Antibodies to CD3/T-cell receptor complex induce death by apoptosis in immature T cells in thymic cultures

SUMMARYApoptosis is a programmed cell death process that helps to regulate both T cell and B cell development. In this study, we have investigated the levels of apoptotic death in cells of the thymuses and spleens (white matter) of autoimmune MRL-lpr/lpr mice with progressive lymphadenopathy and SLE disease activity; we also examined the renal pathology in these animals. Fas is a cell surface receptor, which when activated initiates the sequence of events that lead to apoptosis. In MRL-lpr/lpr mice Fas is defective, so the competency for apoptosis may be reduced. In young animals of advancing age the thymuses enlarged until in 5-month-old females the average weight was three times that at 1 month, and spleen and kidney weights also increased in size disproportionately. At light microscope level apoptotic cells in tissue sections were counted using both routine eosin and haematoxylin staining (to identify them by their morphology) and in situ end-labelling of cells with DNA strand breaks; their presence was further confirmed by electron microscopy. As the mice aged, the numbers of apoptotic cells in thymic cortex, thymic medulla and spleen white pulp areas reduced significantly (P < 0 . 01-0 . 001), whereas in BALB/c normal controls they increased significantly (P < 0 . 05). These changes were coincident with the development of severe lupus, whose activity was assessed by measuring serum anti-ssDNA and antidsDNA antibody titres and urinary protein (albumin) level which were elevated significantly by 5 months of age (P < 0 . 001 for both ssDNA and dsDNA and P < 0 . 01 for urine albumin) compared with their younger counterparts. Thus, lymphoid organ enlargement, decrease in apoptotic indices, elevated serum anti-ssDNA and anti-dsDNA antibody levels, and impaired renal function coincided with the onset and severity of lupus disease in lpr mice. It seems likely that there is a causal relationship between defective deletion of autoreactive lymphoid cells, imperfect Fas-mediated apoptosis and development of murine SLE.

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

An analysis of apoptosis in lymphoid organs and lupus disease in murine systemic lupus erythematosus (SLE)

Ravirajan

Sarraf

Anilkumar

et al. 1996

“…015% EDTA in buffered NaCl and fed into a Beckman J2-21 ultracentrifuge with a JE-6B rotor at 2100 rev/min. A fraction with > 90% monocytes was obtained at a flow rate of [20][21] …”

Section: Separation Of Mononuclear Cellsmentioning

confidence: 99%

Histaminergic regulation of interferon-gamma (IFN-γ) production by human natural killer (NK) cells

Asea¹,

Hansson²,

Czerkinsky³

et al. 1996

SUMMARYMonocytes, recovered from human peripheral blood by counter-current centrifugal elutriation, effectively inhibit the production of IFN-°by CD3 ÿ /56 NK cells in response to IL-2. This study aimed at defining the nature of the inhibitory signal, particularly the importance of monocyte-derived reactive metabolites of oxygen. It was found that monocytes recovered from patients with chronic granulomatous disease (CGD), a condition characterized by deficient NADPH-oxidase activity of phagocytes, did not inhibit IFN-°production by NK cells. Further, catalase, a scavenger of hydrogen peroxide, completely reversed the inhibitory signal, whereas scavengers of the superoxide anion, hypohalous acids, the hydroxyl radical, or nitric oxide synthesis inhibitors such as L-NMMA were ineffective. Inhibition of IFN-°production was operating on a pre-translational level, as indicated by the inability of enriched NK cells to accumulate IFN-°mRNA in the presence of elutriated monocytes. Hydrogen peroxide, at micromolar concentrations, reconstituted the inhibition of IFN-°production when added to enriched NK cells. Histamine, a biogenic amine which inhibits the generation of reactive oxygen metabolites in monocytes, abrogated the inhibition of IFN-°production in NK cells; by this mechanism, histamine strongly synergized with IL-2 to induce IFN-°in mixtures of NK cells and monocytes. The synergizing effect of histamine was specifically mediated by H 2 -type histamine receptors. We conclude that: (i) the induction of IFN-°mRNA in NK cells is effectively down-regulated by products of the oxidative metabolism of monocytes; and (ii) histamine effectively enhances IFN-°production by preventing monocyte-induced oxidative damage to NK cells.

“…Induction of apoptosis is a key mechanism to delete autoreactive T cells during thymic selection [9] and to eliminate activated T cells in the periphery during the termination of an immune response [10]. CD95, also known as APO-1 or Fas, is a member of the death receptor family [11] important for T cell homeostasis.…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Strauß

Osen

Debatin

2002

150

SUMMARYImmunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graftversus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigenspecific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.