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
StatePublished - 2001
Externally publishedYes

Keywords

  • Antibodies
  • Cytokines
  • In vivo animal models
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

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