Since genotypes, sex and age difference affects the introduction of autoimmune complication; selection of an appropriate animal model is important to investigate the pathogenesis of ARF/RHD and associated complications. to better understanding of the fundamental mechanisms underpinning features of ARF/RHD. In the Lewis rat autoimmune valvulitis model the Rabbit Polyclonal to FOXD3 development of myocarditis and valvulitis with the infiltration of mononuclear cells along with generation of antibodies that cross-react with cardiac tissue proteins following exposure to GAS antigens were found to be similar to ARF/RHD. We have recently shown that Lewis rats injected with recombinant GAS antigens simultaneously developed cardiac and neurobehavioral changes. Since ARF/RHD is multifactorial in origin, an animal model which exhibit the characteristics of several of the cardinal diagnostic criteria observed in ARF/RHD, would be advantageous to determine the early immune responses to facilitate biomarker discovery as well as provide a suitable model to evaluate treatment options, safety and efficacy of vaccine candidates. This review focuses on some of the common small animals and their advantages and limitations. toxin injection and booster injection of GAS antigens. (B) Antibody and T cell response can be assessed in brain, heart and knee joints following injection of GAS antigens. (C) Standard behavioral tests to assess neurobehavioral changes following exposure to GAS antigens. (D) ECG and ECHO changes will demonstrate impairment cardiac function. (E) Characteristic mononuclear cell infiltration in the myocardium and valvular tissue (arrows) can be demonstrated in the histological sections of cardiac tissue from rats injected with GAS antigens. (F) IgG deposition can be demonstrated in sections of brain following incubation with sera from rats exposed to GAS antigens. CFA, Complete Freund’s Adjuvant; IFA, Complete Freund’s Adjuvant; PBS, Phosphate Buffered Saline; GAS rM5, Recombinant M5 protein of Group A streptococcus; ELISA, Enzyme Linked Immunosorbent Assay; Th, Helper T-cell; TNF, Tumor Necrosis Factor; IFN, Interferon; IgG, immunoglobulin G; IL, interleukin; MNC, Mononuclear Cell. The hallmark features of ARF/RHD includes lesions in myocardium and valves (Figure 1E). In Hoechst 33342 Lewis rats repeat injection with whole-killed GAS or recombinant GAS M proteins induced tissue cross-reactive antibodies and T cells (26, 27, 30, 31, 33, 34, 46, 48). Moreover, the involvement of Th-17 cells and associated regulators observed in the pathological process may potentially be considered as biomarkers for RHD (Figure 1B) (49, 50). In a separate experiment, in response to different streptococcal antigens, including both GAS and subsp. (SDSE/GGS), Lewis rats developed typical histological lesions with infiltration of inflammatory cells into cardiac tissue providing experimental evidence that streptococci other than GAS could trigger and/or exacerbate post-streptococcal carditis (Table 1). Lewis rats were also used to assess the preclinical immunogenicity and safety of a GAS M protein-based vaccine candidate (51, 52). Therefore, the Hoechst 33342 Lewis rat model is not only useful in elucidating the pathophysiological mechanisms in ARF/RHD, but also provides an opportunity to identify, validate streptococcal epitopes that are truly pathogenic to ARF/RHD. It also enables the assessment of safety and efficacy of GAS antigen based prototype vaccine candidates (51, 52). Animal Models of Neurobehavioral Complications Associated With Streptococcal Infection The two major neurobehavioral complications associated with post GAS infections are Sydenham chorea (SC) and pediatric autoimmune neuropsychiatric disorders associated with streptococcus (PANDAS) (53). SC is a neurological movement disorder described in ARF and is one of the major criterions for the diagnosis ARF (18). PANDAS is a sudden onset of obsessive-compulsive disorder (OCD) associated with GAS infection and not known to be clinically associated with ARF (54). The complex immunopathological mechanisms that mediated immune damage following GAS infections that leads to SC and PANDAS remain unclear (55). However, it has been shown that antibodies against GAS cross-react with neurotransmitter receptors (D1 and D2 dopamine Hoechst 33342 receptors), signaling kinases and ion channels, located primarily in the basal ganglia of the brain in susceptible hosts due to molecular mimicry (56). In the past many studies have been carried out to develop an animal model to investigate the post streptococcal neurobehavioral disorders (Table 1) (57C62). Initial experiments were carried.