Mechanisms whereby cytotoxic T lymphocytes damage guinea-pig ventricular myocytes in vitro

Felzen, Bella; Berke, Gideon; Rosen, Dalia; Binah, Ofer

doi:10.1007/bf00374256

Cited by 11 publications

(14 citation statements)

References 43 publications

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“…Rose and Hill [22] noted at least four possible mechanisms of cardiac damage during the autoimmune process: (1) IL-1-induced nitric oxide; (2) TNF-; (3) cytotoxic CD8 + , and (4) antibodies to cardiac antigens. Of these, in our previous studies we have focused on mechanisms utilized by cytotoxic T lymphocytes (CTL) to bring about myocyte dysfunction [15,37]. Although we have not provided direct proof implicating CTL in the observed electrophysiological perturbations in myocarditis, a large body of evidence indicates that CTL, probably operating via the Fas/ FasL pathway, are key players.…”

Section: Namentioning

confidence: 94%

“…The notion that the electrophysiological perturbations of diseased myocytes may indeed contribute to the decline in cardiac function, and are not merely 'markers' of heart failure, is indicated by the following observations: (1) direct Fas triggering in isolated myocytes caused electrophysiological perturbations similar, if not identical to those observed in diseased myocytes (see discussion below) [37]. Additionally, we have recently found (unpublished results) that Fas activation by the Fas-antibody Jo2 attenuated I to by 90%, again resembling the findings of the present work.…”

Section: Electrophysiological Alterations In Myocarditismentioning

confidence: 99%

“…Although we have not provided direct proof implicating CTL in the observed electrophysiological perturbations in myocarditis, a large body of evidence indicates that CTL, probably operating via the Fas/ FasL pathway, are key players. The contribution of CTL-induced, Fas-mediated myocardial damage in myocarditis is strongly indicated by the striking similarity between the electrophysiological disturbances seen in diseased myocytes and those induced by direct activation of the Fas receptor [37]. We have recently shown that the interaction of murine ventricular myocytes with perforin-deficient CTL (operating via the Fas/FasL pathway) or exposure to Jo2, resulted in APD prolongation, generation of early afterdepolarizations and triggered arrhythmias [37], as well as attenuation of I to .…”

Section: Namentioning

confidence: 99%

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Cardiac Dysfunction in Murine Autoimmune Myocarditis

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Shilkrut

Rubinstein

et al. 1999

Journal of Autoimmunity

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Section: Namentioning

confidence: 94%

Section: Electrophysiological Alterations In Myocarditismentioning

confidence: 99%

Section: Namentioning

confidence: 99%

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Cardiac Dysfunction in Murine Autoimmune Myocarditis

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Shilkrut

Rubinstein

et al. 1999

Journal of Autoimmunity

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“…More recent work from this group [23,24] has shown that cytotoxic T lymphocytes activated by conconavalin A treatment induce similar changes in isolated adult guinea pig ventricular myocytes. Taken together, these experiments strongly suggest that degranulation of allosensitized cytotoxic T lymphocytes can induce functional changes in target cardiac myocytes and can, in addition, cause myocyte lysis.…”

Section: Effects Of Lymphocytes On Cardiac Myocytesmentioning

confidence: 99%

Effects of cellular elements of the immune response on myocyte function and survival

Barry

1996

Heart Failure Rev

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The immune response is known to be associated with abnormalities of systolic and diastolic cardiac function during cardiac transplant rejection [1-3] and myocarditis [4]. In addition, autoimmunity may be an important contributor to depressed function in idiopathic dilated cardiomyopathy [5,6]. This immune response may impair cardiac performance by altering the function of individual myocytes, by causing myocyte necrosis and thus reducing the mass of functioning myocardium, or by a combination of these effects. The immune response consists of both cellular and humoral components. The cellular component can result in direct interaction of an inflammatory cell with the myocyte, or an indirect effect produced on the myocyte by virtue of secretion of soluble products such as cytokines by the inflammatory cell. The effects of cytokines on myocardial cells are considered at length in other articles in this issue. In this discussion we consider primarily the effects of direct interaction of various inflammatory cells participating in the immune response on myocyte function and survival. Components of the Cellular Inflammatory InfiltrateIt is first appropriate to consider the nature of the cellular infiltrate that occurs in an immune-mediated cardiac inflammation. Tilney and associates [7,8] showed that acutely rejecting cardiac rat allografts contain macrophages (15-25%), lymphocytes (75%), and neutrophils (5%). Of the lymphocytes, approximately 35% were B cells and the remainder were T lymphocytes. The initial infiltrate consists primarily of lymphocytes, with infiltration by a larger number of macrophages and neutrophils occurring with more complete rejection. Acute murine viral myocarditis is also associated with an infiltrate of macrophages and lymphocytes, including natural killer (NK) cells [9]. Recent work from our laboratory with the murine heterotopic mouse heart transplant model [10] demonstrated that the heart-infiltrating cell population consists of 44% lymphocytes, 30% macrophages, and 20% neutrophils 5-7 days after transplantation. Further studies in our laboratory have documented that the function of the transplanted heart is significantly depressed at this point [11]. We will therefore consider which components of this immune infiltrate could be responsible for cardiac depression during immune-mediated injury and the mechanisms involved. The work to be described will be focused primarily on the transplant rejection model, although, as mentioned earlier, it is very likely that similar mechanisms are involved in the myocardial functional depression noted during myocarditis, and possibly during autoimmune injury associated with idiopathic dilated cardiomyopathy. Effects of Lymphocytes on Cardiac MyocytesWe will first consider the effects oflymphocytes on myocyte function and survival. There are several types of lymphocytes that are involved in immune reactions. Cellular responses are mediated by T lymphocytes. Helper T lymphocytes (HTL; CD4 ÷) recognize endocytosed peptides that are bound to class II MHC mol...

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“…This enables investigation of a variety of functional properties, e.g. electrophysiology, myocyte shortening and intracellular [Ca 2+ ] ([Ca 2+ ] i ) [10,11]. These studies have shown that PEL-myocyte interaction can result in deterioration of action potential characteristics, generation of delayed afterdepolarizations and contracture, eventually leading to destruction of the myocyte.…”

Section: Introductionmentioning

confidence: 99%

Involvement of the IP 3 cascade in the damage to guinea-pig ventricular myocytes induced by cytotoxic T lymphocytes

Felzen

Berke

Gardner

et al. 1997

Pfl�gers Archiv European Journal of Physiology

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We have shown previously that the interaction between cytotoxic T lymphocytes (CTL) and ventricular myocytes, an in vitro model for heart transplant rejection, results in electrophysiological and morphological alterations indicative of overload of the intracellular [Ca2+] ([Ca2+]i). Since these deleterious effects cannot be accounted for by increased L-type Ca2+ current (ICa,L), we hypothesize that [Ca2+]i overload due to Ca2+ release from intracellular stores, e.g. sarcoplasmic reticulum (SR), is initiated by CTL-induced activation of the inositol trisphosphate (IP3) cascade. Patch-clamp and fura-2-fluorescence techniques were utilized to record transmembrane potentials and [Ca2+]i from ventricular myocytes bound to peritoneal exudate CTL (PEL). In ventricular myocyte-PEL conjugates (after 60 min), resting potential was reduced (compared with the nonconjugated state) from -80.9 +/- 0.7 to -59.9 +/- 2.5 mV, action potential amplitude from 139.5 +/- 1.4 to 80.6 +/- 1.7 mV and action potential duration to 50% repolarization (APD50) from 797 +/- 97 to 52 +/- 12 ms. The ratio of fluorescence at 340 and 380 nm (R340/380) increased from a control value (in nonconjugated myocytes) of 0.71 +/- 0.02 to 2.07 +/- 0.03, 30 min, after conjugate formation, and exceeded 4.0 at 60 min, before myocyte destruction. Heparin (50 micrograms/ml), an antagonist of IP3-induced Ca2+ release from SR channels, or U-73122 (2 microM), a phospholipase C (PLC) inhibitor (drugs were included in the pipette solution), prevented PEL-induced morphological and electrophysiological alterations. Accordingly, heparin attenuated the PEL-induced increase in [Ca2+]i; after 60 min of PEL-myocyte interaction, R340/380 was 1.15 +/- 0.09 (compared with approximately 4.0 in the absence of heparin). The results indicate that CTL-mediated damage to ventricular myocytes is, at least partially, mediated by PLC activation and IP3-induced Ca2+ release from intracellular stores. Pharmacological targeting of IP3 in heart transplant rejection is thus suggested.

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Mechanisms whereby cytotoxic T lymphocytes damage guinea-pig ventricular myocytes in vitro

Cited by 11 publications

References 43 publications

Cardiac Dysfunction in Murine Autoimmune Myocarditis

Cardiac Dysfunction in Murine Autoimmune Myocarditis

Effects of cellular elements of the immune response on myocyte function and survival

Involvement of the IP 3 cascade in the damage to guinea-pig ventricular myocytes induced by cytotoxic T lymphocytes

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