Paal Christian Klykken

Assessment of autoimmunity-inducing potential using the brown Norway rat challenge model.

The development of autoimmune disease in humans is thought to occur as a result of the interactions of a genetic predisposition of the host and environmental factors. There is evidence that treatment with certain drugs and exposure to environmental toxicants increase the risk associated with the development and severity of autoimmune disease. When exposed to certain chemicals, Brown Norway (BN) rats develop autoimmune disease similar to human systemic lupus erythematosus (SLE) characterized by elevation of antibody levels to self and non-self antigens which can result in the formation of immune complexes and lead to a fatal glomerulonephritis. A unique characteristic of the BN rat model is that the increase in IgE is self-limiting with levels eventually returning to normal. The objective of these studies was to determine if the BN rat and the self-limiting nature of the IgE response could be used in identifying compounds capable of initiating autoimmune responses. Two compounds known to produce autoimmunity, mercuric chloride and D-penicillamine, were studied as were, trichloroethylene and silicone gel, two agents suspected of inducing autoimmune disease. The results indicated that the BN rat model may prove useful for detecting compounds with the potential to produce autoimmunity, particularly if a HgCl(2) challenge is incorporated into the evaluation.

A silicone-based controlled-release device for accelerated proteolytic debridement of wounds.

A new device for rapid enzymatic debridement of cutaneous wounds has been developed using a controlled‐release, silicone‐based, dried emulsion. A dehydrated serine protease of the subtilisin family, previously untested for wound debridement, was incorporated into the emulsion. This device exhibited excellent storage stability. Moisture from the wound triggered an even, reproducible, and complete release of the enzyme within the first 8 hours. The device maintains a moist wound environment that allows the enzyme to achieve nearly complete digestion of the hardened eschar of full‐thickness burns in a porcine model after an exposure period of 24 hours. Debridement was faster than in untreated wounds or wounds treated with a currently available enzyme ointment. Following rapid enzymatic debridement, healing appeared to progress normally, with no histological evidence of damage to adjacent healthy tissue.

DEVELOPMENT AND VALIDATION OF A LISTERIA MONOCYTOGENES HOST RESISTANCE MODEL IN FEMALE FISCHER 344 RATS

The mouse has been used almost exclusively as the experimental animal for host resistance studies in the United States. Host resistance models in mice have been validated and these types of studies are an integral part of the National Toxicology Programs (NTP) immunotoxicology testing program. Given that the Fischer 344 rat is the animal of choice for the NTPs toxicology studies, it was desirable to develop host resistance assays in this rat strain, eliminating the need to extrapolate doses between mouse and rat models. These studies were aimed at the development and the validation of a host resistance model to Listeria monocytogenes, a gram-positive, facultative intracellular bacterium, in the Fischer 344 rat. The results demonstrated that L. monocytogenes infection in the Fischer 344 rat produces a very similar disease with respect to onset and duration as in the mouse. Animals inoculated with up to 3 105 viable colony forming units (CFU) of L. monocytogenes were capable of resisting overt disease whe...

Antisilicone antibodies are biologically unlikely.

Dear Editor, In the recent publication “The association between silicone implants and both antibodies and autoimmune diseases” [1], the investigators evaluated the sera and capsular tissue from patients undergoing reconstructive procedures for burn scars. Fifteen patients with burn scar contractures were implanted with silicone tissue expanders, while 15 burn patients were not. The investigators reported elevations in serum immunoglobulin (Ig) E and the presence of antisilicone antibodies in the capsular tissue for the silicone-implanted group. Given the historical interest in this topic and the existing consensus that there is no antisilicone immune response, a closer examination of this study is warranted. Tissue expanders typically use the same silicone elastomer as silicone breast implants, which have been extensively studied and scrutinized as a result of the breast implant debate. Three independent review panels have carefully assessed the specific issue of silicone immunogenicity. All three groups concluded that there is no convincing evidence to support an association of silicone breast implants with immune-related human heath conditions [2–4]. One report also pointed out that the enzymelinked immunosorbent assay (ELISA) methodology used to measure antisilicone antibodies is flawed, and the existence of antisilicone antibodies is biologically unlikely [2]. If antisilicone antibodies do not exist, is there a plausible explanation for their observations? A number of studies have demonstrated that proteins, including antibody proteins, will bind nonspecifically to silicone. In the case of Goldblum et al. who first reported on the existence of an antisilicone antibody [5], further research by Goldblum and others determined that these observations were not due to a specific antisilicone antibody but to different circulating levels of albumin [6, 7]. As albumin and IgG can compete for nonspecific adsorption onto silicone substrates, low levels of albumin in their “positive” patient sera allowed for more nonspecific adsorption of the IgG fraction. Theoretical calculations [8] and experimental ELISA-based data [9] confirm the high affinity of human IgGs for silicone surfaces. The elevations in serum IgE also have biologically plausible explanations. A selective increase in serum IgE has been observed following surgical procedures, and the magnitude of increase appears to correlate with the surgical injury intensity [10]. Unfortunately, the investigators failed to account for the additional tissue expander implant procedure in this present study. Alternatively, ethylene oxide (ETO) gas is used to sterilize a variety of silicone medical devices, and residual ETO can react with endogenous proteins to create neo-antigens. In several patients who have experienced silicone shunt malfunctions, there was no evidence of an infection, but the patients presented with elevated eosinophil counts and serum IgE antibodies specifically directed toward ETO protein conjugates [11]. We believe the authors were too quick to reach their conclusions, unaware of other more likely mechanisms and Clin Rheumatol (2008) 27:1077–1078 DOI 10.1007/s10067-008-0913-1

Comments on a Case Report of a Tenckhoff Catheter Allergy

To the Editor: The recent case report by Patel et al. (1), entitled Pruritic Rash and Eosinophilia in a Patient Receiving Peritoneal Dialysis recounts the experience of a 28year-old woman on peritoneal dialysis with rash and eosinophilia. An allergy to the Tenckhoff dialysis catheter was suspected and a patch test gave positive results. Following a successful kidney transplant, dialysis was discontinued, the catheter removed, and the eosinophilia as well as the rash resolved. The positive patch test using ‘‘shaved fragments taken from a new Tenckhoff catheter’’ taken together with the rapid resolution of immune symptoms after catheter explantation suggest that the patient may indeed have had a rare allergic reaction to a material in the catheter. However, the supposition of an allergy to silicone is not supported by the literature. Silicone materials have been extensively studied and scrutinized as a result of the breast implant debate. Three independent review panels (the Institute of Medicine, the National Scientific Panel appointed by the judge for the U.S. Multidistrict Litigation, and the United Kingdom’s Independent Review Group) carefully assessed the specific issue of silicone immunogenicity. All three groups concluded that there is no convincing evidence to support, or lend biologic plausibility to an association of silicone breast implants with immune-related human health conditions. They further found only insufficient or flawed evidence that silicones can elicit an immunotoxic response, trigger a specific immune reaction, or amplify an autoimmune-like disease (2–4). As such, the authors should have considered other sources of antigenic stimulation before using the phrase ‘‘silicone allergy.’’ There is more in the catheter than just silicone. Dialysis catheters are generally sold sterile and ethylene oxide is commonly utilized to sterilize Tenckhoff catheters (5). Residual ethylene oxide can cause tissue reactions ranging from simple allergy (6) to analphylaxis (7) to burns (8). Ethylene oxide is a highly reactive alkylating agent that can react with endogenous proteins to create a neo-antigen and precipitate an allergic reaction (9). In addition, the presence of chemical additives or their by-products might explain the patient’s unusual reaction. Tenckhoff catheters are assembled from several components, including most prominently an extruded silicone elastomer tube with adhered Dacron cuff(s). Room-temperature vulcanizing (RTV) silicone adhesive may be used to bond the Dacron cuff(s) to the silicone tube. The majority of such materials are tin-catalyzed and the immunogenicity of tin moieties has been noted in the clinical literature (10–12). Alternatively, adhesive reaction by-products may have caused false-positive readings in the immune sensitization tests. The most common reaction mechanism for medical silicone RTV adhesives is acetoxy-cure, which liberates acetic acid as a by-product. If the catheter was made with peroxide-initiated silicone rubber, other sources of antigenic stimulation should also have been considered. Residual by-products are generated from the decomposition of the peroxide vulcanization agent and if not properly removed, can adversely affect biocompatibility of the elastomer. Depending on the initiator used peroxide by-products might include 2,4-dichlorobenzoic acid, tert-butyl alcohol, 2-methyl-3-butyn-2-ol, and methyl vinyl ketone (13). Material safety data sheets for 2-methyl-3-butyn2-ol (14–16) and Commission of the European Communities review of methyl vinyl ketone (17) indicate that allergic reactions are possible with these substances. In summary, while initial case reports do add value to the clinical literature, it is incumbent upon the authors to rule out other plausible explanations for their reported observations before using provocative phrases like ‘‘silicone allergy.’’ If the patient’s rash is linked to an allergic response, based on extensive study of silicone implants—critically reviewed by independent scientific panels—it most certainly is not an allergic response to silicone.