Augmented therapeutic results elicited by splenectomy in combined modality treatment of spontaneous murine breast cancer

Stolfi, Robert L.; Stolfi, Leslie M.; Fugmann, Ruth A.

doi:10.1007/bf00200072

Cited by 10 publications

(8 citation statements)

References 18 publications

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“…In contrast to C5b-7, C5b-8 mediates low levels of cytolytic activity [53,59]. It is probable that dimeric or oligomeric C5b-8 complexes are required for cytolysis to occur.…”

Section: The C5b-8 Complexmentioning

confidence: 90%

Molecular mechanisms of cytolysis by complement and by cytolytic lymphocytes

Podack

1986

J of Cellular Biochemistry

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Recent advances in our understanding of the mechanism of NK cell and cytolytic Tlymphocyte (CTL)-mediated cytolysis have revealed intriguing analogies of lymphocytic effector mechanisms with those of complement. Each of these cytolytic effector systems assembles on target membranes cytolytically active, tubular complexes from hydrophilic precursor proteins. Membrane insertion of the tubular complexes gives rise to ultrastructural membrane lesions and causes target cell lysis by disruption of the target membrane ( Fig. 1). Assembly of tubular transmembrane complexes involves the polymerization of monomeric precursor proteins to transmembrane pores that serve to lyse cells directly and to permit entry of additional lytic factors. This review will summarize the molecular events resulting in the formation of membrane lesions by lymphocytes and by complement and our knowledge of additional cytolytic factors. It will become apparent that there are striking analogies in the morphology and function of the tubular complexes, their mode of assembly, as well as their utilization as transmembrane channels for entry of cytolytic factors. ASSEMBLY OF THE MEMBRANE ATTACK COMPLEX (MAC) OF COMPLEMENTFormation of the MAC proceeds in a stepwise assembly of five proteins to a complex with approximately 20 subunits. The assembly may be divided into two stages with regard to function, structure, and control: (1) The insertional event carried out by the trimolecular C5b-7 complex. This reaction proceeds without overt lysis but it sets the stage for subsequent membrane damage. (2) Membrane damage by binding of C8 and polymerization of C9 to the tubular transmembrane complex that is responsible for formation of the ultrastructural membrane lesion.For the purpose of this review, the second stage, the formation of membrane lesions by polymerization of C9, will be described first because it exemplifies

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“…In contrast to C5b-7, C5b-8 mediates low levels of cytolytic activity [53,59]. It is probable that dimeric or oligomeric C5b-8 complexes are required for cytolysis to occur.…”

Section: The C5b-8 Complexmentioning

confidence: 90%

Molecular mechanisms of cytolysis by complement and by cytolytic lymphocytes

Podack

1986

J of Cellular Biochemistry

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“…The structural entity associated with the complement lesion was first visualized in the electron microscope by Dourmashkin and co-workers (1-3) as a ring-like structure of v20 nm outer and -10 nm inner diameter. Those researchers also showed that formation of the morphological lesion requires participation of all five terminal complement proteins, including C9, although lysis of sheep erythrocytes proceeds in the absence of C9 (4). Based in part on the physical appearance of the lesion in the electron microscope and in part on the properties of low molecular weight ionophores, Mayer (5) introduced the "doughnut" theory, which describes the lesion as a stable hollow structure composed of proteins C5b, C6, C7, C8, and C9.…”

mentioning

confidence: 98%

Proteolytic modification of human complement protein C9: loss of poly(C9) and circular lesion formation without impairment of function.

Dankert¹,

Esser²

1985

Proc. Natl. Acad. Sci. U.S.A.

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We have compared the ability of thrombincleaved C9 (C9") with that of native C9 to produce tubular or ring-like poly(C9) and to express the classical complement lesion on target membranes. Three procedures were used to produce poly(C9): (i) limited proteolysis with trypsin, (it) interaction with small unilamellar lipid vesicles, and (iii) incubation with a 2-to 4-fold molar excess of ZnC12. In contrast to C9, which could be converted to tubular poly(C9), C9n was converted to smaller peptides by the first procedure and was aggregated into string-like poly(C9) by the other two methods. C9-depleted human serum (R-9 serum) was reconstituted with either C9 or C9" and these sera were then used to lyse sensitized sheep erythrocytes. Numerous classical complement lesions could be detected on ghost membranes obtained from cells lysed by C9-reconstituted R-9 serum but only a few on ghost membranes produced by C9n-reconstituted R-9 serum. C9' was shown to be hemolytically as active as C9 even when tested under "single-hit" conditions and it was about twice as efficient when compared with C9 in releasing sucrose and inulin from resealed ghosts. These results are interpreted to indicate that formation of the classical complement lesion is only incidental to lysis and not an obligatory event and that enlargement of the "functional pore size" of the complement lesion is not linked to formation of a circular membrane attack complex.One hallmark of serum complement is its ability to lyse erythrocytes and bacteria and it is now axiomatic that lysis results from the formation of lesions on the target membrane. The structural entity associated with the complement lesion was first visualized in the electron microscope by Dourmashkin and co-workers (1-3) as a ring-like structure of v20 nm outer and -10 nm inner diameter. Those researchers also showed that formation of the morphological lesion requires participation of all five terminal complement proteins, including C9, although lysis of sheep erythrocytes proceeds in the absence of C9 (4). Based in part on the physical appearance of the lesion in the electron microscope and in part on the properties of low molecular weight ionophores, Mayer (5) introduced the "doughnut" theory, which describes the lesion as a stable hollow structure composed of proteins C5b, C6, C7, C8, and C9. This structure was considered to provide a water-filled transmembrane pore of -10 nm diameter that allows polar substances to equilibrate across the hydrophobic membrane barrier, and cell death results from ensuing colloid-osmotic effects.An alternative view for the mechanism of immune hemolysis was presented by Kinsky (6) and Lachmann and coworkers (7,8), who suggested that lysis is caused by a detergent-like action of the terminal complement proteins that assemble on the target to form a "leaky patch." This hypothesis is supported by studies by Esser and co-workers, (9-11), who investigated the effect of the terminal proteins on lipid organization in the target membrane and the mechanism of virolysi...

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“…It is reported that there is an absolute requirement for all five components (C5b, C6, C7, C8, and C9) of this lytic complex for killing of a number of Gramnegative bacteria (1)(2)(3). This is unlike the situation for complement-mediated erythrocyte lysis, in which a C5b-8 complex with no C9 is sufficient for lysis (4). Furthermore, the number of C5b-9 complexes that are necessary to kill a bacterium is apparently much larger than the number of C5b-9 required for erythrocyte lysis (ref.…”

mentioning

confidence: 98%

Multimeric complement component C9 is necessary for killing of Escherichia coli J5 by terminal attack complex C5b-9.

Joiner¹,

Schmetz²,

Sanders³

et al. 1985

Proc. Natl. Acad. Sci. U.S.A.

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We studied the molecular composition of the complement C5b-9 complex required for optimal killing of Escherichia coli strain J5. JS cells were incubated in 3.3%, 6.6%, or 10.0% C8-deficient serum previously absorbed to remove specific antibody and lysozyme. This resulted in the stable deposition after washing of 310, 560, and 890 C5b67 molecules per colony-forming unit, respectively, as determined by binding of 125I-labeled C7. Organisms were then incubated with excess C8 and various amounts of 1311-labeled C9. Plots of the logarithm (base 10) of E. coli J5 cells killed (log kill) vs. C9 input were sigmoidal, confirming the multihit nature of the lethal process. When C9 was supplied in excess, 3300, 5700, and 9600 molecules of C9 were bound per organism for cells bearing 310, 560, and 890 C5b-8 complexes, respectively, leading to C9-to-C7 ratios of 11.0:1, 10.8:1, and 11.4:1 and to log kill values of 1.3, 2.1, and 3.9. However, at low inputs of C9 that lead to C9-to-C7 ratios of <3.3:1, no killing occurred, and this was independent of the number of C5b-9 complexes bound. Formation of multimeric C9 at C9-to-C7 ratios permissive for killing was confirmed by electron microscopy and by binding of 1251-labeled antibody with specificity for multimeric but not monomeric C9. These experiments are the first to demonstrate a biological function for C9 polymerization and suggest that multimeric C9 is necessary for optimal killing of E. coli J5 cells by C5b-9.

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Augmented therapeutic results elicited by splenectomy in combined modality treatment of spontaneous murine breast cancer

Abstract: Summary. Because it had been reported that splenectomy produces a tumor-inhibitory effect in several trans

Cited by 10 publications

References 18 publications

Molecular mechanisms of cytolysis by complement and by cytolytic lymphocytes

Molecular mechanisms of cytolysis by complement and by cytolytic lymphocytes

Proteolytic modification of human complement protein C9: loss of poly(C9) and circular lesion formation without impairment of function.

Multimeric complement component C9 is necessary for killing of Escherichia coli J5 by terminal attack complex C5b-9.

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