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)

We tested whether the in vivo infusion of recombinant, soluble CTLA4 fused with Ig heavy chains, as a surrogate ligand used to block CD28/CTLA4 T-cell costimulation, could prevent efficient T-cell activation and thereby reduce graft-versus-host disease (GVHD). Lethally irradiated B10.BR recipients of major histocompatibility complex disparate C57BL/6 donor grafts received intraperitoneal injections of human CTLA4-Ig (hCTLA4-Ig) or murine CTLA4-Ig (mCTLA4-Ig) in various doses and schedules beginning on day -1 or day 0 of bone marrow transplantation (BMT). In all five experiments, recipients of CTLA4-Ig had a significantly higher actuarial survival rate compared to mice injected with an irrelevant antibody control (L6) or saline alone. Survival rates in recipients of hL6 or PBS were 0% at 29 to 45 days post-BMT. In recipients of CTLA4-Ig, survival rates were as high as 63% mice surviving 3 months post-BMT. However, protection was somewhat variable and recipients of CTLA4-Ig were not GVHD-free by body weight, clinical appearance, and histopathologic examination. There were no significant differences in the survival rates in comparing injection dose, injection duration, or species of CTLA4-Ig (hCTLA4-Ig v mCTLA4-Ig). Splenic and peripheral blood flow cytometry studies of long-term hCTLA4-Ig-injected survivors showed a significant peripheral B-cell and CD4+ T-cell lymphopenia, consistent with GVHD. A kinetic study of splenic reconstitution was performed in mice that received hCTLA4-Ig and showed that mature splenic localized CD8+ T-cell repopulation was not significantly different in recipients of hCTLA4-Ig compared with hL6, despite the significant increase in actuarial survival rate in that experiment. These data suggest that the beneficial effect of hCTLA4-Ig on survival is not mediated by interfering with mature donor-derived T-cell repopulation post-BMT. Neither hCTLA4-Ig nor mCTLA4-Ig interfered with hematopoietic recovery post-BMT. We conclude that CTLA4-Ig (most likely in combination with other agents) may represent an important new modality for GVHD prevention.
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PMID:In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. 751 23

2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole (THI) is an immunosuppressive component of caramel food colouring that causes lymphopenia in mice and rats by an unknown mechanism. In this study we investigated some of the affects of THI on the murine immune system. Initially we showed that splenic T lymphocytes from mice treated with 50 mg/l THI in their drinking water were unable to launch a mixed lymphocyte reaction (MLR) against allogeneic stimulator cells, and had decreased and delayed interleukin-2 (IL-2) production. However, these T cells exhibited a normal proliferative response to concanavalin A (Con A), immobilized anti-CD3 monoclonal antibody (mAb) and anti-CD3 plus anti-CD28 mAb. Furthermore, the MLR response could be restored by the addition of IL-2 to the MLR culture. Homing studies using intravenous injection of fluorescence-labelled splenocytes showed that THI treatment decreased absolute numbers of labelled T and B lymphocytes in the blood and the spleen. Furthermore, these labelled cells reappeared in the blood and the spleen when mice were taken off THI, indicating that lymphocyte recirculation and splenic homing were modified reversibly by THI treatment. Cessation of THI treatment also resulted in a rapid reappearance of MLR responsiveness in the spleen, indicating that THI treatment does not functionally impair recirculating T cells. Collectively these data are compatible with the concept that a rapidly recirculating population of T cells, which produce IL-2 in an allogeneic MLR, are lost from the blood and spleen following THI treatment, and are sequestered in other, yet to be identified, tissues.
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PMID:The immunosuppressive compound 2-acetyl-4-tetrahydroxybutyl imidazole inhibits the allogeneic mixed lymphocyte reaction by sequestration of a recirculating subpopulation of T cells. 866 39

CD28 on T cells provides a potent costimulatory signal for T cell activation. Down-regulation of CD28 on peripheral T cells has been reported in certain clinical conditions, but full studies on the mechanism and biological significance have not been performed. Our extensive phenotype analysis of peripheral blood lymphocytes (PBL) from SLE patients revealed that the absolute number of CD28+ T cells of both CD4 and CD8 phenotypes was selectively decreased, while that of CD28- T cells was maintained. CD28+ T cells from SLE patients exhibited mostly normal proliferative responses to both CD28-dependent and -independent stimulations. In contrast, CD28- T cells were hyporesponsive to anti-CD3 stimulation in both SLE and normal controls. These results implied that the selective decrease of CD28+ T cells in SLE does not result from a hyporesponsiveness of CD28+ T cells. To investigate the reason for the selective loss of CD28+ T cells, we determined the appearance of apoptotic cells in culture with or without anti-CD3 stimulation. Apoptotic cells defined by merocyanine (MC)540 were gradually increased from 12 h to 24 h. Anti-CD3-induced apoptosis of CD28+ T cells was significantly accelerated in SLE, whereas apoptosis of CD28- T cells was hardly detected in both SLE and normal controls. Comparative analysis between CD28+ and CD28- T cells on CD95 (Fas) and Bcl-2 expression, which are related to activation-induced cell death (AICD), did not show a major difference, although CTLA4, which has been demonstrated to transmit an apoptosis-inducing signal, was expressed only on CD28+ T cells. Our results suggest that CD28-mediated costimulation influences T cell susceptibility to AICD and may be involved in T cell lymphopenia in SLE.
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PMID:Preferential elimination of CD28+ T cells in systemic lupus erythematosus (SLE) and the relation with activation-induced apoptosis. 891 66

Severe combined immune deficiency (SCID) is a heterogeneous disorder characterized by profound defects in cellular and humoral immunity. We report here an infant with clinical and laboratory features of SCID and selective CD4 lymphopenia and lack of CD28 expression on CD8(+) T cells. T cells from this patient showed poor blastogenic responses to various mitogens and IL-2. Other T cell antigen receptor- induced responses, including upregulation of CD69, were similarly inhibited. However, more proximal T cell antigen receptor signaling events, such as anti-CD3 induced protein tyrosine phosphorylation, phosphorylation of mitogen-associated protein kinase, and calcium mobilization were intact. Although p59fyn and ZAP-70 protein tyrosine kinases were expressed at normal levels, a marked decrease in the level of p56lck was noted. Furthermore, this decrease was associated with the presence of an alternatively spliced lck transcript lacking the exon 7 kinase encoding domain. These data suggest that a deficiency in p56lck expression can produce a SCID phenotype in humans.
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PMID:Defective expression of p56lck in an infant with severe combined immunodeficiency. 966 84

T cell fate following antigen encounter is determined by several intracellular signals generated by the interaction of the T cell with an antigen-presenting cell. In the periphery activation requires T cell receptor signaling (signal one) in combination with costimulatory signals (signal two), usually provided through the cognate interaction of CD28 and B7 molecules. Provision of signal one alone to purified murine peripheral T cells in vitro induces apoptosis or anergy rather than promoting activation. These T cells can be rescued from apoptosis if they are provided with costimulation supplied, for example, by engaging the CD28 co-receptor with an anti-CD28 monoclonal antibody or by adding an exogenous source of interleukin-2. However, a majority of peripheral T cells from autoimmune, diabetes-prone Biobreeding (BB) rats exhibited different responses to these stimuli. T cells from these rats could not be rescued from apoptosis by costimulation. This was not due to the inability of BB-DP T cells to upregulate CD28 and the IL-2 receptor in response to TCR crosslinking. The failure of these costimulatory interactions to rescue BB-DP T cells segregated with the diabetes-susceptibility gene iddm1. Iddm1 in the rat causes peripheral T cell lymphopenia, which is associated with a dramatically shortened peripheral T cell life span. Our results indicate that a diabetogenic gene may contribute to autoimmunity by negating costimulatory signals important for the survival of long-lived peripheral T cells.
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PMID:A diabetogenic gene prevents T cells from receiving costimulatory signals. 1035 84

CVID is a primary immune disorder in which hypogammaglobulinaemia may be associated with a number of T cell defects including lymphopenia, anergy, impaired lymphocyte proliferation and deficient cytokine secretion. In this study we show that T cells of CVID subjects, in comparison with control T cells, undergo spontaneous apoptosis in culture and markedly accelerated apoptosis after gamma-irradiation. Although costimulation of the CD28 receptor following engagement of the TCR/CD3 receptor normally provides a second signal necessary for IL-2 secretion, CD28 costimulation in CVID does not significantly increase IL-2 production, nor does this combination of activators enhance the survival of irradiated CVID T cells, as it does for cultured normal T cells. Addition of IL-2 enhances CVID T cell survival, suggesting that the IL-2 signalling pathways are normal. CVID T cells have similar expression of Bcl-2 to control T cells. CD3 stimulation up-regulates T cell expression of bcl-xL mRNA for normal T cells, but anti-CD28 does not augment bcl-xL expression for CVID subjects with accelerated apoptosis. Defects of the CD28 receptor pathway, leading to cytokine deprivation and dysregulation of bcl-xL, could lead to poor T cell viability and some of the cellular defects observed in CVID.
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PMID:Enhanced apoptosis of T cells in common variable immunodeficiency (CVID): role of defective CD28 co-stimulation. 1084 30

Ag-specific proliferation of CD4+ T cells is regulated, in part, by costimulatory signals through CD28. The proliferative response during primary activation is an important determinant of the ability of the T cell to respond to Ag re-encounter. Proliferation of mature CD4+ T cells during lymphopenia (homeostatic proliferation) requires interaction with endogenous peptide MHC. However, the role of costimulation during homeostatic proliferation is unclear, as is the ability of homeostatic proliferation to regulate secondary T cell responses. Using a TCR transgenic system and serial adoptive transfers we find that homeostatic proliferation of CD4+ T cells occurs for at least 5 wk after adoptive transfer into recombination-activating gene (RAG)-/- recipients. Two discrete populations of proliferating T cells can be resolved, one that is highly proliferative and dependent on CD28 signaling, and the other that contains cells undergoing low levels of CD28-independent proliferation. Importantly, naive CD4+ T cells that have undergone homeostatic proliferation acquire both phenotypic and functional characteristics of true memory cells. These studies indicate that functional memory T cells can be generated by encounters with endogenous Ags only. This mechanism of T cell regeneration is possibly active during lymphopenia due to viral infections, such as HIV, transplantation, or cancer therapy, and may explain selected autoimmune diseases.
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PMID:A closer look at homeostatic proliferation of CD4+ T cells: costimulatory requirements and role in memory formation. 1156 85

We report a case of a combined immunodeficiency (CID) in a child affected by trichothiodystrophy (TTD) characterized by an altered response to ultraviolet (UV) light due to a defect in the XPD gene. The XPD gene encodes a subunit of the transcription factor II H (TFIIH), a complex involved in nucleotide-excision repair (NER) and basal transcription. Our patient showed neurological and immune system abnormalities, including CD4 + lymphopenia never previously reported in TTD patients. In vitro immunological studies revealed a marked reduction in T-cell proliferation in response to mitogens and CD3 cross-linking which was partially recovered by the addition of anti-CD28 antibody or exogenous interleukin-2. The patient's T cells displayed alterations in T-cell receptor (TCR/CD3) proximal signalling characterized by marked reduction in Lck kinase activity coupled with a constitutive hyperactivation of Fyn kinase. Despite these alterations, normal levels of Lck and Fyn proteins were detected. The role of antigen-presenting cells (APCs) in the pathogenesis of the T-cell defect was investigated by analysing dendritic cells (DCs) generated from the patient's blood monocytes. In these cells, flow cytometry revealed significantly reduced expression of the CD86 co-stimulatory molecules and HLA glycoproteins. In addition, the patient's DCs showed a decreased ability to stimulate naive T lymphocytes. Overall, the results of our study suggest that a defective TFIIH complex might result in alterations in T cells and DC functions leading to a severe immunodeficiency.
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PMID:Defective dendritic cell maturation in a child with nucleotide excision repair deficiency and CD4 lymphopenia. 1173 70

Seventeen volunteers received an intravenous bolus of endotoxin (2 ng/kg of body weight). Endotoxin-induced lymphopenia was constituted mainly by cells with an immature phenotype (CD45RA(+) CD45RO(-)) that were less likely to undergo apoptosis (CD28(+)), whereas cells with the highest rates of disappearance were characterized by an activated phenotype (CD45RA(-) CD45RO(+)) as well as a phenotype linked to apoptosis (CD95(+) CD28(-)). In conclusion, endotoxin-induced lymphopenia reflects the disappearance from the circulation of activated lymphocytes prone to undergo apoptosis.
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PMID:Activated T lymphocytes disappear from circulation during endotoxemia in humans. 1198 89

T cells expand without intentional antigen stimulation when transferred into adult lymphopenic environments. In this study, we show that the physiologic lymphopenic environment existing in neonatal mice also supports CD4 T cell proliferation. Strikingly, naive CD4 T cells that proliferate within neonates acquire the phenotypic and functional characteristics of memory cells. Such proliferation is inhibited by the presence of both memory and naive CD4 T cells, is enhanced by 3-day thymectomy, is independent of IL-7, and requires a class II MHC-TCR interaction and a CD28-mediated signal. CD44(bright) CD4 T cells in neonates have a wide repertoire as judged by the distribution of Vbeta expression. Thus, lymphopenia-induced T cell proliferation is a physiologic process that occurs during the early postnatal period.
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PMID:Neonates support lymphopenia-induced proliferation. 1253 Sep 82


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