ABSTRACT
Although the wide clinical experience shows that vaccines are generally safe, concern has been expressed for a causal link between vaccines and autoimmune diseases. Even though the mechanisms of autoimmunity are ill-elucidated, the role of pre-existing risk factors including genetic predisposition and environmental factors is largely accepted. The present study was undertaken to test the hypothesis that vaccines can promote autoimmunity in genetically-prone individuals when simultaneously exposed to a chemical known to induce autoimmune reactions. Female lupus-prone (NZB x NZW) F(1) mice were given 1 microg or 10 microg of a hepatitis B vaccine at 2-week intervals in conjunction with 40 microg of mercuric chloride three times per week for 6 weeks. A marked increase in serum IgG levels and a slight increase in anti-nuclear autoantibody (ANA) levels were seen in the mice given 10 microg of the vaccine plus mercuric chloride. No straightforward conclusion can be drawn from these results because of the extreme experimental conditions of this study. Nevertheless, the results tend to support the hypothesis that vaccination could enhance the risk of autoimmunity in genetically susceptible individuals when exposed to certain environmental chemicals.
Subject(s)
Autoimmune Diseases/chemically induced , Environmental Exposure/adverse effects , Environmental Pollutants/toxicity , Hepatitis B Vaccines/adverse effects , Mercuric Chloride/toxicity , Animals , Autoantibodies/biosynthesis , Autoantibodies/immunology , Body Weight/drug effects , Cell Nucleus/immunology , DNA/immunology , Female , Fluorescent Antibody Technique, Indirect , Immunoglobulin G/metabolism , Mice , Mice, Inbred NZB , Proteinuria/metabolismABSTRACT
The popliteal lymph node (PLN) assay has been proposed as a tool to predict drugs and chemicals with the potential to induce systemic autoimmune reactions in man. In this assay, weight and cellularity indices typically are the measured endpoints. The present study was conducted to test whether incorporation of tritiated thymidine could improve sensitivity of the PLN assay. Male and female Balb/c mice were injected with 20 microCi of [3H]-methyl-thymidine intravenously 7 days after receiving 0.5, 1 or 2 mg of diphenylhydantoin, streptozotocin, sulfamethoxazole, ofloxacin, phenobarbital, or metformin intradermally. Results obtained with incorporation of tritiated thymidine were compared to weight indices. No consistent or marked differences in these endpoints were noted whatever the compound used. This study shows that incorporation of tritiated thymidine does not improve sensitivity of the PLN assay.
Subject(s)
Drug Evaluation, Preclinical/methods , Local Lymph Node Assay , Lymph Nodes/metabolism , Thymidine/metabolism , Animals , Female , Lymph Nodes/drug effects , Lymph Nodes/immunology , Male , Metformin/immunology , Metformin/toxicity , Mice , Mice, Inbred BALB C , Ofloxacin/immunology , Ofloxacin/toxicity , Phenobarbital/immunology , Phenobarbital/toxicity , Phenytoin/immunology , Phenytoin/toxicity , Random Allocation , Streptozocin/immunology , Streptozocin/toxicity , Sulfamethoxazole/immunology , Sulfamethoxazole/toxicity , TritiumABSTRACT
The exacerbation of pre-existing autoimmune diseases is a potential toxic effect of immunoactive drugs. An increase in the incidence of autoimmune thyroiditis has been noted in patients treated with human recombinant interleukin-2 (rIL-2). In contrast, human rIL-2 tends to protect mice from autoimmunity. As the effects of murine rIL-2 on autoimmunity have not been reported in mice, lupus-prone female (NZBxNZW) F1 mice were treated with 20,000 IU murine rIL-2 intraperitoneally, twice weekly for 13 weeks, beginning at 15 weeks of age. No evidence of an exacerbating effect of murine IL-2 on the lupus disease of (NZBxNZW) F1 mice was observed as no change in the following parameters were seen, namely mean survival time, mean body weight, anti-DNA and antinuclear antibody production. These results show that: 1) like human rIL-2, murine rIL-2 does not exacerbate autoimmunity in mice; 2) the biological effects of human as well as murine rIL-2 in mice differ from those seen with human rIL-2 in man. These latter findings suggest that the selection of the relevant animal species for immunotoxicity studies with recombinant cytokines and derivatives may be less straightforward than previously thought.
Subject(s)
Autoimmunity/drug effects , Interleukin-2/toxicity , Lupus Erythematosus, Systemic/immunology , Animals , Antibodies, Antinuclear/blood , Body Weight/drug effects , DNA/immunology , Female , Humans , Immunoglobulin G/blood , Lupus Erythematosus, Systemic/pathology , Mice , Mice, Inbred NZB , Proteinuria/etiology , Recombinant Proteins/toxicityABSTRACT
The field of vaccines is markedly evolving with the introduction and development of many new concepts and formulations, as well as new indications. Based on the current clinical experience, vaccines can be considered safe in most cases. Nevertheless, allergy and, to a lesser extent, autoimmunity have repeatedly been described or suspected as rare adverse consequences of human vaccines. The mechanisms of these adverse reactions are ill-elucidated, if at all. No animal models have been adequately standardized and validated to predict the risk of allergy and autoimmunity associated with vaccines. However, a number of existing models can be considered for use, but need refinement to be applied to vaccine evaluation. Finally, because the preclinical safety evaluation has not received much attention in the past, efforts should be paid to design specific and cost-effective procedures to meet the current expectations.
