appeared within 3 years of the introduction of the vaccine, and numerous cases were reported in the literature around the turn of the century. Although these complications were initially attributed to the attenuated rabies virus in the vaccine, neurological complications were also found to be frequently associated with administration of the killed virus vaccine, which began in 1919. Thus, it appeared likely that the complications were related to injection of the nervous tissue used for preparation of the vaccine: individuals receiving the vaccine developed antibodies that reacted with brain extracts. The next major advance in the development of animal models for organ-specific autoimmune disease was the demonstration by Rivers and associates (Rivers and Schwentker, 1935) in the 1930s that monkeys repeatedly injected with central nervous system (CNS) extracts developed neurological dysfunction. Pathological examination of injected monkeys disclosed extensive areas of myelin destruction associated with perivascular infiltrates of mononuclear cells. In the model developed by Rivers, induction of experimental allergic encephalomyelitis (EAE) in monkeys required repeated injections of CNS tissue; however, studies in the 1940s demonstrated that the disease could be induced by a single injection of brain antigen emulsified in adjuvant containing killed Mycobacterium tuberculosis (Morgan, 1947; Kabat et al., 1947). This observation formed the basis for the creation of other experimental models of organ-specific disease, all involving injection of tissue-specific antigens in some form of adjuvant.
Multiple sclerosis (MS) is the commonest demyelinating disorder of the brain and spinal cord. The etiology of MS remains unknown, but immune-mediated destruction of myelin is thought to be a likely pathogenic mechanism of CNS damage in this disease. EAE produced by injection of CNS antigens has served for the past 50 years as an excellent animal model for studying the pathogenesis of MS (McFarlin, 1977). The CNS antigen involved was initially identified as myelin basic protein (MBP), and certain sequences were shown to be encephalitogenic for a given species but not for others. The major differences in encephalitogenic activities of MBP from various sources result from minor differences in amino acid composition. Other components of myelin, particularly proteo-lipid protein (PLP), were later shown to be antigenic as well. Early experiments showed that EAE could be passively transferred with T lymphocytes, but not by antibodies, defining EAE as the prototypic cell-mediated, organ-specific autoimmune disease. Although EAE can be induced in many species, the two most widely studied animal models of EAE are those produced in rats and mice. For many years, mice were regarded as relatively resistant to induction of EAE; however, modification of some of the methods used in other species and use of genetically susceptible mouse strains have facilitated the use of mice for studying EAE. One advantage of the mouse model is that whereas EAE in rats is a monophasic illness, in certain mouse strains relapsing forms of the disease can be produced that mimic in many respects the relapsing nature of MS in man. Detailed procedures for inducing active EAE in mice and for transferring the disease to normal recipients (passive EAE) are described in unit 15.1. Methods of inducing EAE in rats, including adoptive transfer (passive EAE) of the disease to normal rats, are described in unit 15.2. One critical requirement for the successful use of either methodology is availability of a purified preparation of CNS antigens. unit 15.1 describes biochemical procedures for purification of bovine MBP and PLP, and unit 15.2 describes techniques for purification of guinea pig MBP. Table 15.1.1 provides a very complete and useful guide to the specific encephalitogenic peptide sequences of both MBP and PLP that are capable of inducing EAE in many inbred mouse strains.
In man, type I or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that results from destruction of the insulin-producing P cells of the islets of Langerhans in the pancreas. The specific lesion of the disease is called insulitis and is manifest as an infiltration of the islets with mononuclear cells, including both CD8+ and CD4+ T cells.
Autoantibodies against islet cells are frequently observed in IDDM, but their role in disease pathogenesis remains poorly defined. T cells specific for a number of islet-cell antigens have also been documented in IDDM, but the nature of the islet-cell antigen(s) responsible for initiation of the disease also remains unknown. There are two major animal models, NOD (non-obese diabetic) mice and BB (BioBreeding) rats (see Tables A.1E.4 and A.1H.1), for the study of spontaneous diabetes; both have many features in common with human IDDM. The BB rat strain originated from a commercial colony of Wistar rats at the BioBreeding Laboratories in Ottawa, Canada. The animals spontaneously develop a disease similar to IDDM, including insulitis and autoantibodies against islet cells (Crisa et al., 1992). A diabetes-resistant (DR) subline of BB rats developed by selective breeding is histocompatible to the diabetes-prone (DP) rats. DP rats have a pronounced lymphopenia due to a lack of T cells. T cells that express the RT6 alloantigen are particularly low in DP rats, and their absence may be crucial to the development of diabetes. Restoration of RT6+ T cells by infusion from DR rats prevented diabetes in DP rats, whereas depletion of the cells by an anti-RT6 antibody triggered diabetes in DR rats. A complete guide to the use of BB rats to study experimental IDDM is presented in unit 15.3. In addition, protocols are provided for the induction of disease in DR-BB rats by depletion of RT6+ T cells and for the prevention of disease in DP-BB rats by transfer of RT6+ T cells from DR-BB rats. One important parameter that must be considered before using the BB rat model is that both susceptibility and incidence of disease can be markedly influenced by the presence of viral infections in the animal colony. Successful use of these animals requires constant monitoring of the animal colony; a support protocol is included detailing serological analysis of serum samples for the presence of antibodies to many viruses and bacteria. unit 15.12 describes another method for inducing diabetes in rats following the removal of regulatory T cells. Thymectomy and irradiation are used to render animals partially T cell deficient. Using the animal model described, rats that do not normally develop autoimmune disease spontaneously develop diabetes following this procedure.
Protocols involving the use of diabetogenic NOD mice are described in unit 15.9. Unlike the BB rat model, NOD mice do not exhibit T cell lymphocytopenia, but rather the inverse. In addition, NOD mice develop IDDM under the influence of their physical environment, particularly diet and exposure to microbial pathogens. A protocol for maintaining NOD mice under conditions permissive of full expression of their autoimmune potential is included in this unit, as are methods for diagnosing and partially quantitating the degree of insulitis developing in such mice. The unit also contains a protocol for isolating T cell pancreatic infiltrates in autoimmune NOD mice for use in adoptive transfer studies or for establishing autoreactive T cell lines. A cell isolation method is provided to prepare pancreatic islet cells as a source of islet antigens. Finally, a protocol is included to guide the investigator in the selection and use of transgenes in NOD mice.
Rheumatoid arthritis is the most common autoimmune disease in man. No animal model completely resembles the human disease. Rheumatoid arthritis is a complex disease and involves antibodies including an IgM anti-IgG autoantibody called rheumatoid factor; some of the tissue damage in this disease is caused by depostion of immune complexes. It is very likely that T cells recognizing a joint antigen(s) also play important roles in disease pathogenesis by secreting cytokines that initiate local inflammation within the joint and promote the recruitment of granulocytes and macrophages, leading to destruction of the joint. MRL-lpr/lpr mice (Table A.1E.4) have a form of arthritis with certain pathologic features in common with human rheumatoid arthritis, and these mice produce high levels of IgM and IgG rheumatoid factors. Several different experimental models that have some features in common with human rheumatoid arthritis have been developed in mice and rats, including collagen-induced arthritis, adjuvant arthritis, and streptococcal
Animal Models for Autoimmune and
Was this article helpful?
Did You Know That Herbs and Spices Have Been Used to Treat Rheumatoid Arthritis Successfully for Thousands of Years Do you suffer with rheumatoid arthritis Would you like to know which herbs and spices naturally reduce inflammation and pain 'Treating Rheumatoid Arthritis with Herbs, Spices and Roots' is a short report which shows you where to start.