Experimental animal models for rheumatoid arthritis

Rheumatoid Arthritis (RA) is an autoimmune systemic disorder of unknown etiology and is characterized by chronic inflammation and synovial infiltration of immune cells. RA is associated with decreased life expectancy and quality of life. The research on RA is greatly simplified by animal models that help us to investigate the complex system involving inflammation, immunological tolerance and autoimmunity. The animal models of RA with a proven track record of predictability for efficacy in humans include: collagen type II induced arthritis in rats as well as mice, adjuvant induced arthritis in rats and antigen induced arthritis in several species. The development of novel treatments for RA requires the interplay between clinical observations and studies in animal models. However, each model features a different mechanism driving the disease expression; the benefits of each should be evaluated carefully in making the appropriate choice for the scientific problem to be investigated. In this review article, we focus on animal models of arthritis induced in various species along with the genetic models. The review also discussed the similarity and dissimilarities with respect to human RA.     

Experimental African trypanosomiasis: IFN-gamma mediates early mortality

In this study, we demonstrate that Kupffer cells in the livers of highly susceptible BALB/c mice infected with Trypanosoma congolense were loaded with trypanosomal antigen and appeared highly activated. This was associated with an enlarged capillary bed in the livers and decreased blood pressure of these mice towards the terminal stage. Blocking of murine IL-10 receptor (IL-10R)in vivo shortened the survival time of highly susceptible T. congolense-infected BALB/c mice. Anti-IL-10R treatment decreased the survival of relatively resistant T. congolense-infected C57BL/6 mice dramatically. Blocking of the IL-10R also significantly shortened the survival time of mice infected with T. brucei. The acute death of trypanosome-infected mice treated with anti-IL-10R antibodies in vivo was associated with focal liver necrosis, with significantly increased plasma levels of IL-6, IL-10, IL-12p40 and IFN-gamma and enhanced synthesis of IL-6, IL-12p40 and IFN-gamma by spleen cell cultures. Anti-IL-10R-induced death of T. congolense-infected C57BL/6 mice could be prevented by administration of a neutralizing antibody specific forIFN-gamma. We conclude that phagocytosis of a critical number of trypanosomes by Kupffer cells leads to a systemic inflammatory response syndrome and, depending on the degree of Kupffer cell activation, is followed by death that is mediated by IFN-gamma. The role of trypanosome-pulsed macrophages, T cells and genetic influences is discussed in a synopsis.     

Experimental induction of atherosclerosis in rabbits

Summary By changing the usual dose of cholesterol it was possible to shorten the period of experimental induction of atherosclerosis from 3–6 months to 2 months. The daily dose of cholesterol equalled 1% of the total weight of food fed to the rabbits. This was continued for 2 months. Taking into consideration that large amounts of vegetable oil change the usual diet of the animals, cholesterol was mixed with grated carrots (3 gm of cholesterol to 100 gm of grated carrots).Presented by Active Member AMN SSSR N. N. Anichkov     

Experimental oral candidiasis in animal models

Oral candidiasis is as much the final outcome of the vulnerability of the host as of the virulence of the invading organism. We review here the extensive literature on animal experiments mainly appertaining to the host predisposing factors that initiate and perpetuate these infections. The monkey, rat, and mouse are the choice models for investigating oral candidiasis, but comparisons between the same or different models appear difficult, because of variables such as the study design, the number of animals used, their diet, the differences in Candida strains, and the duration of the studies. These variables notwithstanding, the following could be concluded. (i) The primate model is ideal for investigating Candida-associated denture stomatitis since both erythematous and pseudomembranous lesions have been produced in monkeys with prosthetic plates; they are, however, expensive and difficult to obtain and maintain. (ii) The rat model (both Sprague-Dawley and Wistar) is well proven for observing chronic oral candidal colonization and infection, due to the ease of breeding and handling and their ready availability. (iii) Mice are similar, but in addition there are well characterized variants simulating immunologic and genetic abnormalities (e.g., athymic, euthymic, murine-acquired immune deficiency syndrome, and severe combined immunodeficient models) and hence are used for short-term studies relating the host immune response and oral candidiasis. Nonetheless, an ideal, relatively inexpensive model representative of the human oral environment in ecological and microbiological terms is yet to be described. Until such a model is developed, researchers should pay attention to standardization of the experimental protocols described here to obtain broadly comparable and meaningful data.     

Experimental vaccines in animal models for schistosomiasis

Considerable morbidity and mortality results from the affliction of an estimated 200 million people worldwide by several species of schistosomes; 779 million are exposed to the disease in 74 different countries. Even though anti-parasitic drugs and other control measures, including public hygiene and snail control are available, the advent of an effective vaccine still remains the most potentially powerful means for the control of this disease. The putative vaccine could be administered to small children prior to the time when their contact with infected water is maximal, so as to prevent severe infection in the subsequent years. This review attempts to summarize the status of schistosome vaccine development with special emphasis on functionally important vaccine candidates. The importance of utilizing both murine and nonhuman primate models as a prerequisite for clinical trials is discussed.     

Defect of suppressor cell induction in patients with juvenile rheumatoid arthritis

We studied the suppressor cell activity induced by concanavalin A (Con A) in 9 patients with acute febrile juvenile rheumatoid arthritis (JRA). The suppressor activity of JRA patients was higher than that of normal controls. However, the activity was significantly reduced by treating Con A-activated cells with mitomycin C (MMC) (P less than 0.05). On the other hand, the suppressor activity of normal controls and systemic lupus erythematosus (SLE) patients was not affected by MMC treatment. Two of 5 SLE patients showed low activity even before MMC treatment. The addition of the culture supernatant of Con A-stimulated peripheral blood mononuclear cells from a normal donor restored the induction of suppressor activity of JRA which was decreased by MMC treatment. The results indicated that patients with acute febrile type of JRA had reduced MMC resistant suppressor cell activity and that this was due to a defect in the ability of the cells to produce soluble factors needed to induce MMC resistant suppressor cells.     

Carbohydrate immunity in American trypanosomiasis

Conclusions Glycoconjugates from Trypanosomatidae are strong immunogens in man. They have been studied mainly for the identification of specific and sensitive diagnostic reagents of human disease, selection of structures directly related to the virulence of infective forms, characterization of antigens implicated in autoimmunity, protection of experimentally infected animals and, most importantly, to further our understanding of their role in parasitic developmental cell biology. The multiplicity of their chemical structures forms a complex picture from which several research groups try to discern among individual molecules to build a general view of the parasite interaction with the host. Some molecules seem to mediate parasite-host cell interaction. Since they comprise many components, one may expect a variety of cell receptors to be sequentially or cooperatively recognized. Some are targets for agglutinating and lytic or protective antibodies. Recognition of their relative importance or immunodominance in relation to the type of reaction focused on is of primary importance. The search for specific diagnostic reagents is far from terminated, mainly because more sensitive methods are required for blood-bank donor screening as well as for better definition of the criteria of cure in drug-treated patients. Dispersion of available published information is a result of the use of different research groups of parasites of different developmental phases, strains and sources which makes necessary a careful analysis of data for comparative interpretation. In the case of glycoconjugates, however, a major problem is the correct identification of the chemical structures, so that active substances from cell extracts and supernatant fluids can be comparatively analyzed and assigned specific biological functions. Finally, emphasis should be put on the need for unbiased inspection of all kinds of glycoconjugate species, irrespective of the reagents and methods eventually used to detect the more familiar parasite antigens. The urgent need for fine and ever more sensitive carbohydrate analysis in this field should stimulate creation and maintenance of specialized laboratories with this main objective.     

The reaction of rheumatoid factor with animal gamma-globulins: quantitative considerations

Bis-diazotized benzidine has been conjugated to the γ-globulins of three species to produce soluble aggregates and insoluble aggregates for use in the study of the rheumatoid factor. Soluble aggregates have proved useful in the study of the interaction of rheumatoid factor with human and rabbit γ-globulins by agar diffusion methods. Insoluble complexes have provided a method for the absorption and quantitative determination of the rheumatoid factor capable of reacting with the γ-globulins of various species.

The rheumatoid factor in three sera extensively studied has been demonstrated to consist of a heterogeneous entity, which reacts in toto with human γ-globulin and moieties of which also react with rabbit, bovine and equine γ-globulins. The extent of cross-reactivity with rabbit and bovine γ-globulins has been demonstrated to differ from one serum to another.

The characteristics of the reactivities of rheumatoid factor make it seem most probable that the rheumatoid factor is an antibody to denatured human γ-globulin possessing cross-reactivity with other mammalian γ-globulins.

     

Experimental bovine trypanosomiasis. Changes in serum immunoglobulins,complement and complement components in infected animals.

In three calves experimentally infected with Trypanosoma congolense the amounts of IgG1 and IgG2 were little changed and similar to those of normal animals. IgM increased in amount early in the infection and the amount of the increase appeared related to the parasite burden. The amounts of IgA and IgE were both much decreased and this also appeared related to the numbers of parasites in the blood. There was a decrease in the amounts of total haemolytic complement and complement components C1, C1q and C3 in the infected calves. Furthermore the amounts of properdin fluctuated with the cyclical changes in numbers of T. congolense parasites in the individual calves. No significant change in the amount of C8 was observed. It is considered that activation of both the alternative and the classical complement pathways occurs in trypanosome infected animals but that neither pathway goes to its terminal stages.     

Experimental bovine trypanosomiasis. Changes in the catabolism of serum immunoglobulins and complement components in infected cattle.

The turnover of serum proteins of calves experimentally infected with Trypanosoma congolense was compared to that of normal uninfected cattle. All proteins examined had much increased catabolic rates in infected animals. In normal animals the average half-lives in days for each protein were: IgG1 17.4, IgG2 22.4, IgM 4.8, IgA 3.4, IgE 1.9, C1 5.6 and C3 2.9. In trypanosome infected cattle the average half-lives were IgG1 1.9, IgG2 1.7, IgM 0.9, IgA 1.2, IgE 0.9, C1 1.2 and C3 1.1 days.     

Experimental induction of ring fibers in regenerating skeletal muscle

Light microscopy and electron microscopy were used to study the formation of ring fibers induced experimentally in regenerating muscle subjected to tenotomy-induced tension deficiency. Anterior tibial rat muscles were injured by intramuscular injection of mepivacain, tenotomized at varying stages of the regenerative process, and analyzed 30 days after sectioning the tendon. The combination of regeneration and tenotomy led to the appearance of ring fibers at different developmental stages. Ring fibers were not observed in regenerating control muscles and were scarce in tenotomized controls. Our results showed that the regenerative phase in which tension deficiency was established had a significant influence on the number of developing ring fibers; the number increased when tenotomy was performed during subsarcolemmic myofibrillogenesis in regenerating fibers. As a consequence, one might hypothesize that tension deficiency during muscle fiber repair plays a critical role in ring fiber formation.