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 journalArticle

24 Citations (Scopus)

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

Fingerprint

Isogeneic Transplantation
Bone Marrow Transplantation
Monoclonal Antibodies
Cytokines
Antibodies
Interferons
CD40 Ligand
Goblet Cells
Cecum
Poisons
Knockout Mice
Small Intestine
Intestines
Hyperplasia
Colon
Ligands
Morbidity
Growth
Serum

Keywords

  • Antibodies
  • Cytokines
  • In vivo animal models
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

Cite this

Antibodies to CD40 induce a lethal cytokine cascade after syngeneic bone marrow transplantation. / Hixon, Julie A.; Blazar, Bruce R.; Anver, Miriam R.; Wiltrout, Robert H.; Murphy, William J.

In: Biology of Blood and Marrow Transplantation, Vol. 7, No. 3, 2001, p. 136-143.

Research output: Contribution to journalArticle

Hixon, Julie A. ; Blazar, Bruce R. ; Anver, Miriam R. ; Wiltrout, Robert H. ; Murphy, William J. / Antibodies to CD40 induce a lethal cytokine cascade after syngeneic bone marrow transplantation. In: Biology of Blood and Marrow Transplantation. 2001 ; Vol. 7, No. 3. pp. 136-143.
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