scholarly journals New Rat Model of Pneumocystis Pneumonia Induced by Anti-CD4+ T-Lymphocyte Antibodies

2003 ◽  
Vol 71 (11) ◽  
pp. 6292-6297 ◽  
Author(s):  
Timothy D. Thullen ◽  
Alan D. Ashbaugh ◽  
Kieran R. Daly ◽  
Michael J. Linke ◽  
Paul E. Steele ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
Host Defense ◽  
T Lymphocyte ◽  
Rat Model ◽  
Cell Function ◽  
Opportunistic Infections ◽  
Pneumocystis Pneumonia ◽  
Cell Number ◽  
Limited Attention

ABSTRACT The CD4+ T lymphocyte plays a central role in host defense against Pneumocystis pneumonia but has received only limited attention in rats. CD4+ T-cell-depleting (OX-38) and nondepleting (W3/25) monoclonal antibodies, which recognize an identical or adjacent epitope, were administered for up to 14 weeks to Lewis rats that had been exposed to Pneumocystis. While OX-38 produced a greater decrease in circulating CD4+ cells than W3/25, both antibody treatments resulted in similar effects on the health of the rats and the levels of Pneumocystis pneumonia, which were milder than those found with corticosteroids. W3/25 also did not enhance the severity of Pneumocystis pneumonia achieved with corticosteroids alone. We conclude that CD4+ cell function is more important than CD4+ cell number in host defense against Pneumocystis in the rat and that this new model permits study of opportunistic infections in the rat without the confounding effects of corticosteroids.

scholarly journals The effect of desferrithiocin, an oral iron chelator, on T-cell function

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2052-2059 ◽  
Author(s):  
BE Bierer ◽  
DG Nathan
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Function ◽  
Iron Chelator ◽  
Lymphocyte Function ◽  
Ferrous Chloride ◽  
Inhibition Of Proliferation ◽  
T Cell Function

Abstract Desferrithiocin is a new, potent, orally available iron chelator. To determine whether this drug might be useful not only for iron-overload but also for immunosuppression, we studied the in vitro effects of desferrithiocin on T-lymphocyte function. Like deferoxamine, desferrithiocin inhibited, in a dose-dependent fashion, mitogen- and lectin-induced proliferation of both human and murine T cells. It was active at a concentration of 10 micrograms/mL. The inhibition of proliferation was reversed by ferrous chloride, but not by other metal salts, recombinant IL-2, or conditioned medium. Desferrithiocin also inhibited proliferation of constitutively dividing, and factor- independent EBV-transformed B cell and leukemic T-cell lines. Although desferrithiocin inhibited the induction of cytotoxic T lymphocyte (CTL) activity, it did not inhibit CTL- or natural killer-induced cytotoxicity. The agent did not inhibit the expression of activation antigens such as the IL-2 receptor on T cells, nor early measures of T- cell activation such as the influx of intracellular calcium. Thus, desferrithiocin, like deferoxamine, is a potent and reversible inhibitor of T-cell proliferation. This anti-proliferative effect inhibits T-cell function. Bioavailability after oral administration is a unique property of desferrithiocin, and would make it an attractive alternative to deferoxamine. Its immunomodulating properties may therefore be exploited in vivo to inhibit graft rejection or autoreactive T cells.

scholarly journals Clonotypic structures involved in antigen-specific human T cell function. Relationship to the T3 molecular complex.

1983 ◽  
Vol 157 (2) ◽  
pp. 705-719 ◽  
Author(s):  
S C Meuer ◽  
K A Fitzgerald ◽  
R E Hussey ◽  
J C Hodgdon ◽  
S F Schlossman ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
T Cell ◽  
Cell Surface ◽  
Cell Function ◽  
Cell Clone ◽  
Interleukin 2 ◽  
Cytotoxic T Cell ◽  
Surface Molecules ◽  
Human T Cell ◽  
T Cell Clone

Monoclonal antibodies were produced against a human cytotoxic T cell clone, CT8III (specificity: HLA-A3), with the view of defining clonally restricted (clonotypic) surface molecules involved in its antigen recognition function. Two individual antibodies, termed anti-Ti1A and anti-Ti1B, reacted exclusively with the CT8III clone when tested on a panel of 80 additional clones from the same donor, resting or activated T cells, B cells, macrophages, thymocytes, or other hematopoietic cells. More importantly, the two antibodies inhibited cell-mediated killing and antigen-specific proliferation of the CT8III clone but did not affect the functions of any other clone tested. This inhibition was not secondary to generalized abrogation of the CT8III clone's function, because interleukin 2 responsiveness was enhanced. To examine the relationship of the structures defined by anti-clonotypic antibodies with known T cell surface molecules, antibody-induced modulation studies and competitive binding assays were performed. The results indicated that the clonotypic structures were associated with, but distinct from, the 20,000-mol wt T3 molecule expressed on all mature T lymphocytes. Moreover, in contrast to anti-T3, anti-Ti1A and anti-Ti1B each immunoprecipitated two molecules of 49,000 and 43,000-mol wt from 131I-labeled CT8III cells under reducing conditions. The development of monoclonal antibodies to such polymorphic T cell surface structures should provide important probes to further define the surface receptor for antigen.

scholarly journals Primary CLL Xenograft: A Model System to Study the Role of T-Cells in CLL Biology and Therapeutic Response

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3284-3284
Author(s):  
Ceri E Oldreive ◽  
Anna Skowronska ◽  
Angelo Agathanggelou ◽  
Helen M Parry ◽  
Sergey Krysov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Conflicts Of Interest ◽  
Xenograft Model ◽  
Cell Number ◽  
Biological Properties ◽  
T Cell Subsets ◽  
Cell Phenotype

Abstract The interaction between chronic lymphocytic leukaemia (CLL) cells and T-cells is an important aspect of CLL biology. CLL cells require T-cell support for their proliferation and in addition induce proliferation of regulatory and cytotoxic (CD8+) T-cells. T-cell number and repertoire are both markedly affected by CLL therapy and there is considerable interest in how current treatments modulate the interaction between T-cells and the tumour clone. In this study we investigated whether this relationship was maintained in a xenotransplantation model. CLL engraftment in NOG mice was facilitated by humanisation of the murine microenvironment by allogeneic CD34+ umbilical cord cells or CD14+ monocytes. Accelerated engraftment of both CLL and T-cell compartments was observed in xenografts derived from patients with progressive CLL, suggesting that the biological properties of both subsets are maintained in the murine model. Furthermore, the distribution of helper (CD4+), cytotoxic (CD8+) and regulatory (CD4+CD25+FoxP3+) T-cells was maintained within the xenografts, including retention of the CD4:CD8 ratio. Interestingly, the anergic PD-1+CD160+CD244+TIM3+ T-cell phenotype reported in CLL patients was also evident in T-cells expanded in xenograft models. Consistent with an anergic T-cell phenotype, T-cells from CLL xenografts lacked anti-tumour activity in vitro. Importantly, such anergic cells were observed when T-cells were reconstituted from allogeneic cord blood cells as well as autologous cells, suggesting that CLL cells have the ability to shape T-cell populations of different origin in diverse microenvironments. Finally, to investigate the interaction between specific T-cell subsets and engrafted CLL cells, CD4+, CD8+, and CD25+ T-cells were depleted prior to generation of xenografts. CD8+ T-cell depletion significantly prolonged CLL engraftment (p≤0.01) whereas neither depletion of CD4+ nor CD25+cells had a significant impact. In summary, our results demonstrate that the relationship between CLL tumour cells and reactive T-cells is accurately maintained in a murine xenograft model. Such models will be of great value for investigation of aspects of T-cell function in CLL biology. Disclosures No relevant conflicts of interest to declare.

scholarly journals The effect of desferrithiocin, an oral iron chelator, on T-cell function

Blood ◽  
1990 ◽  
Vol 76 (10) ◽  
pp. 2052-2059
Author(s):  
BE Bierer ◽  
DG Nathan
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Function ◽  
Iron Chelator ◽  
Lymphocyte Function ◽  
Ferrous Chloride ◽  
Inhibition Of Proliferation ◽  
T Cell Function

Desferrithiocin is a new, potent, orally available iron chelator. To determine whether this drug might be useful not only for iron-overload but also for immunosuppression, we studied the in vitro effects of desferrithiocin on T-lymphocyte function. Like deferoxamine, desferrithiocin inhibited, in a dose-dependent fashion, mitogen- and lectin-induced proliferation of both human and murine T cells. It was active at a concentration of 10 micrograms/mL. The inhibition of proliferation was reversed by ferrous chloride, but not by other metal salts, recombinant IL-2, or conditioned medium. Desferrithiocin also inhibited proliferation of constitutively dividing, and factor- independent EBV-transformed B cell and leukemic T-cell lines. Although desferrithiocin inhibited the induction of cytotoxic T lymphocyte (CTL) activity, it did not inhibit CTL- or natural killer-induced cytotoxicity. The agent did not inhibit the expression of activation antigens such as the IL-2 receptor on T cells, nor early measures of T- cell activation such as the influx of intracellular calcium. Thus, desferrithiocin, like deferoxamine, is a potent and reversible inhibitor of T-cell proliferation. This anti-proliferative effect inhibits T-cell function. Bioavailability after oral administration is a unique property of desferrithiocin, and would make it an attractive alternative to deferoxamine. Its immunomodulating properties may therefore be exploited in vivo to inhibit graft rejection or autoreactive T cells.

scholarly journals CD4+ T-Cell Lymphopenia in Frequent Platelet Donors Who Have Ceased Platelet Donation for at Least 1 Year

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2550-2550
Author(s):  
Mahboubeh Rahmani ◽  
Brooke M Fortin ◽  
Nancy Berliner ◽  
Nicolas C Issa ◽  
Donna S Neuberg ◽  
...  
Keyword(s):  
T Cell ◽  
Skin Cancer ◽  
T Lymphocyte ◽  
Opportunistic Infections ◽  
Cd4 T Cell ◽  
Donor Center ◽  
T Cell Lymphopenia ◽  
History Of ◽  
Study Participants ◽  
To Receive

Abstract Introduction We recently discovered that a number of frequent apheresis platelet donors at our donor center had CD4+ T-lymphocyte counts below 200 cells/µL. The cause appears to be repeated extraction of these cells by the Trima Accel Automated Blood Collection System's leukoreduction system chamber. Plateletpheresis at our donor center has been conducted exclusively with this instrument since 2006. How long CD4+ T-cell lymphopenia persists after stopping plateletpheresis is unknown. Whether there are infectious or other complications that could relate to CD4+ T-cell lymphopenia in former donors is also unknown. We therefore investigated the blood counts (including CD4+ T-lymphocyte counts) and medical histories of former platelet donors who had a history of frequent platelet donation but had stopped donating platelets for at least 12 months. Methods We mailed a questionnaire to former frequent apheresis platelet donors who had not donated platelets at our donor center for at least 12 months. Donors who replied to the questionnaire were contacted by phone to schedule a study visit. Frequent platelet donation was defined as 20-24 plateletpheresis sessions in at least one 365-day period starting in 2011. Donors who consented to participate in the study confirmed that they had not donated platelets in the prior 12 months, provided a blood sample for analysis, and completed a health questionnaire that included questions about opportunistic infections and malignancies. Medical records of these donors were also reviewed, where available. Approval for the study was obtained from the Partners HealthCare Institutional Review Board (2017P002880) and all participants provided written informed consent. Results Of 52 former frequent platelet donors identified as eligible to receive a questionnaire, one was known to have died of a myocardial infarction and another had requested not to receive communications from the donor center. Therefore, 50 potential study candidates were mailed a questionnaire. Twelve questionnaires were returned as undeliverable. Five potential study candidates returned the questionnaire but either declined to participate in the study or did not respond when contacted to schedule a study visit. Fourteen former frequent platelet donors elected to participate in the study after receiving the first mailing of the questionnaire. Of these 14 study participants, 6 were female and all were Caucasian. The median age was 65. The most common reason for ceasing platelet donation was a positive HLA antibody test (5 participants) followed by "low white blood cells," "heart trouble," and "inconvenience" (2 participants each). All former donors had tested negative for HIV while donating platelets. There were 2 participants with CD4+ T-lymphocyte counts below 200 cells/µL (Figure 1); one of these participants had prior CD4+ T-lymphocyte counts available for review. These showed that the CD4+ T-lymphocyte count in this former donor had improved slightly since ceasing donation one year earlier (Figure 2). Three study participants had a CD4+ T-lymphocyte count between 200 and 300 cells/µL. A review of prescription medications and medical problems did not identify an etiology for the low CD4+ T-lymphocyte counts. Responses to the health questionnaire showed that no study participant had ever had a severe infection, an infection with an unusual pathogen ("bug"), or thrush. Two former frequent platelet donors had a history of shingles, both of whom had CD4+ T-lymphocyte counts slightly below the normal range (441-2156 cells/µL) at the time of participation in the study. Five former donors had a history of cancer: Two episodes of squamous cell skin cancer (1 participant), papillary thyroid carcinoma (1 participant), glioblastoma (1 participant), basal cell skin cancer (1 participant), and squamous cell skin cancer as well as melanoma in situ (1 participant). Conclusion In our small cohort, there is no evidence that CD4+ T-cell lymphopenia predisposes to opportunistic infections or to malignancies classically associated with immune dysregulation. Plateletpheresis-associated CD4+ T-cell lymphopenia has improved slightly in one former frequent platelet donor a year after ceasing plateletpheresis but the count remains below 200 cells/µL. Frequent plateletpheresis involving a leukoreduction system chamber should be considered in the differential diagnosis of idiopathic CD4+ lymphopenia. Disclosures Gansner: Novimmune SA: Research Funding; UpToDate: Patents & Royalties.

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