Antibodies to CD40 induce a lethal cytokine cascade after syngeneic bone marrow transplantation

Julie A. Hixon, Bruce R. Blazar, Miriam R. Anver, Robert H. Wiltrout, William J. Murphy

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

CD40 stimulation, by either antibody or ligand, has been shown to inhibit the growth of a variety of neoplastic cells, both in vivo and in vitro. In this study, we assessed the effects of CD40 stimulation using a murine agonistic CD40 monoclonal antibody (MoAb) (FGK115) or a soluble recombinant murine CD40 ligand (srmCD40L) in both lethally irradiated and nonirradiated BALB/c mice. Toxicity after CD40 stimulation was not observed in nonirradiated animals receiving up to 100 μg of the agonist anti-CD40 MoAb. However, as little as 10 μg of the agonistic anti-CD40 MoAb induced acute toxicity resulting in 100% morbidity of lethally irradiated animals by 4 days after irradiation. Histological evaluation of animals receiving anti-CD40 MoAb revealed severe intestinal lesions with disruption of the villi, goblet cell depletion, and crypt hyperplasia of the small intestine, colon, and cecum. Delaying the administration of anti-CD40 MoAb or reducing the amount of irradiation given resulted in increased survival and less severe lesions. Analysis of serum cytokine levels in lethally irradiated mice receiving agonistic anti-CD40 showed a marked increase of interferon (IFN)-γ. Lethally irradiated IFN-γ knockout mice given the agonistic anti-CD40 MoAb demonstrated significant increases in survival and minimal gut lesions compared with wild-type mice receiving the same regimen, suggesting that IFN-γ plays a major role in this toxic reaction. These results indicate that CD40 stimulation using agonistic antibodies following lethal irradiation leads to a fatal, cytokine-induced disease affecting the intestine.

Original languageEnglish (US)
Pages (from-to)136-143
Number of pages8
JournalBiology of Blood and Marrow Transplantation
Volume7
Issue number3
DOIs
StatePublished - 2001

Bibliographical note

Funding Information:
This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-CO-56000, and supported in part by National Institutes of Health Grants RO1 AI34495, RO1 HL63452 and R37 HL56067. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Keywords

  • Antibodies
  • Cytokines
  • In vivo animal models
  • Transplantation

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