Acute toxicity of CD40 stimulation following syngeneic bone marrow transplantation: Role of interferon-gamma

Abstract

CD40 stimulation, by either antibody or ligand has been demonstrated to selectively inhibit the growth of various neoplastic cells in vitro and in vivo. We first assessed the effects of CD40 stimulation on normal mice using both a recombinant soluble ligand (srCD40L) or an agonist mAb, and found that B cell expansion occurred but no overt toxicity was observed. Surprisingly, when CD40 stimulation was administered following a syngeneic bone marrow transplant (BMT), all mice receiving as little as 10 ug injections of anti-CD40 antibody succumbed within 4 days whereas mice receiving the srCD40L did not show any adverse effects. Histological evaluation of the mice indicated that mice treated with CD40 mAbs exhibited significant gut pathology with marked crypt hyperplasia, goblet cell depletion, and villous blunting in the gut. Delaying administration of the anti-CD40 mAb resulted in protection from this toxicity. As CD40 stimulation has been shown to induce cytokine production by monocytes and other CD40+ cells, we hypothesized that cytokines may be responsible for mediating the pathology following BMT. Serum cytokine levels of mice following the BMT revealed that mice receiving antibodies to CD40 had markedly elevated levels of interferon-gamma. Interestingly, mice receiving the srCD40L had no increases in interferon levels indicating that interferon levels correlated with pathology. Interferon-gamma knockout (KO) mice were then used as recipients of syngeneic BMT with or without anti-CD40 treatment. Treatment of these KO mice with anti-CD40 resulted in significantly greater increases in survival compared to control mice receiving the antibodies. These results indicate that CD40 stimulation using agonist antibodies following BMT can induce a fatal cytokine-induced disease affecting the gut tissues.