UMLS:C0024312 - FACTA Search

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Query: UMLS:C0024312 (lymphopenia)
4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study was carried out to evaluate the influence of a short-period IL-2 administration on the efficacy of chemotherapy in metastatic colorectal cancer patients with pretreatment lymphocytopenia, which was defined as a lymphocyte count of less than 1500/mm3. The study included 144 consecutive metastatic colorectal cancer patients, who underwent chemotherapy with oxaliplatin plus 5-fluorouracil. Lymphocytopenia was seen in 41/144 (28%) patients, who were randomized to receive chemotherapy alone or chemotherapy after a prechemoimmunotherapy with IL-2 (3 MIU twice/day for 3 consecutive days), whereas patients with a normal pretreatment lymphocyte count received only chemotherapy. A normalization of the lymphocyte number was achieved in 12/19 lymphocytopenic patients pretreated with IL-2. The objective tumor regression rate achieved in patients with a normal lymphocyte count prior to chemotherapy was significantly higher compared to that obtained in lmphocytopenic patients treated with chemotherapy alone (54/103 vs. 3/22, p < 0.01), whereas no significant difference occurred between patients with normal lymphocyte count and lymphocytopenic patients pretreated with IL-2 (54/103 vs. 8/19). This study confirms that pretreatment lymphocytopenia is associated with reduced efficacy of chemotherapy in metastatic colorectal cancer patients. Moreover, it suggests that pretreatment with IL-2 before the onset of chemotherapy may enhance the efficacy of chemotherapy in lymphocytopenic patients. Therefore, the administration of IL-2 before the onset of chemotherapy to improve the immune status of cancer patients may be considered as a new chemoimmunotherapeutic combination, which may be recommended in the treatment of advanced cancer patients, particularly in those with cancer-related immune alterations.
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PMID:Enhancement of the efficacy of chemotherapy with oxaliplatin plus 5-fluorouracil by pretreatment with IL-2 subcutaneous immunotherapy in metastatic colorectal cancer patients with lymphocytopenia prior to therapy. 1627 25

To evaluate morphological characteristics and development of the immune system at different ages in neonatal pigs, 4 piglets were euthanized at 7, 14, and 18 d of age for collection of blood, bile, and intestinal tissue for morphological measurements. Blood was collected for differential cell counts, lymphocyte blastogenesis, immunoglobulin (Ig) concentrations, cytokine concentrations, and flow cytometric analysis. Bile was collected for quantification of Ig-A and Ig-M. Villus width and crypt depth from duodenum sections, as well as ileum crypt depth, were reduced (P < or = 0.08) in 18-d-old pigs compared with 7-d-old pigs. No age-related differences (P > or = 0.11) were observed in the number of goblet cells with neutral and acidic mucins, serum or enteric Ig concentrations, IL-2, IL-4, spontaneous lymphocyte proliferation, or leukocyte concentrations. When measured as counts per minute (cpm) and as a stimulation index (SI), lymphocyte proliferation responses to phytohaemagglutinin increased (P = 0.05) between 7 and 14 d of age; no changes (P = 0.10) occurred at 18 d of age. No age-related changes (P = 0.39) were observed in response to pokeweed mitogen (PWM) when measured as cpm; however, the SI from PWM-induced lymphocytes decreased (P = 0.04) 4-fold between 7 and 18 d of age. The CD4+:CD8+ and populations of lymphocytes expressing CD2+CD4+CD8- (T helper cells) and CD25+CD4+CD8- (activated T helper cells) were greater (P > or = 0.04) at 7 d of age than at 14 and 18 d. Populations of T lymphocytes, cytotoxic T cells (CD2+CD4-CD8+), activated lymphocytes (CD25+), and activated cytotoxic T cells (CD25+CD4-CD8+) were greater (P > or = 0.02) in 18-d-old pigs compared with 7-d-old pigs, whereas CD2+CD4-CD8- [double negative cells] were lower (P = 0.08) in 18-d-old pigs compared with 14-d-old pigs. The percentage of CD2+ T cells was 8.4% at 7 d of age, and by the time the pigs reached 18 d of age, the percentage of CD2+ T cells was 33.8%. Moreover, the percentage of gammadelta T cells was greater (P = 0.02) in 18-d-old pigs than in 7-d-old pigs (74.8 vs. 46.1%, respectively). Results indicate that the porcine immune system and gut are continuously changing as the young pig matures. Changes occurred in lymphocyte phenotypic expression and functional capabilities, as well as morphology and mucin production, and their role may be to further protect the neonate from antigenic challenge as protection from passive immunity declines.
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PMID:Ontogeny of T lymphocytes and intestinal morphological characteristics in neonatal pigs at different ages in the postnatal period. 1647 48

We compared the kinetics of T-cell recovery after extensive ex vivo and in vivo T-cell depleted autologous stem cell transplantation (SCT) for multiple sclerosis (MS; n=8) with unmodified SCT for hematological malignancies (HM; n=39). Both patient group showed a very protracted recovery of 'naive' CD4(+), 45R0(-) ( approximately CD45RA(+)) T-cells. Within the 'primed' CD4(+), 45R0(+) T-cells, the 'central memory' cells expressing the CD62L and CD27 markers were the slowest to recover. The repopulating T-cells were highly activated, as shown by increased expression of HLA-DR and the apoptosis marker CD95. The capability of CD4(+) and CD8(+) T-cells to produce IFN-gamma, IL-2 and TNF-alpha had reached normal ranges from 2 months post SCT onwards. Unexpectedly, the kinetics of T-cell recovery between 3 and 12 months post transplant was similar in T-depleted and unmodified SCT. Before SCT, the HM patients showed lymphopenia of all T-cell subsets, upregulated HLA-DR and CD95 expression and increased cytokine responses. We suggest that the similar kinetics of T-cell recovery in the two patient groups may be explained by the susceptibility to apoptosis of the activated CD4(+) T-cells in the autografts of the HM patients. This susceptibility to apoptosis would interfere with a swift and sustained CD4(+) T-cell regeneration post SCT.
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PMID:T-lymphocyte reconstitution following rigorously T-cell-depleted versus unmodified autologous stem cell transplants. 1651 23

Autologous transfer of anti-CD3/anti-CD28 (CD3/CD28)-activated CD4(+) T cells may benefit patients receiving autologous stem cell transplant with severe CD4 lymphopenia. Interleukin (IL)-15, an IL-2-like cytokine that promotes T cell survival may enhance immune reconstitution in conjunction with adoptive immunotherapy. We investigated the effect of IL-15 on effector and regulatory function of CD3/CD28-activated CD4(+) T cells. IL-15 upregulated CD45RO and CD25 whereas it down regulated CD62L expression of CD3/CD28-stimulated CD4(+) T cells. Both type 1 (IFN-gamma, tumor necrosis factor (TNF)-alpha) and type 2 (IL-5 and IL-10) production by CD3/CD28-activated CD4(+) T cells was further enhanced by IL-15. Co-culture experiments revealed that CD3/CD28-activated CD4(+) T cells down regulated proliferation of autologous peripheral blood lymphocytes (PBLs) and CD8(+) PBL subsets upon TCR ligation, a contact-dependent effect that was further enhanced by pretreatment with IL-15. Flow cytometric analysis of cell mixture with carboxyfluorescein diacetate succinimidyl ester and Annexin-V-PE staining revealed that CD3/CD28+IL-15-activated CD4(+) T cells showed increased apoptosis over CD4(+) T cells stimulated with CD3/CD28 alone. Taken together, pretreatment of CD3/CD28-activated CD4(+) T cells with IL-15 may increase regulatory function but may aggravate activation-induced apoptosis of CD3/CD28 CD4(+) T cells.
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PMID:Effect of interleukin-15 on effector and regulatory function of anti-CD3/anti-CD28-stimulated CD4(+) T cells. 1656 41

Studies in cancer patients have suggested that breast tumors recruit regulatory T cells (Tregs) into the tumor microenvironment. The extent to which local Tregs suppress antitumor immunity in breast cancer is unknown. We questioned whether inhibiting systemic Tregs with an IL-2 immunotoxin in a model of neu-mediated breast cancer, the neu-transgenic mouse, could impact disease progression and survival. As in human breast cancer, cancers that develop in these mice attract Tregs into the tumor microenvironment to levels of approximately 10-25% of the total CD4+ T cells. To examine the role of Tregs in blocking immune-mediated rejection of tumor, we depleted CD4+CD25+ T cells with an IL-2 immunotoxin. The treatment depleted Tregs without concomitant lymphopenia and markedly inhibited tumor growth. Depletion of Tregs resulted in a persistent antitumor response that was maintained over a month after the last treatment. The clinical response was immune-mediated because adoptive transfer of Tregs led to a complete abrogation of the therapeutic effects of immunotoxin treatment. Further, Treg down-modulation was accompanied by increased Ag-specific immunity against the neu protein, a self Ag. These results suggest that Tregs play a major role in preventing an effective endogenous immune response against breast cancer and that depletion of Tregs, without any additional immunotherapy, may mediate a significant antitumor response.
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PMID:IL-2 immunotoxin therapy modulates tumor-associated regulatory T cells and leads to lasting immune-mediated rejection of breast cancers in neu-transgenic mice. 1678 2

Although recent work has suggested that lymphopenia-induced homeostatic proliferation may improve T cell-mediated tumor rejection, there is little direct evidence isolating homeostatic proliferation as an experimental variable, and the mechanism by which improved antitumor immunity occurs via homeostatic proliferation is poorly understood. An adoptive transfer model was developed in which tumor-specific 2C/RAG2(-/-) TCR transgenic CD8+ T cells were introduced either into the lymphopenic environment of RAG2(-/-) mice or into P14/RAG2(-/-) mice containing an irrelevant CD8+ TCR transgenic population. RAG2(-/-), but not P14/RAG2(-/-) recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection. Despite absence of tumor rejection in P14/RAG2(-/-) recipients, 2C cells did become activated, as reflected by CFSE dilution and CD44 up-regulation. However, these cells showed poor IFN-gamma and IL-2 production upon restimulation, consistent with T cell anergy and similar to the hyporesponsiveness induced by administration of soluble peptide Ag. To determine whether homeostatic proliferation could uncouple T cell anergy, anergic 2C cells were transferred into RAG(-/-) recipients, which resulted in vigorous homeostatic proliferation, recovery of IL-2 production, and acquisition of the ability to reject tumors. Taken together, our data suggest that a major mechanism by which homeostatic proliferation supports tumor rejection is by maintaining and/or re-establishing T cell responsiveness.
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PMID:Homeostatic proliferation as an isolated variable reverses CD8+ T cell anergy and promotes tumor rejection. 1698 89

We previously reported the clinical phenotype of two siblings with a novel inherited developmental and immunodeficiency syndrome consisting of severe intrauterine growth retardation and the impaired development of specific lymphoid lineages, including transient CD8 alphabeta T lymphopenia and a persistent lack of blood NK cells. We describe here the elucidation of a plausible underlying pathogenic mechanism, with a cellular phenotype of impaired survival of both fresh and herpesvirus saimiri-transformed T cells, in the surviving child. Clearly, NK cells could not be studied. However, peripheral blood T lymphocytes displayed excessive apoptosis ex vivo. Moreover, the survival rates of CD4 and CD8 alphabeta T cell blasts generated in vitro, and herpesvirus saimiri-transformed T cells cultured in vitro, were low, but not nil, following treatment with IL-2 and IL-15. In contrast, Fas-mediated activation-induced cell death was not enhanced, indicating a selective excess of cytokine deprivation-mediated apoptosis. In keeping with the known roles of IL-2 and IL-15 in the development of NK and CD8 T cells in the mouse model, these data suggest that an impaired, but not abolished, survival response to IL-2 and IL-15 accounts for the persistent lack of NK cells and the transient CD8 alphabeta T lymphopenia documented in vivo. Impaired cytokine-mediated lymphocyte survival is likely to be the pathogenic mechanism underlying this novel form of inherited and selective NK deficiency in humans.
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PMID:Familial NK cell deficiency associated with impaired IL-2- and IL-15-dependent survival of lymphocytes. 1714 86

Naive CD4 cells from aged mice respond inefficiently to Ag, but the factors that underlie the age-associated defects remain unclear. We have used two approaches to isolate recent thymic emigrants (RTE) in young and aged mice and have compared their capacity to respond to antigenic stimulation ex vivo. An in situ intrathymic CFSE injection labeled developing thymocytes and allowed the identification of RTE in secondary lymphoid tissues. Analysis of CFSE-labeled RTE and control unlabeled naive CD4 cells indicated that cells from aged mice were defective in their ability to increase intracellular Ca(2+) concentration following TCR cross-linking. Aged naive and RTE CD4 also secreted less IL-2 and proliferated less than that of comparable young CD4 populations. Defects in effector generation in aged RTE were overcome by the addition of IL-2 to cultures. RTE from both polyclonal and TCR transgenic mice were compromised, indicating that defects were independent of TCR specificity. In the second model, the cotransfer of congenic marker-labeled young and aged BM cells into young and aged syngeneic hosts revealed that hyporesponsiveness in aged RTE was caused by a combination of defects intrinsic to CD4 progenitors and defects induced by the aged environment. Depletion of peripheral CD4 cells in aged mice led to production of new RTE that were not defective. The results of this study suggest that defects induced by environmental and lineage intrinsic factors act together to reduce responses to Ag in aged naive CD4 cells and that these defects can be overcome in aged CD4 cells produced during recovery from lymphopenia.
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PMID:Environmental and intrinsic factors lead to antigen unresponsiveness in CD4(+) recent thymic emigrants from aged mice. 1723 78

Allogeneic immune responses are modulated by a subset of host T cells with regulatory function (Treg) contained within the CD4(+)CD25(high) subset. Evidence exists that Treg expand after peritransplantation lymphopenia, inhibit graft rejection, and induce and maintain tolerance. Little, however, is known about the role of Treg in the clinical setting. IL-2 and activation by T cell receptor engagement are instrumental to generate and maintain Treg, but the influence of immunosuppressants on Treg homeostasis in humans in vivo has not been investigated. This study monitored Treg phenotype and function during immune reconstitution in renal transplant recipients who underwent profound T cell depletion with Campath-1H and received sirolimus or cyclosporine (CsA) as part of their maintenance immunosuppressive therapy. CD4(+)CD25(high) cells that expressed FOXP3 underwent homeostatic peripheral expansion during immune reconstitution, more intense in patients who received sirolimus than in those who were given CsA. T cells that were isolated from peripheral blood long term after transplantation were hyporesponsive to alloantigens in both groups. In sirolimus- but not CsA-treated patients, hyporesponsiveness was reversed by Treg depletion. T cells from CsA-treated patients were anergic. Thus, lymphopenia and calcineurin-dependent signaling seem to be primary mediators of CD4(+)CD25(high) Treg expansion in renal transplant patients. These findings will be instrumental in developing "tolerance permissive" immunosuppressive regimens in the clinical setting.
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PMID:Regulatory T cells and T cell depletion: role of immunosuppressive drugs. 1728 24

In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen-self-major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced "homeostatic" proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8(+) T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.
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PMID:An intense form of homeostatic proliferation of naive CD8+ cells driven by IL-2. 1766 94

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