Administration of Adenosine Diphosphate-Ribosyl Transferase Antagonist Allows in vivo Control of Anti-Dinitrophenyl Response

Abstract

3-Methoxybenzamide (3MB) is one of a series of chemical inhibitors of the nuclear enzyme adenosine diphosphate (ADP)-ribosyl transferase (ADPRT), which has been shown to inhibit cell differentiation in vitro, but has no effect on differentiation independent proliferation. Treatment of mice with an optimal concentration of 3MB (20 mg/kg body weight) at or 1 day after dinitrophenyl-keyhole limpet haemocyanin (DNP-KLH) immunisation reduced anti-DNP plaque-forming cell (PFC) numbers to less than 10% of those of control animals. The period for maximum PFC suppression showed a narrow time window relative to immunisation, suggesting that in vivo, as in vitro, 3MB was acting only on those lymphocytes differentiating in response to antigen. Experimental findings showed that it was possible to select for PFC derived from different populations of DNP-responsive lymphocytes by adjusting the time of 3MB treatment relative to immunisation. When 3MB was used with antigen priming, the residual PFC showed a lower average affinity than PFC in mice treated with 3MB 3 days after priming, suggesting a differential selection of those lymphocytes responding either ‘early’ or ‘late’ in the primary immune response.

The Therapeutic Effects of PJ34 [N-(6-Oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide.HCl], a Selective Inhibitor of Poly(ADP-Ribose) Polymerase, in Experimental Allergic Encephalomyelitis Are Associated with Immunomodulation

“…In addition to the effects of PARP on inflammatory processes, there is evidence that PARP activity may modulate immune cell function (Broomhead and Hudson, 1985;King et al, 1989;McNerney et al, 1989;Weltin et al, 1995;Chiarugi, 2002). However, there is some controversy as to whether or not PARP inhibitors directly interfere with T-cell reactivity which may be explained by differences in the experimental approaches and PARP inhibitors utilized (Broomhead and Hudson, 1985;McNerney et al, 1989;Weltin et al, 1995;Chiarugi, 2002). For example, several widely used pharmacological inhibitors of PARP have also been found to scavenge free radicals in addition to preventing enzyme activity .…”

“…For example, PARP inhibitors have been shown to interfere with lymphocyte proliferation in response to mitogenic stimulation (Broomhead and Hudson, 1985;Weltin et al, 1995). Therefore the reduction in CNS inflammatory processes in MBP-immunized mice treated with PJ34 could conceivably result from an effect on the T-cell response to MBP.…”

Inhibitors of poly(ADP‐ribose) polymerase‐1 suppress transcriptional activation in lymphocytes and ameliorate autoimmune encephalomyelitis in rats

“…These results, along with the evidence that PHE and BZD reduced transcription of Th‐1 cytokines such as IL‐2, IFNγ and TNFα in both cultured lymphocytes and spinal cord of rats with EAE, suggest that PARP‐1 inhibitors impaired the autoimmune response by reducing lymphocyte activation. This hypothesis is corroborated by studies demonstrating that PARP‐1 expression is increased in proliferating lymphocytes (McNerney et al ., 2001) and PARP‐1 inhibitors such as BZD analogues and PHE itself impair B‐ and T‐cell activation in vitro and in vivo (Broomhead & Hudson, 1985; McNerney et al ., 1987; Exley et al ., 1987; Weltin et al ., 1995).…”