Gadolinium Chloride Toxicity in the Rat

Aj, Spencer; Sa, Wilson; J, Batchelor; Reid, Alexandra; Rees, Jeremy A.; Harpur, Ernest S.

doi:10.1177/019262339702500301

Cited by 127 publications

(92 citation statements)

References 26 publications

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“…45,46 However, clinical application of Kupffer cell-depleting agents might be hampered by their side effects. 47,48 Activated Kupffer cells are the main source of the membrane-bound TNFa precursor, which is processed to produce the mature, secreted cytokine. 49 This further implicates TNFa as a candidate to modulate the early immune response.…”

Section: Discussionmentioning

confidence: 99%

Modulation of TNFα, a determinant of acute toxicity associated with systemic delivery of first-generation and helper-dependent adenoviral vectors

et al. 2006

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Understanding the determinants of the host innate immune response to systemic administration of adenoviral (Ad) vectors is critical for clinical gene therapy. Acute toxicity occurs within minutes to hours after vector administration and is characterized by activation of innate immune responses. Our data indicate that in mice, indicators of vector toxicity include elevations of cytokine levels, liver transaminase levels and thrombocytopenia. To discern potential targets for blunting this host response, we evaluated genetic factors in the host response to systemically administered first-generation Ad vectors (FGV) and helper-dependent Ad vectors (HDV) containing b-galactosidase expression cassettes. A preliminary screen for modulation of vector-induced thrombocytopenia revealed no role for interferon-g, mast cells or perforin. However, vector-induced thrombocytopenia and interleukin 6 (IL-6) expression are less evident in tumor necrosis factor alpha (TNFa)-deficient mice. Moreover, we also demonstrated that TNFa blockade via antibody or huTNFR:Fc pretreatment attenuates both thrombocytopenia (440% increase in platelet count) and IL-6 expression (480% reduction) without affecting interleukin 12 , liver enzymes, hematological indices or vector transduction in a murine model. Our data indicate that the use of HDV, in combination with clinically approved TNFa immunomodulation, may represent an approach for improving the therapeutic index of Ad gene therapy for human clinical trials.

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Section: Discussionmentioning

confidence: 99%

Modulation of TNFα, a determinant of acute toxicity associated with systemic delivery of first-generation and helper-dependent adenoviral vectors

et al. 2006

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“…46 Gadolinium is also a potent inhibitor of the reticuloendothelial system. 34, 47 All GBCAs and gadolinium chloride have been found to stimulate fibroblast proliferation in tissues taken from healthy subjects.…”

Section: 45mentioning

confidence: 99%

Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update

Ramalho

Semelka

Ramalho

et al. 2015

American Journal of Neuroradiology

367

244

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SUMMARY:In current practice, gadolinium-based contrast agents have been considered safe when used at clinically recommended doses in patients without severe renal insufficiency. The causal relationship between gadolinium-based contrast agents and nephrogenic systemic fibrosis in patients with renal insufficiency resulted in new policies regarding the administration of these agents. After an effective screening of patients with renal disease by performing either unenhanced or reduced-dose-enhanced studies in these patients and by using the most stable contrast agents, nephrogenic systemic fibrosis has been largely eliminated since 2009. Evidence of in vivo gadolinium deposition in bone tissue in patients with normal renal function is well-established, but recent literature showing that gadolinium might also deposit in the brain in patients with intact blood-brain barriers caught many individuals in the imaging community by surprise. The purpose of this review was to summarize the literature on gadolinium-based contrast agents, tying together information on agent stability and animal and human studies, and to emphasize that low-stability agents are the ones most often associated with brain deposition.ABBREVIATIONS: DN ϭ dentate nuclei; GBCA ϭ gadolinium-based contrast agent; NSFϭ nephrogenic systemic fibrosis

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“…Additionally, GdCl 3 is quickly eliminated with a half-life of about 15 min. 40,42 Therefore, we believe that GdCl 3 administrated 8 days before heart transplantation should have minimal toxicity for the transplanted heart. The dependence on recipient phagocytes was also verified by coating donor apoptotic splenocytes with PSspecific annexin V. Therefore, the process of phagocytosis of apoptotic cells is a critical step in the induction of immune tolerance.…”

Section: Percent Of Survivalmentioning

confidence: 99%

Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient

et al. 2004

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Cell death through apoptosis plays a critical role in regulating cellular homeostasis. Whether the disposal of apoptotic cells through phagocytosis can actively induce immune tolerance in vivo, however, remains controversial. Here, we report in a rat model that without using immunosuppressants, transfusion of apoptotic splenocytes from the donor strain prior to transplant dramatically prolonged survival of heart allografts. Histological analysis verified that rejection signs were significantly ameliorated. Splenocytes from rats transfused with donor apoptotic cells showed a dramatically decreased response to donor lymphocyte stimulation. Most importantly, blockade of phagocytosis in vivo, either with gadolinium chloride to disrupt phagocyte function or with annexin V to block binding of exposed phosphotidylserine to its receptor on phagocytes, abolished the beneficial effect of transfused apoptotic cells on heart allograft survival. Our results demonstrate that donor apoptotic cells promote specific allograft acceptance and that phagocytosis of apoptotic cells in vivo plays a crucial role in maintaining immune tolerance.

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Gadolinium Chloride Toxicity in the Rat

Cited by 127 publications

References 26 publications

Modulation of TNFα, a determinant of acute toxicity associated with systemic delivery of first-generation and helper-dependent adenoviral vectors

Modulation of TNFα, a determinant of acute toxicity associated with systemic delivery of first-generation and helper-dependent adenoviral vectors

Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update

Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient

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