(-)CD25(+) subpopulations, known to be the location of TCR beta-chain rearrangement. IL-7 added to TN cultures established from old mice significantly both reduces apoptosis and increases the percentage of live cells within CD44(+)CD25(+) and CD44(-)CD25(+) subpopulations after 24 h, with prosurvival effects remaining after 5 days. SCF failed to demonstrate prosurvival effects in old or young cultures, and IL-7 and SCF together did not improve upon IL-7 alone. IL-7R expression did not decline with age, ruling out the possibility that the age-associated increase in apoptosis was attributed to reduced IL-7R expression. Compared with PBS, treatment of old mice with IL-7 produced significant increases in live TN cells. By comparison, treatment with SCF failed to increase live TN numbers, and IL-7 and SCF together failed to significantly improve thymopoiesis above that shown by IL-7 alone. Thus, treatment with IL-7 alone can reverse the age-associated defect in TN thymocyte development revealed by in vitro studies to be located at the stages of TCR beta-chain rearrangement.
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PMID:Il-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. 1116 Jan 92

Pathogenic T cells in organ-specific autoimmune diseases use a limited number of TCR alpha- and beta-chains. In experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats by immunization with myelin basic protein, encephalitogenic T cells mainly use Vbeta8.2 TCR and clonal expansion of the Vbeta8.2 spectratype containing the EAE-specific complementarity-determining region 3 (CDR3) sequence, DSSYEQYFGPG, is found in the spinal cord throughout the course of clinical EAE. In the present study we performed temporal and spatial analyses of Vbeta8.2 spectratype expansion by CDR3 spectratyping and subsequent DNA hybridization with a probe specific for the encephalitogenic CDR3 sequence to elucidate the kinetics of encephalitogenic T cells during the induction phase after neuroantigen sensitization. It was demonstrated that Vbeta8.2 spectratype expansion and/or the positive signal in Southern blot were first detected in the regional lymph nodes as early as day 3 postimmunization and was disseminated over the lymphoid organs by day 6. Because perfusion of immunized rats with PBS erased the positive signals on day 3 postimmunization, the majority of Vbeta8.2-positive encephalitogenic T cells at the very early stage would reside within the lymphatic or blood vessels. Furthermore, removal of the draining lymph node 1, 3, and 6 days after immunization in the foot pad did not ameliorate clinical EAE. These findings strongly suggest that encephalitogenic T cells disseminate throughout the whole body very rapidly after sensitization. Analysis of pathogenic T cells at the clonal level provides useful information for designing effective immunotherapy.
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PMID:Tracking of V beta 8.2-positive encephalitogenic T cells by complementarity-determining region 3 spectratyping and subsequent Southern blot hybridization in Lewis rats after neuroantigen sensitization. 1538 83

Mycobacterial phosphatidylinositol tetramannosides (PIM4) are agonists for a distinct population of invariant human (Valpha24) and mouse (Valpha14) NKT cells, when presented by CD1d. We determined the crystal structure at 2.6-A resolution of mouse CD1d bound to a synthetic dipalmitoyl-PIM2. Natural PIM2, which differs in its fatty acid composition is a biosynthetic precursor of PIM4, PIM6, lipomannan, and lipoarabinomannan. The PIM2 headgroup (inositol-dimannoside) is the most complex to date among all the crystallized CD1d ligands and is remarkably ordered in the CD1d binding groove. A specific hydrogen-bonding network between PIM2 and CD1d orients the headgroup in the center of the binding groove and above the A' pocket. A central cluster of hydrophilic CD1d residues (Asp(153), Thr(156), Ser(76), Arg(79)) interacts with the phosphate, inositol, and alpha1-alpha6-linked mannose of the headgroup, whereas additional specificity for the alpha1- and alpha2-linked mannose is conferred by Thr(159). The additional two mannoses in PIM4, relative to PIM2, are located at the distal 6' carbon of the alpha1-alpha6-linked mannose and would project away from the CD1d binding groove for interaction with the TCR. Compared with other CD1d-sphingolipid structures, PIM2 has an increased number of polar interactions between its headgroup and CD1, but reduced specificity for the diacylglycerol backbone. Thus, novel NKT cell agonists can be designed that focus on substitutions of the headgroup rather than on reducing lipid chain length, as in OCH and PBS-25, two potent variants of the highly stimulatory invariant NKT cell agonist alpha-galactosylceramide.
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PMID:Structural characterization of mycobacterial phosphatidylinositol mannoside binding to mouse CD1d. 1698 95

Expression of MCP-1 in the central nervous system (CNS) is associated with various neuroinflammatory diseases, including multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In this study, we found that MCP-1 was decreased in the CNS but increased in the gut following oral administration of myelin basic protein (MBP) correlating with protection from EAE. To study the trafficking and the fate of T cells during oral tolerance, MBP-specific TCR transgenic (Tg) CD4(+) T cells were labeled using 5,6-carboxy-succinimidyl-fluorescein-ester (CFSE) and transferred intravenously to syngeneic B10.PL recipients before feeding with either MBP or PBS. We observed that the CFSE-labeled T cells traffic to the peripheral lymphoid tissue and the Peyer's patches (PP). The labeled T cells proliferate in vivo in both the lymph node and the PP 48h after MBP feeding, but the cells are maintained in the PP longer than in the LN. CFSE-labeled cells in the PP have high levels of CD69 and Fas expression which is accompanied by increased apoptosis after MBP feeding. Our observations suggest that oral administration of autoantigen induces an elevation of MCP-1 in the gut, early T cell trafficking and activation in the periphery and the PP, followed by deletion of autoreactive T cells in the PP.
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PMID:The Peyer's patch is a critical immunoregulatory site for mucosal tolerance in experimental autoimmune encephalomylelitis (EAE). 1800 71

Healthy liver, intestine, lung, and skin harbor resident lymphocytes with conventional and unconventional phenotypes. Lymphocytes also have been detected in healthy mice kidneys; however, these cells have not been well studied and have been largely overlooked. To better characterize the intra-renal lymphocytes, we extensively perfused C57BL/6J mice with PBS and then isolated mononuclear cells for flow cytometry analysis. We observed T cells, B cells, and NK cells in normal mice kidneys after extensive perfusion. Approximately 50% of kidney T lymphocytes expressed intermediate levels of CD3 (CD3int T cells). Similar to liver and lung, a high percentage of unconventional CD3+CD4(-)CD8(-) double-negative T cells was observed in normal mice kidneys, from which 11% expressed B220 antigen. Unlike the spleen and blood, the classic CD4+ and CD8+ T lymphocytes in the kidney had a high proportion of activated CD69+ and effector/memory CD44- CD62L ligand phenotypes. Also, a small percentage of CD4+CD25+forkhead box p3+ and NKT cells was observed in perfused and exanguinated kidneys. In addition, a distinct TCR repertoire was found on intra-renal conventional and unconventional T cells compared with those from the spleen. Finally, after 24 h of renal ischemia reperfusion injury (IRI), increased production of cytokines IFN-gamma and TNF-alpha by CD4+ and CD8+ T cells, isolated from perfused kidneys, was observed. These data suggest that some of these cells harbored in the kidney could be implicated in the immune response of the IRI pathogenic process.
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PMID:Normal mouse kidneys contain activated and CD3+CD4- CD8- double-negative T lymphocytes with a distinct TCR repertoire. 1876 77


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