Inhibition of Human Helper T Cell Function In Vitro by d-Penicillamine and CuSO4

Lipsky, Peter E.; Ziff, Morris

doi:10.1172/jci109759

Cited by 120 publications

(40 citation statements)

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“…It may, therefore, be suggested that the observed inhibition by -Pen and cupric ion is expressed through the action of H202 produced by these two agents. This is also consistent with previous findings that H202 suppresses the functions of T (18,22) and natural killer cells (27).…”

Section: Resultssupporting

confidence: 94%

“…Although a variety of actions ofthis drug have been reported to be responsible for its therapeutic efficacy (14)(15)(16)(17)(18)(19)(20)(21)(22), the mechanism underlying its beneficial effects has not been adequately explained. To investigate the possible effects of D-Pen on angiogenesis, we have studied the action ofthis drug on basal and endothelial cell growth factor (ECGF)-stimulated proliferation of human umbilical vein EC, and also on ECGF-induced neovascularization in vivo.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine.

Matsubara¹,

Saura²,

Hirohata³

et al. 1989

J. Clin. Invest.

118

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Section: Resultssupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine.

Matsubara¹,

Saura²,

Hirohata³

et al. 1989

J. Clin. Invest.

118

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“…This effect was observed in isolated T cells incubated with methyldopa and in T cells from patients taking methyldopa. Other studies demonstrating a selective effect on suppressor T-cell function by SLE-inducing drugs have not been reported, although it has been suggested that autoantibody formation induced by D-penicillamine therapy may also be related to suppressor T-cell dysfunction caused by this drug (33).…”

Section: Tmitomentioning

confidence: 99%

Immunomodulatory effect of procainamide in man. Inhibition of human suppressor T-cell activity in vitro.

Ochi¹,

Goldings²,

Lipsky³

et al. 1983

J. Clin. Invest.

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A B S T R A C T Procainamide (PA) induces the production of a number of autoantibodies in a high proportion of treated individuals and in some a syndrome closely resembling systemic lupus erythematosus. The mechanism underlying this action of PA is unclear. To examine the possibility that PA might induce autoantibody formation by altering normal immunoregulatory mechanisms, the action of this drug on an in vitro model of antibody formation in man was examined. PA was found to augment the generation of immunoglobulin-secreting cells (ISC) from human peripheral blood mononuclear cells (PBM) in response to pokeweed mitogen but had no effect on pokeweed mitogen-induced tritiated thymidine incorporation. When purified populations of B and T cells were used, PA enhanced the generation of ISC in B-cell cultures supported by untreated T cells but not by T cells treated with mitomycin C. These results indicate that PA augmented B-cell responses by inhibiting suppressor T-cell activity and not by augmenting helper T-cell or B-cell function. N-Acetyl-procainamide had no effect on the generation of ISC in this system.The effect of PA on concanavalin A (Con A)-induced suppressor cell activity was also examined to determine whether PA altered the generation or expression of suppressor T-cell function. PBM were cultured with 30 Aig/ ml of Con A for 48 h to generate suppressor cells. When these were co-cultured with fresh PBM, the number of ISC generated was decreased by 58.1±3.4% (mean ±SEM, n = 6). Cells that had been similarly incubated without Con A were not inhibitory. The addition of PA to the Con A-stimulated cultures inhibited the generation of suppressor cells as indicated by the fact that the response of fresh cells co-cultured with the Con A-stimulated cells was diminished by only 27.2±4.3%. In this system too, N-acetyl-procaimamide had no effect. By contrast, adding PA only to the co-culture of Con A-

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“…DP together with copper sulfate or Cp-Cu can inhibit T lymphocyte proliferation in vitro (7). T helper cells appear to be particularly sensitive to inhibition by DP and copper sulfate (17,18), although a recent study suggests that B lymphocytes are more sensitive to H202 than are T celis (19). Natural killer cell function is also inhibited by reactive oxygen species released from activated monocytes and polyrnorphonuclear leukocytes (20).…”

Section: Discussionmentioning

confidence: 99%

In vitro production and scavenging of hydrogen peroxide by D‐penicillamine. Relationship to copper availability

Staite

Messner

Zoschke

1985

Arthritis & Rheumatism

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The capacity of D-penicillamine (DP) to produce or scavenge hydrogen peroxide was investigated. DP added to copper produced H202. Greater production was observed with copper sulfate than with copper bound to ceruloplasmin. In contrast, DP in the absence of copper scavenged H202, as measured in a direct assay. Furthermore, DP or D-cysteine alone reversed H202-mediated inhibition of concanavalin A-stimulated mononuclear cell proliferation. These opposing immunomodulating properties of DP may be relevant to its toxic or therapeutic actions in rheumatoid arthritis.Although D-penicillamine (DP) has been used for many years in the treatment of rheumatoid arthritis (RA), the mechanism of action by which the drug exerts its beneficial effects remains obscure (1). Several properties of the drug have been described, including effects on collagen metabolism (2), inhibition of in vitro gamma globulin denaturation (3), and reduction of immune complexes including rheumatoid factor in the serum and synovial fluid of RA patients (43).Other studies suggest a more direct role for DP in the immunopathologic events associated with RA. For example, copper augments the inhibitory effects of February 20, 1985. DP on in vitro blastogenesis by mitogen-stimulated human mononuclear cells (6). Recently, this inhibitory effect was shown to be partly reversible with sodium borohydride, an antioxidant. Furthermore, inhibition was unaffected by superoxide dismutase, but was completely reversed with catalase, an enzyme that degrades hydrogen peroxide (7). We have shown that either exogenously added H202 or H202 released from polymorphonuclear leukocytes and monocytes stimulated with phorbol myristate acetate can inhibit lymphocyte transformation (8,9). Thus, DP and copper may interact to generate H202 and subsequently inhibit lymphocyte proliferation. There is, however, disagreement about whether DP can be oxidized by free copper ions or by copper bound to ceruloplasmin (CuWe have therefore examined the interaction between DP and either free or protein-bound copper in relation to the quantity of H202 produced. Our results show that depending on the availability of copper, DP can either produce or scavenge H202. These opposing effects are reflected in the ability of D-penicillamine to modulate lymphocyte transformation in vitro. CP) (10711). MATERIALS AND METHODSMeasurement of hydrogen peroxide production. H202 production was measured by a colorimetric method involving the peroxidase-dependent oxidation of phenol red (PR) (12). Ten microliters of D-penicillamine (Sigma, St. Louis, MO), diluted to appropriate concentrations with 10 mM phosphate buffered saline (PBS) containing 140 mM NaCl and 5.5 mM dextrose, pH 7.4, was added to 10 p1 of aqueous copper sulfate or ceruloplasmin in flat-bottom 96-well microtest plates (Falcon, Oxnard, CA) and incubated for varying times at 37°C. Ceruloplasmin (human, type X; Sigma) contained 2.25 pg of Cu++/mg protein.

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Inhibition of Human Helper T Cell Function In Vitro by d-Penicillamine and CuSO4

Abstract: A B S T R A C T The effect of D-penicillamine (Pen) and mixtures of Pen and copper sulfate on the capacity of normal human peripheral blood mononuclear cells (PBM) to generate immunoglobulin-secreting cells (ISC)

Cited by 120 publications

References 50 publications

Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine.

Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine.

Immunomodulatory effect of procainamide in man. Inhibition of human suppressor T-cell activity in vitro.

In vitro production and scavenging of hydrogen peroxide by D‐penicillamine. Relationship to copper availability

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