Neuropathy in miniature swine after administration of the mutant diphtheria toxin-based immunotoxin, pCD3-CRM9

Patricio Gargollo, Kazuhiko Yamada, Nestor Esnaola, Yasushi Fuchimoto, Kathy L. Newell, David H. Sachs, Christene A. Huang

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background. Effective in vivo T-cell depletion is a critical component of many transplantation tolerance protocols. We have previously demonstrated T-cell depletion in miniature swine using a CRM9-based CD3-immunotoxin, pCD3-CRM9. CRM9 is a mutant form of diphtheria toxin (DT) that binds less efficiently than wild-type DT to the DT receptor (proHB-EGF) of primates. In this report, we describe and characterize the dose-dependent neurotoxicity associated with CRM9-based immunotoxin administration in swine. Methods. Miniature swine were treated with varying doses of pCD3-CRM9 followed by daily monitoring for symptoms of neuropathy, including limb weakness, paresis, sluggishness, and/or respiratory distress. Animals demonstrating severe respiratory distress were euthanized and peripheral nerve, spinal cord, and skeletal muscle tissue samples were obtained at autopsy for microscopic examination. Unconjugated CRM9 was administered to one animal to define its toxicity independent of the effects of T-cell depletion. Results. Excellent T-cell depletion was obtained using doses of pCD3-CRM9 greater than 0.1 mg/kg. However, neurotoxicity was observed at these doses, as manifested by transient muscle weakness or paresis, which in some cases progressed to respiratory failure and death. Dorsal root ganglia samples revealed pathological changes typical of diphtheritic polyneuropathy. The animal receiving unconjugated CRM9 exhibited the same neurotoxic side effects as those receiving the pCD3-CRM9 conjugate. Conclusions. Administration of pCD3-CRM9 immunotoxin provides excellent T-cell depletion in miniature swine but is associated with significant dose-dependent neurotoxicity. A possible reason for CRM9-associated neurotoxicity in swine, but not primates, is suggested on the basis of a known amino acid difference in the exodomain of the DT receptor (proHBEGF) of swine compared with that of primates.

Original languageEnglish
Pages (from-to)818-822
Number of pages5
JournalTransplantation
Volume72
Issue number5
Publication statusPublished - 2001 Sep 15
Externally publishedYes

Fingerprint

Diphtheria Toxin
Miniature Swine
Immunotoxins
T-Lymphocytes
Primates
Swine
Paresis
Transplantation Tolerance
Polyneuropathies
Muscle Weakness
Spinal Ganglia
Peripheral Nerves
Epidermal Growth Factor
Respiratory Insufficiency
Autopsy
Spinal Cord
Skeletal Muscle
Extremities
Amino Acids
Muscles

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Gargollo, P., Yamada, K., Esnaola, N., Fuchimoto, Y., Newell, K. L., Sachs, D. H., & Huang, C. A. (2001). Neuropathy in miniature swine after administration of the mutant diphtheria toxin-based immunotoxin, pCD3-CRM9. Transplantation, 72(5), 818-822.

Neuropathy in miniature swine after administration of the mutant diphtheria toxin-based immunotoxin, pCD3-CRM9. / Gargollo, Patricio; Yamada, Kazuhiko; Esnaola, Nestor; Fuchimoto, Yasushi; Newell, Kathy L.; Sachs, David H.; Huang, Christene A.

In: Transplantation, Vol. 72, No. 5, 15.09.2001, p. 818-822.

Research output: Contribution to journalArticle

Gargollo, P, Yamada, K, Esnaola, N, Fuchimoto, Y, Newell, KL, Sachs, DH & Huang, CA 2001, 'Neuropathy in miniature swine after administration of the mutant diphtheria toxin-based immunotoxin, pCD3-CRM9', Transplantation, vol. 72, no. 5, pp. 818-822.
Gargollo P, Yamada K, Esnaola N, Fuchimoto Y, Newell KL, Sachs DH et al. Neuropathy in miniature swine after administration of the mutant diphtheria toxin-based immunotoxin, pCD3-CRM9. Transplantation. 2001 Sep 15;72(5):818-822.
Gargollo, Patricio ; Yamada, Kazuhiko ; Esnaola, Nestor ; Fuchimoto, Yasushi ; Newell, Kathy L. ; Sachs, David H. ; Huang, Christene A. / Neuropathy in miniature swine after administration of the mutant diphtheria toxin-based immunotoxin, pCD3-CRM9. In: Transplantation. 2001 ; Vol. 72, No. 5. pp. 818-822.
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abstract = "Background. Effective in vivo T-cell depletion is a critical component of many transplantation tolerance protocols. We have previously demonstrated T-cell depletion in miniature swine using a CRM9-based CD3-immunotoxin, pCD3-CRM9. CRM9 is a mutant form of diphtheria toxin (DT) that binds less efficiently than wild-type DT to the DT receptor (proHB-EGF) of primates. In this report, we describe and characterize the dose-dependent neurotoxicity associated with CRM9-based immunotoxin administration in swine. Methods. Miniature swine were treated with varying doses of pCD3-CRM9 followed by daily monitoring for symptoms of neuropathy, including limb weakness, paresis, sluggishness, and/or respiratory distress. Animals demonstrating severe respiratory distress were euthanized and peripheral nerve, spinal cord, and skeletal muscle tissue samples were obtained at autopsy for microscopic examination. Unconjugated CRM9 was administered to one animal to define its toxicity independent of the effects of T-cell depletion. Results. Excellent T-cell depletion was obtained using doses of pCD3-CRM9 greater than 0.1 mg/kg. However, neurotoxicity was observed at these doses, as manifested by transient muscle weakness or paresis, which in some cases progressed to respiratory failure and death. Dorsal root ganglia samples revealed pathological changes typical of diphtheritic polyneuropathy. The animal receiving unconjugated CRM9 exhibited the same neurotoxic side effects as those receiving the pCD3-CRM9 conjugate. Conclusions. Administration of pCD3-CRM9 immunotoxin provides excellent T-cell depletion in miniature swine but is associated with significant dose-dependent neurotoxicity. A possible reason for CRM9-associated neurotoxicity in swine, but not primates, is suggested on the basis of a known amino acid difference in the exodomain of the DT receptor (proHBEGF) of swine compared with that of primates.",
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AU - Newell, Kathy L.

AU - Sachs, David H.

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N2 - Background. Effective in vivo T-cell depletion is a critical component of many transplantation tolerance protocols. We have previously demonstrated T-cell depletion in miniature swine using a CRM9-based CD3-immunotoxin, pCD3-CRM9. CRM9 is a mutant form of diphtheria toxin (DT) that binds less efficiently than wild-type DT to the DT receptor (proHB-EGF) of primates. In this report, we describe and characterize the dose-dependent neurotoxicity associated with CRM9-based immunotoxin administration in swine. Methods. Miniature swine were treated with varying doses of pCD3-CRM9 followed by daily monitoring for symptoms of neuropathy, including limb weakness, paresis, sluggishness, and/or respiratory distress. Animals demonstrating severe respiratory distress were euthanized and peripheral nerve, spinal cord, and skeletal muscle tissue samples were obtained at autopsy for microscopic examination. Unconjugated CRM9 was administered to one animal to define its toxicity independent of the effects of T-cell depletion. Results. Excellent T-cell depletion was obtained using doses of pCD3-CRM9 greater than 0.1 mg/kg. However, neurotoxicity was observed at these doses, as manifested by transient muscle weakness or paresis, which in some cases progressed to respiratory failure and death. Dorsal root ganglia samples revealed pathological changes typical of diphtheritic polyneuropathy. The animal receiving unconjugated CRM9 exhibited the same neurotoxic side effects as those receiving the pCD3-CRM9 conjugate. Conclusions. Administration of pCD3-CRM9 immunotoxin provides excellent T-cell depletion in miniature swine but is associated with significant dose-dependent neurotoxicity. A possible reason for CRM9-associated neurotoxicity in swine, but not primates, is suggested on the basis of a known amino acid difference in the exodomain of the DT receptor (proHBEGF) of swine compared with that of primates.

AB - Background. Effective in vivo T-cell depletion is a critical component of many transplantation tolerance protocols. We have previously demonstrated T-cell depletion in miniature swine using a CRM9-based CD3-immunotoxin, pCD3-CRM9. CRM9 is a mutant form of diphtheria toxin (DT) that binds less efficiently than wild-type DT to the DT receptor (proHB-EGF) of primates. In this report, we describe and characterize the dose-dependent neurotoxicity associated with CRM9-based immunotoxin administration in swine. Methods. Miniature swine were treated with varying doses of pCD3-CRM9 followed by daily monitoring for symptoms of neuropathy, including limb weakness, paresis, sluggishness, and/or respiratory distress. Animals demonstrating severe respiratory distress were euthanized and peripheral nerve, spinal cord, and skeletal muscle tissue samples were obtained at autopsy for microscopic examination. Unconjugated CRM9 was administered to one animal to define its toxicity independent of the effects of T-cell depletion. Results. Excellent T-cell depletion was obtained using doses of pCD3-CRM9 greater than 0.1 mg/kg. However, neurotoxicity was observed at these doses, as manifested by transient muscle weakness or paresis, which in some cases progressed to respiratory failure and death. Dorsal root ganglia samples revealed pathological changes typical of diphtheritic polyneuropathy. The animal receiving unconjugated CRM9 exhibited the same neurotoxic side effects as those receiving the pCD3-CRM9 conjugate. Conclusions. Administration of pCD3-CRM9 immunotoxin provides excellent T-cell depletion in miniature swine but is associated with significant dose-dependent neurotoxicity. A possible reason for CRM9-associated neurotoxicity in swine, but not primates, is suggested on the basis of a known amino acid difference in the exodomain of the DT receptor (proHBEGF) of swine compared with that of primates.

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