Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo. A novel approach to immunosuppressive therapy.

Abstract

Lymphoid cells were thought to be uniquely susceptible to excess 2'-deoxyadenosine (dAdo), when exposed to inhibitors of adenosine deaminase (ADA). However, we now find that human monocytes are as sensitive as lymphocytes to dAdo or to the ADA-resistant congener 2-chloro-2'-deoxyadenosine (CldAdo). Monocytes exposed in vitro to CldAdo, or to dAdo plus deoxycoformycin rapidly developed DNA strand breaks. Both the DNA damage and the toxicity of CldAdo or dAdo toward monocytes were blocked by deoxycytidine, but not by inhibitors of poly(ADP-ribose) polymerase. A partial decrease in RNA synthesis and a gradual decline of cellular NAD were early biochemical events associated with monocyte DNA damage. Low CIdAdo concentrations (5-20 nM) inhibited monocyte phagocytosis and reduced the release of interleukin 6. Higher CldAdo concentrations led to a dose-and time-dependent loss of monocyte viability.Circulating monocytes disappeared within 1 wk in patients with cutaneous T cell Iymphoma or with rheumatoid arthritis during continuous CldAdo infusion. The marked sensitivity of human monocyte function and survival to CldAdo in vitro, together with the monocyte depletion in patients receiving CIdAdo chemotherapy, suggests that CldAdo or other dAdo analogues offer a novel therapeutic strategy for chronic inflammatory and autoimmune diseases characterized by inappropriate monocyte deployment or function. (J. Clin. Invest. 1990.

Streptococcus suis synthesizes deoxyadenosine and adenosine by 5’-nucleotidase to dampen host immune responses

“…dAdo has a cytotoxic effect on several human or animal immune cells [18,19]. The mouse macrophages RAW 264.7 were used to determine whether the dAdo generated by NT has the same effect.…”

“…Carrera et al . showed that human monocytes were sensitive to dAdo and monocytes exposed to dAdo in vitro developed DNA strand breaks [18]. DNA damage appears to be requisite for toxicity and dAdo causes the DNA damage through effects on enzymes implicated in DNA synthesis or repair [18].…”

“…showed that human monocytes were sensitive to dAdo and monocytes exposed to dAdo in vitro developed DNA strand breaks [18]. DNA damage appears to be requisite for toxicity and dAdo causes the DNA damage through effects on enzymes implicated in DNA synthesis or repair [18]. The i n vivo transcriptome analysis in mouse blood indicated that the WT strain GZ0565 upregulated the expression of the host genes involved in DNA damage, which was possibly mediated by dAdo synthesized by NT.…”

“…The i n vivo transcriptome analysis in mouse blood indicated that the WT strain GZ0565 upregulated the expression of the host genes involved in DNA damage, which was possibly mediated by dAdo synthesized by NT. DNA from cells dying may provide sufficient dAdo to produce the effects on the function and survival of immune cells [18]. Pathogenic bacteria may use the synthesized dAdo to evade host defenses.…”

Treatment of children with Langerhans cell histiocytosis with 2‐chlorodeoxyadenosine

“…In vitro studies have shown that 2-CdA is a highly selective anti-monocyte agent, which causes decreased monocyte function and viability and decreased IL-6 secretion [32]. Because tissue histiocytes are derived from the same stem cells as circulating monocytes, 2-CdA may thus be a rational agent for the treatment of patients with histiocytic disorders.…”