D-penicillamine -induced autoimmunity

Tournade, H., et al., (1990) D-penicillamine-induced autoimmunity in Brown-Norway rats. Similarities with HgC12-induced autoimmunity. J. Immunol.,144, 2985, 1990... 

Seguin B, Masson MJ, Uetrecht J D-penicillamine-induced autoimmunity in the Brown Norway rat role for both T and non-T splenocytes in adoptive transfer of tolerance. Chem ResToxicol 2004 17 1299-302. 

Limited information exists on the possible role of the danger hypothesis in chemical-induced autoimmune-like derangements. Interestingly, poly I C has been shown to increase the incidence and severity of D-penicillamine-induced autoimmunity in Brown Norway rats (Sayeh Uetrecht, 2001). 

The Brown Norway rat has also been used to study the adverse immune response to D-penicillamine, with effects similar to those seen in some patients (Tournade et al., 1990). Recently, a series of studies have further explored D-penicillamine-induced autoimmunity in the Brown Norway rat, in particular with respect to immunoregulation (Masson Uetrecht, 2004). Interestingly, only 60-80% of all treated Brown Norway rats develop the autoimmune disease in addition, low-dose pretreatment with D-penicillamine has been shown to tolerize the animals to subsequent normally auto-immunogenic doses (Donker et al., 1984 Masson Uetrecht, 2004). It appeared that the observed tolerance is mediated by immune cells, including T and non-T cells. This again illustrates that idiosyncracy also occurs in animals and moreover that these diseases are subject to regulatory mechanisms. 

Tournade H, Pelletier L, Pasquier R, Vial M-C, Mandet C, Druet P. D-penicillamine-induced autoimmunity in Brown Norway rats similarities with HgCl2-induced autoimmunity. J Immunol 1990 144 2985-2991. 

Seguin B, Teranishi M, Uetrecht JP. Modulation of D-penicillamine-induced autoimmunity in the Brown Norway rat using pharmacological agents that interfere with arachidonic acid metabolism or synthesis of inducible nitric oxide synthase. Toxicology 2003 190 267-278. 

Teunissen MB, Koomen CW, de Waal Malefyt R, Wierenga EA, Bos JD (1998) Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 111 645-649 Toumade H, Pelletier L, Pasquier R, Vial MC, Mandet C, Druet P (1990) D-penicillamine-induced autoimmunity in Brown-Norway rats. Similarities with HgC12-induced autoimmunity. J Immunol 144 2985-2991... 

Guery J-C, Tournade H, Pelletier L, Druet E, Druet P (1990) Rat anti-glomerular basement membrane antibodies in toxin-induced autoimmunity and in chronic graft-versus-host reaction share recurrent idiotypes. Eur J Immunol 20 101-105 Hall C (1982) Gold and D-penicillamine induced renal disease. In Bacon PA, Hadler NM (eds) The kidney and rheumatic disease. Butterworth, London, p246... 

Of all rat strains, the Brown Norway (BN) rat is used most frequently in relation to chemical-induced autoimmunity. This strain displays clinically manifested autoimmune disease following exposure to a number of chemicals. HgCl2 is the most scrutinized compound in the BN rat but D-penicillamine [6-8], gold-salts [9,10],hexachlorobenzene (HCB) [11-14] and recently, nevirapine [15], have all been shown to induce clinical effects. Captopril [7] and felbamate [16] appeared not to induce autoimmune effects in BN rats. 

Only a few drugs have been identified as being capable of inducing autoimmune phenomena in mice. Among these are D-penicillamine, quinidine, streptozotocin (an anti-neoplastic drug that is also used as a model compound to induce diabetes) and procainamide. 

Balazs, T.Jmmunogenetically controlled autoimmune reactions induced by mercury, gold and D-penicillamine in laboratory animals A review from the vantage point of premarketing safety studies. Toxicol. Ind. Health., 3, 331, 1987... 

Masson, M.J., and Uetrecht, J.P., Tolerance induced by low dose D-penicillamine in the brown Norway rat model of drug-induced autoimmunity is immune-mediated. Chem. Res. Toxicol., 17, 82, 2004. 

Monestier, M., Novick, K.E., and Losman, M.J., D-penicillamine- and quinidine-induced antinuclear antibodies in A.SW (H-2s) mice Similarities with autoantibodies in spontaneous and heavy metal-induced autoimmunity. Eur. J. Immunol., 24, 723, 1994. 

Nitrofurantion D-Penicillamine Peripheral neuritis Autoimmunity drug-induced SLE, myasthenia gravis, pemphigus, glomerulonephritis, Goodpasture s disease... 

The exact phenotype of the regulatory T cells in the case of low-dose D-penicillamine tolerance is not known, and non-lymphoid cells probably play a role as well. In another example of drug-induced autoimmune responses, the phenotype of regulatory T cells was identified as CD4+CD25+ (Layland et ah, 2004). In this study, CD4+CD25+ cells isolated from mice (A/J strain) exposed to procainamide, mercuiy(II) chloride, or gold salts were capable of preventing antinuclear antibody formation in similarly treated recipient mice, but also in mice subsequently treated with one of the other two chemicals. 

The adverse effects of D-penicillamine in animals are similar to those observed in humans. A study on the effects of D-penicillamine in various strains of mice indicated that D-penicillamine facilitates the induction of autoantibodies in animals with an inherent susceptibility to autoimmunity (Brik et al., 1995). Studies using the popliteal lymph node assay demonstrated that D-penicillamine is capable of inducing an antigen (i.e. compound)-specific T cell response controlled by non-MHC as well as MHC-linked genetic loci (Hurtenbach et al., 1987). 

A number of studies have been performed to induce systemic immunosensitization and autoimmunity (i.e. autoantibody formation or autoreactive T cells) in mice, and, again, occurrence of disease appears to be strain dependent. Robinson et al. (1986) compared in one study a large number of MHC-defined mouse strains with respect to induction of antinuclear autoantibodies by mercury(II) chloride (subcutaneously, detected after 0.5-2 months), gold salts (intramuscularly, detected after 1-5 months), and D-penicillamine (orally, detected after 4.5-5 months) and reported that A.SW mice were high responders to all three chemicals. 

The potential to induce autoimmune phenomena in mice has been successfully identified for only a few drugs. D-Penicillamine has been shown to induce anti-ssDNA and anti-insulin antibodies in C57BL/Ks (H2d) and C3H/He (H2k) mice but not in Balb/c or C57BL/6 mice after subcutaneous exposure for four weeks (Brik et al., 1995). Also after oral treatment (for 7-8 months, in the drinking-water), D-penicillamine (and in the same study, also quinidine) induced an increase in autoantibodies in A.SW/Sn (H2s) mice (Monestier et al., 1994). 

D-Penicillamine. A drug that is able to induce a variety of autoantibodies and autoimmune diseases (e.g. myasthenia gravis, polymyositis). Disease usually remits within one year after the medication is stopped. 

Myasthenia gravis, acquired. The most well understood autoimmune disease. Muscle weakness usually affecting ocular and oropharyngeal muscles due to an autoimmune attack against the neuromuscular junction (e.g. nicotinic acetylcholine receptor). May be idiopathic, paraneoplastic (thymic tumour), or drug-induced (D -penicillamine). 

Emery P Panayi GS (1989) Autoimmune reactions to D-penicillamine. In Kammuller ME, Bloksma N, Seinen W eds. Autoimmunity and toxicology immune disregulation induced by drugs and chemicals. Amsterdam, Elsevier, pp 167-182. 

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