**5. Therapeutic strategies**

of polymorphisms in genes encoding testosterone, progesterone, and androgens is what trigger an imbalance in the hormone complex with immune system and thus be associated with

266 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

A higher prevalence of arthritis is present in females, but in murine models, it has been shown that for CIA and antibody-induced arthritis models, male mice and rats (CIA only) exhibit a higher prevalence. Castration of male mice produces a high prevalence of arthritis in the SCW

Another hormone that can also be a marker is cortisol secreted during periods of stress. In mice it has been shown to reduce the sensitivity to be induced in the CIA model; therefore, it usually confers some protection [61]. **Tables 2** and **3** summarize the in vivo models for the study of RA and the information of the genetic, immunological, and environmental animal

**Genetic Immunological Environmental**

Arthritis is induced by transfer of antibodies in the serum to susceptible mice, transgenic mice and induced by adjuvants

Generates knowledge about several inflammation-related molecules and their implications in its signaling pathways.

The model of adjuvant arthritis was the first to be described in



1956

a time.

mice

Reference [42, 62] [51, 62] [58, 63, 64]

Transgenic mice C57BL/6, K/BxN DBA 1/J

When in contact with external pollutants, in the animal model, the induction of RA in the CIA

This model gives the facility to know how the environmental influences the intestinal flora and the development of RA.

The main environmental risk factor for the development of arthritis is smoking and the first murine model of this factor was


described in 1992.

obsolete.

model increases.

RA [59].

model [60].

**Characteristic Model**

Model genetic background

Year of development

Phenotypic expression

models used in RA, respectively.

model.

Advantages -A specific genetic model

Limitation - Place of indeterminate integration. - Expensive model. -Variable gene expression

Transgenic mice deficient in a specific gene to evaluate the effect of this in the murine

allows studying how the disease is developed during prolonged periods and with possibility of repetition. -It allows knowing the functioning of the genes involved in RA.

In 1991 the first genetic model was developed, which was of mice that overexpressed the human TNF-α gene

RA, rheumatoid arthritis; CIA, collagen induced arthritis.

**Table 3.** Comparison of animal models for the study of RA.

Over the years, different RA therapies have been developed; one of the most representatives is TNF blockers, which, although effective, generate some notable side effects. The importance of animal models serves to generate the knowledge and evaluation of new therapies [52]. All these models are intended to induce inflammation and subsequent destruction of one or more peripheral joints in different animal species, with rodent species, such as mice and rats, being the most frequently used. The most common administration routes for evaluation of compounds in murine RA models are two, as shown in **Figure 2**. The most common administration route used for molecules including viral vectors such as lentivirus, retrovirus, and adeno-associated virus is intra-articular, which consists of administering a vector that contains a gene with regulatory effects on some mechanism of RA in the joint of the animal model being evaluated. Recently, murine models have been evaluated in which the viral vector is administered systemically (intravenously), and these have been able to reduce the inflammation generated by the disease as well as other clinical symptoms, without decreasing the effectiveness associated with the route of administration [52].

Some of the therapeutical goals of drugs, irrespective of their route of administration, include regularizing cytokine levels, since there is an overproduction of these, adjusting the expression levels of transcriptional products that cause inflammation and bone degradation, and decreasing chemokines and adhesion molecules, all of which are determinants of RA pathogenesis [52].

The models most used for the evaluation of exogenous substances that help reduce the disease are varied [65]; besides they depend on the animal model, as thus illustrated.

**Figure 2.** Animal models in RA. The models that are currently used for the generation of RA in mice and rats are varied and depend on the purpose. This can be generated by adjuvants with susceptible animals or spontaneously with genetically modified animals. There are several routes of administration which depend on the vehicle to be administered; for gene therapy the most used are the intra-articular and systemic routes.

#### **5.1. Rat models**

#### *5.1.1. Streptococcal cell wall (SCW) arthritis*

The SCW arthritis rat model is an experimentally induced inflammatory model with many features which resembles RA in humans. This model is used for studies of pathogenesis, therapy, and obtaining genetic knowledge in the acute and chronic phases of inflammation. Arthritis is induced in strains of rats that are susceptible (Lewis rat strain) and is performed by intraperitoneal injection of peptidoglycan polysaccharide polymers, which are obtained from the cell wall of *Streptococcus pyogenes* group A, D58 strain. This model representatively generates the severity of the arthritis and also generates granulomas in the liver, spleen, and peritoneum, granulomatous enterocolitis, and uveitis [66].

protein of the joint cartilage, and its induction with native collagen and adjuvants produces polyarthritis of a cross-immune response to the homologous collagen. The susceptibility of CIA is linked to the expression of certain complexes such as MHC II, which plays a primordial role in T cells [73]. The generation of antibodies specific for type II collagen is highly characterized. Mice used are B-cell deficient and resistant to developing CIA. The antibodies were shown to induce CIA

Animal Models of Rheumatoid Arthritis http://dx.doi.org/10.5772/intechopen.72554 269

For the generation of this AR model, it is necessary to obtain anti-collagen type II antibodies, which are obtained from a CIA model. These antibodies can be extracted from different bio-

These antibodies are important for the generation of CIA pathogenesis. This transfer shows that arthritis is identical in mice with restriction of T cells. Several studies confirm that the development of the model depends on the joint response of B and T cells toward anti-CII antibodies [75]. The importance of knowing RF in RA is not well understood. It is believed to serve in the formation of immune complexes and in the formation of the complement system, which in turn attracts neutrophils to the site of inflammation [76]. The information is unclear to date, and arthritis is also believed to be induced by the binding of citrullinated peptide epitopes or

This model is discussed in DBA1/J type mice, and since it is generated from a serum with antibodies in a CIA model, its targets are generally the same as IL-1β and TNF-α, although other therapies have also been discussed and approved, such as the inhibition of CTLA41g-

CIA is an autoimmune disease that is generated in rodents that are usually genetically predisposed to present features very similar to arthritis, with these being immunized with type II collagen emulsified with complete Freund's adjuvant [34]. CIA in mice exhibits a restriction to MHC II in animals expressing H-2q and H-2r molecules [79]. Trentham et al. (1980), described the administration of type II collagen from chicken, emulsified in complete Freund's adjuvant (CFA) is capable of producing rat arthritis [80]. It was later described that this disease can also

This experimental model of arthritis was designed and described primarily in rats, but currently a mouse strain with genetic predisposition to arthritis, strain DBA/1, is used [11]. Due to its restriction to MHC II, it is obvious that T lymphocytes play a prominent role in the autoimmune response, both in the production and regulation of pro-inflammatory cytokines and in the modulation of the B-cell response [79]. Activated T lymphocytes also activate macrophages to produce pro-inflammatory cytokines, TNFα, IL-1, and IL-6, among others, inducing the expression of chemokines and adhesion molecules with the consequent infiltration of

Histologically, the CIA presents intense synovitis that correlates with the development of the disease. About 5 weeks after application of type II collagen, the animals develop a polyarthritis

in the DBA1/J mice strain although the arthritis generated is very mild [74].

stimulated T cells and the decrease in B cells with anti-CD20 [78].

polymorphonuclear cells, MN and formation of pannus.

logical matrices such as serum.

by cross-reactivity [77].

*5.2.2. Collagen-induced arthritis*

be induced in mice [81].

Commonly the streptococcal walls are formed by peptidoglycans (PG) bound to specific polysaccharides. These peptidoglycans have the function of triggering chronic arthritis, followed by a systemic response. Once these PGs are deposited in aqueous solution, three events may occur, which may be deposited in articular tissues. These may last a long time that stimulate the macrophages and pro-inflammatory mechanisms of T-cell activation [67].

The SWC model with Lewis rats (endogenous strain that is highly susceptible) is initiated after injection of the PGs in aqueous form. Once the inoculation takes place, it is necessary to observe the animals daily to verify the development of arthritis during the first 6 days, after this they can be checked every 2–3 days for at least 6–8 weeks. The acute response of this model develops from the first 48 hours to the next 10–21 days; finally, the chronic phase is triggered, which persists for several months in the animal model [67].

The conventional way of generating the model is using a systemic approach, which is obtained by intraperitoneal injection. But there are other alternatives that have been used in later years, such as injection of the cell wall intra-articularly. Strategic application will cause local inflammation with edema in 24 hours and after 3 weeks; the inflammation will be very little noticeable but will be accompanied by synovial infiltration of monocytes and remnant lymphocytes. The presence and importance of Th1 cells in the generation of arthritis for this inflammation model have been strongly suggested [68]. A single intraperitoneal administration of the cell wall is sufficient to generate arthritis and cause remission, although early experiments suggest that systemic administration was performed [69]. Among the main therapeutic targets to be evaluated in this model are direct components of the immune system such as cytokines. There are different studies in which inhibiting the IL-37 and P2X7 receptor, regulating the function of IL-10, and decreasing IL-21 production will produce resistance to joint inflammation when presented with this SCW model [70–72].

#### **5.2. Mouse model**

#### *5.2.1. Passive transfer of CIA antibodies*

The gold standard animal model for the study of RA is arthritis induced by collagen (CIA). The induction is performed by injecting type II collagen, which is the most predominant constituent protein of the joint cartilage, and its induction with native collagen and adjuvants produces polyarthritis of a cross-immune response to the homologous collagen. The susceptibility of CIA is linked to the expression of certain complexes such as MHC II, which plays a primordial role in T cells [73].

The generation of antibodies specific for type II collagen is highly characterized. Mice used are B-cell deficient and resistant to developing CIA. The antibodies were shown to induce CIA in the DBA1/J mice strain although the arthritis generated is very mild [74].

For the generation of this AR model, it is necessary to obtain anti-collagen type II antibodies, which are obtained from a CIA model. These antibodies can be extracted from different biological matrices such as serum.

These antibodies are important for the generation of CIA pathogenesis. This transfer shows that arthritis is identical in mice with restriction of T cells. Several studies confirm that the development of the model depends on the joint response of B and T cells toward anti-CII antibodies [75].

The importance of knowing RF in RA is not well understood. It is believed to serve in the formation of immune complexes and in the formation of the complement system, which in turn attracts neutrophils to the site of inflammation [76]. The information is unclear to date, and arthritis is also believed to be induced by the binding of citrullinated peptide epitopes or by cross-reactivity [77].

This model is discussed in DBA1/J type mice, and since it is generated from a serum with antibodies in a CIA model, its targets are generally the same as IL-1β and TNF-α, although other therapies have also been discussed and approved, such as the inhibition of CTLA41gstimulated T cells and the decrease in B cells with anti-CD20 [78].

#### *5.2.2. Collagen-induced arthritis*

**5.1. Rat models**

*5.1.1. Streptococcal cell wall (SCW) arthritis*

peritoneum, granulomatous enterocolitis, and uveitis [66].

268 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

The SCW arthritis rat model is an experimentally induced inflammatory model with many features which resembles RA in humans. This model is used for studies of pathogenesis, therapy, and obtaining genetic knowledge in the acute and chronic phases of inflammation. Arthritis is induced in strains of rats that are susceptible (Lewis rat strain) and is performed by intraperitoneal injection of peptidoglycan polysaccharide polymers, which are obtained from the cell wall of *Streptococcus pyogenes* group A, D58 strain. This model representatively generates the severity of the arthritis and also generates granulomas in the liver, spleen, and

Commonly the streptococcal walls are formed by peptidoglycans (PG) bound to specific polysaccharides. These peptidoglycans have the function of triggering chronic arthritis, followed by a systemic response. Once these PGs are deposited in aqueous solution, three events may occur, which may be deposited in articular tissues. These may last a long time that stimulate

The SWC model with Lewis rats (endogenous strain that is highly susceptible) is initiated after injection of the PGs in aqueous form. Once the inoculation takes place, it is necessary to observe the animals daily to verify the development of arthritis during the first 6 days, after this they can be checked every 2–3 days for at least 6–8 weeks. The acute response of this model develops from the first 48 hours to the next 10–21 days; finally, the chronic phase is

The conventional way of generating the model is using a systemic approach, which is obtained by intraperitoneal injection. But there are other alternatives that have been used in later years, such as injection of the cell wall intra-articularly. Strategic application will cause local inflammation with edema in 24 hours and after 3 weeks; the inflammation will be very little noticeable but will be accompanied by synovial infiltration of monocytes and remnant lymphocytes. The presence and importance of Th1 cells in the generation of arthritis for this inflammation model have been strongly suggested [68]. A single intraperitoneal administration of the cell wall is sufficient to generate arthritis and cause remission, although early experiments suggest that systemic administration was performed [69]. Among the main therapeutic targets to be evaluated in this model are direct components of the immune system such as cytokines. There are different studies in which inhibiting the IL-37 and P2X7 receptor, regulating the function of IL-10, and decreasing IL-21 production will produce resistance to joint inflamma-

The gold standard animal model for the study of RA is arthritis induced by collagen (CIA). The induction is performed by injecting type II collagen, which is the most predominant constituent

the macrophages and pro-inflammatory mechanisms of T-cell activation [67].

triggered, which persists for several months in the animal model [67].

tion when presented with this SCW model [70–72].

*5.2.1. Passive transfer of CIA antibodies*

**5.2. Mouse model**

CIA is an autoimmune disease that is generated in rodents that are usually genetically predisposed to present features very similar to arthritis, with these being immunized with type II collagen emulsified with complete Freund's adjuvant [34]. CIA in mice exhibits a restriction to MHC II in animals expressing H-2q and H-2r molecules [79]. Trentham et al. (1980), described the administration of type II collagen from chicken, emulsified in complete Freund's adjuvant (CFA) is capable of producing rat arthritis [80]. It was later described that this disease can also be induced in mice [81].

This experimental model of arthritis was designed and described primarily in rats, but currently a mouse strain with genetic predisposition to arthritis, strain DBA/1, is used [11]. Due to its restriction to MHC II, it is obvious that T lymphocytes play a prominent role in the autoimmune response, both in the production and regulation of pro-inflammatory cytokines and in the modulation of the B-cell response [79]. Activated T lymphocytes also activate macrophages to produce pro-inflammatory cytokines, TNFα, IL-1, and IL-6, among others, inducing the expression of chemokines and adhesion molecules with the consequent infiltration of polymorphonuclear cells, MN and formation of pannus.

Histologically, the CIA presents intense synovitis that correlates with the development of the disease. About 5 weeks after application of type II collagen, the animals develop a polyarthritis similar to RA that occurs in humans. In general, there is fibrosis and ankylosis of the involved joints, and among the histological alterations, erosion of the subchondral bone and formation of pannus can be observed, also autoantibody formation.

of arthritis. In the case of articular lesions, it is important to note that there is no evidence of a significant increase in the prevalence of this type of disease on IC formation although the recruitment and activation of these cells in IC-induced lesions are considered essential to the

Animal Models of Rheumatoid Arthritis http://dx.doi.org/10.5772/intechopen.72554 271

This model has the advantage that its mechanism of action or effector molecules are generated in a simple way and knowledge of the pathogenesis of the disease is obtained quickly. Among the associated molecules are cytokines IL-1 and TNF-α, essential for the development of the

To generate the induction of RA, FcR, present in mast cells, neutrophils, and macrophages are very important. Activation of the complement pathway, mainly the C5a fragment, which functions as a chemoattractant factor, is also necessary [92, 93]. Also, innate components of the immune system often play an important role in the development of the CIA model. One example is the specificity of the K/BxN model, despite the omnipresence of autoantigen GPI [94].

In this model, the cationic retention principle is used in the passive transfer of anti-lysozyme antibodies in mice, which are injected into the knee with poly-L-lysine-lysozyme. This compound is large enough to be retained in the joints for a prolonged time and contributes to the joint destruction and chronicity of the disease produced by the model. The models with DBA/1 mice show a strong dependence on IL-1, and TNF blockade is usually very ineffective [95].

In this model, immunocomplexes will generate arthritis-like inflammation, which can be triggered in mice and rats (although in a lesser proportion). It is known that complement factors are usually a therapeutic target in this model and have recently added neutrophils, FcRy, and

Mice that are genetically modified will have various uses, such as the removal or introduction of genes for some receptor, cytokines, or other factors that help trigger immune mechanisms in the etiology of RA. Sometimes, spontaneous inflammation occurs, resulting in arthritis or

These models are much discussed at present, due to their ability to generate the disease, without the need to inoculate the animal with adjuvants, antibodies, or some external agent as in

The K/BxN mouse (transgenic KRN T-cell receptor mouse on the background C57BL/6 x NOD) spontaneously develops chronic and progressive inflammation [97]. Clinically visible joint inflammation is observed from the third week of disease onset and thereafter evolves into a chronic and severe type of problem. T cells and B cells generate autoantibodies that promote the perpetuation of disease and joint destruction [98]. In addition to T-cell involvement, B cells secrete autoantibodies that promote joint destruction. Like arthritis with immunocomplexes or passive antibody transfer, and similarly to the CIA model, arthritis can be induced by serum transfer and induces changes in the MHC. Arthritis is mild and nondurable and requires persistence in the injection of serum with anti-CII antibodies. The fragment of Fc immunoglobulins plays an important factor in this model. The K/BxN model is thus an important tool to

disease, as well as macrophages, neutrophils, and mast cells [90, 91].

opsonic components which play a key role in RA inflammation [96].

*5.2.4. Spontaneous arthritis in knockout or transgenic mice*

another inflammatory disorder [52].

the CIA, SWC, and AIA models.

full-blown development of the reaction [89].

All these immunopathological processes of CIA involve a response of T and B lymphocytes. The administration of type II collagen induces a strong activation of cooperating T lymphocytes, which stimulate B lymphocytes to produce antibodies against this protein, and later, a series of antibodies that will interact with cartilage constitutive proteins also activate the complement system. In the serum of arthritic animals, antibodies to different proteins have been detected, in addition to type II collagen [82].

The first antigenic determinants of type II collagen, in the case of DBA 1 mice, have been identified with the H-2q haplotype; the antigenic determinant is between amino acids (aa) 257 and 270 of the protein and in mice with the haplotype H-2r; it is between aa 442 and 456 [83].

Pro-inflammatory cytokines induce synovial cells such as chondrocytes, fibroblasts, and osteoclasts to produce MMPs and other effector molecules, all of which are responsible for cartilage degradation, bone erosion, and fibrosis [84].

B cells also play a key role in the development of CIA. It has been shown that the transfer of immune serum from arthritic mice to healthy mice induces severe inflammation, and although the antibody is no longer detected, the inflammatory response persists. This indicates that the humoral response is capable of triggering more factors that have an important role in establishing the autoimmune response in this model [77].

For the CIA model in rats, the therapeutic agents that have been evaluated are methotrexate and corticosteroids, and for biological targets, it is most common to evaluate the soluble receptor of TNF and IL-1, which have had effective results in decreasing the inflammation generated in the model [85].

CIA model but with mice which is currently the most commonly used with the DBA1/J strain because it has been shown that IL-1β boosts inflammation and perpetuates TNF-α, which have become the main therapeutic targets. Analogous collagen system peptides are currently evaluated for good results by reducing the symptoms of the disease in the murine model [86, 87].

The main route of administration for evaluation of therapeutic compounds, used for this model, is intra-articular; despite being the most used, it has caused controversy in its applicability when used in patients. Therefore, in recent years, efforts have been made to replace it by other means such as the system, which, despite being used recently, has shown favorable results.

#### *5.2.3. Immune complex-induced arthritis (IC)*

There are certain important events in RA as the formation of immunocomplexes. These immunocomplexes have been found in the synovium and joint cartilage of patients with RA [88]. The appearance of such complexes has been associated with the severity of the disease.

The most commonly used experimental models of RA, the antigen-induced arthritis, and the adjuvant-induced arthritis exhibit close resemblance to the pathophysiology of RA. However, they do not allow a precise investigation of the isolated contribution of IC to the development of arthritis. In the case of articular lesions, it is important to note that there is no evidence of a significant increase in the prevalence of this type of disease on IC formation although the recruitment and activation of these cells in IC-induced lesions are considered essential to the full-blown development of the reaction [89].

This model has the advantage that its mechanism of action or effector molecules are generated in a simple way and knowledge of the pathogenesis of the disease is obtained quickly. Among the associated molecules are cytokines IL-1 and TNF-α, essential for the development of the disease, as well as macrophages, neutrophils, and mast cells [90, 91].

To generate the induction of RA, FcR, present in mast cells, neutrophils, and macrophages are very important. Activation of the complement pathway, mainly the C5a fragment, which functions as a chemoattractant factor, is also necessary [92, 93]. Also, innate components of the immune system often play an important role in the development of the CIA model. One example is the specificity of the K/BxN model, despite the omnipresence of autoantigen GPI [94].

In this model, the cationic retention principle is used in the passive transfer of anti-lysozyme antibodies in mice, which are injected into the knee with poly-L-lysine-lysozyme. This compound is large enough to be retained in the joints for a prolonged time and contributes to the joint destruction and chronicity of the disease produced by the model. The models with DBA/1 mice show a strong dependence on IL-1, and TNF blockade is usually very ineffective [95].

In this model, immunocomplexes will generate arthritis-like inflammation, which can be triggered in mice and rats (although in a lesser proportion). It is known that complement factors are usually a therapeutic target in this model and have recently added neutrophils, FcRy, and opsonic components which play a key role in RA inflammation [96].

#### *5.2.4. Spontaneous arthritis in knockout or transgenic mice*

similar to RA that occurs in humans. In general, there is fibrosis and ankylosis of the involved joints, and among the histological alterations, erosion of the subchondral bone and formation

All these immunopathological processes of CIA involve a response of T and B lymphocytes. The administration of type II collagen induces a strong activation of cooperating T lymphocytes, which stimulate B lymphocytes to produce antibodies against this protein, and later, a series of antibodies that will interact with cartilage constitutive proteins also activate the complement system. In the serum of arthritic animals, antibodies to different proteins have

The first antigenic determinants of type II collagen, in the case of DBA 1 mice, have been identified with the H-2q haplotype; the antigenic determinant is between amino acids (aa) 257 and 270 of the protein and in mice with the haplotype H-2r; it is between aa 442 and 456 [83].

Pro-inflammatory cytokines induce synovial cells such as chondrocytes, fibroblasts, and osteoclasts to produce MMPs and other effector molecules, all of which are responsible for

B cells also play a key role in the development of CIA. It has been shown that the transfer of immune serum from arthritic mice to healthy mice induces severe inflammation, and although the antibody is no longer detected, the inflammatory response persists. This indicates that the humoral response is capable of triggering more factors that have an important role in

For the CIA model in rats, the therapeutic agents that have been evaluated are methotrexate and corticosteroids, and for biological targets, it is most common to evaluate the soluble receptor of TNF and IL-1, which have had effective results in decreasing the inflammation

CIA model but with mice which is currently the most commonly used with the DBA1/J strain because it has been shown that IL-1β boosts inflammation and perpetuates TNF-α, which have become the main therapeutic targets. Analogous collagen system peptides are currently evaluated for good results by reducing the symptoms of the disease in the murine model [86, 87].

The main route of administration for evaluation of therapeutic compounds, used for this model, is intra-articular; despite being the most used, it has caused controversy in its applicability when used in patients. Therefore, in recent years, efforts have been made to replace it by other means such as the system, which, despite being used recently, has shown favorable results.

There are certain important events in RA as the formation of immunocomplexes. These immunocomplexes have been found in the synovium and joint cartilage of patients with RA [88]. The appearance of such complexes has been associated with the severity of the disease.

The most commonly used experimental models of RA, the antigen-induced arthritis, and the adjuvant-induced arthritis exhibit close resemblance to the pathophysiology of RA. However, they do not allow a precise investigation of the isolated contribution of IC to the development

of pannus can be observed, also autoantibody formation.

270 Experimental Animal Models of Human Diseases - An Effective Therapeutic Strategy

been detected, in addition to type II collagen [82].

cartilage degradation, bone erosion, and fibrosis [84].

establishing the autoimmune response in this model [77].

generated in the model [85].

*5.2.3. Immune complex-induced arthritis (IC)*

Mice that are genetically modified will have various uses, such as the removal or introduction of genes for some receptor, cytokines, or other factors that help trigger immune mechanisms in the etiology of RA. Sometimes, spontaneous inflammation occurs, resulting in arthritis or another inflammatory disorder [52].

These models are much discussed at present, due to their ability to generate the disease, without the need to inoculate the animal with adjuvants, antibodies, or some external agent as in the CIA, SWC, and AIA models.

The K/BxN mouse (transgenic KRN T-cell receptor mouse on the background C57BL/6 x NOD) spontaneously develops chronic and progressive inflammation [97]. Clinically visible joint inflammation is observed from the third week of disease onset and thereafter evolves into a chronic and severe type of problem. T cells and B cells generate autoantibodies that promote the perpetuation of disease and joint destruction [98]. In addition to T-cell involvement, B cells secrete autoantibodies that promote joint destruction. Like arthritis with immunocomplexes or passive antibody transfer, and similarly to the CIA model, arthritis can be induced by serum transfer and induces changes in the MHC. Arthritis is mild and nondurable and requires persistence in the injection of serum with anti-CII antibodies. The fragment of Fc immunoglobulins plays an important factor in this model. The K/BxN model is thus an important tool to study the role of antibodies in the development of RA [66]. This model alone demonstrates that a specific molecule or antibody is not required to generate arthritis. The receptor of the T cells of the KRN strain recognizes the GPI and, on the other hand, the MHC [99]. This immune recognition of G6PI gives rise to autoantibodies to the isomerase which, when purified, can transfer disease. The relevance of this reactivity to the etiology of RA is unclear. Recognition of G6PI is first obtained by antibodies, and subsequently these can be transferred, although the relevancy of this discovery does not really generate knowledge toward RA.

**6. Future prospect**

intra-articular injection.

**7. Conclusion**

**Acknowledgements**

scholarship holder number 695782.

Animal models, as we have already commented, still are the strongest link to evaluate therapeutic compounds, at least in autoimmune diseases, such as rheumatoid arthritis. In general, each model provides different information about the disease, and it is suggested that for more reliable results, the evaluated compounds have been tested in two different models to have a little more certainty of the effects generated by the molecules that are determined in each experiment. Efforts are currently directed to find a model that can more accurately reproduce the symptoms and signs of RA taking the security of continuing to obtain reliable results. Another strategy is that the route of administration is as aggressive and invasive as possible but reproduces precise results, so other routes are being evaluated such as systemic to thus discontinue

Animal Models of Rheumatoid Arthritis http://dx.doi.org/10.5772/intechopen.72554 273

These studies are carried out with the aim of using as few animals as possible and, in turn, with the least suffering, due to the techniques to inoculate the therapeutic agent to be evaluated, in addition to the fact that the population decline does not interfere in the test results.

Despite decades of research to eradicate the disease, RA remains one of the most prevalent diseases within its scope and even with a well-defined and unknown etiology. Currently, animal models continue to be an effective and necessary tool for the generation of knowledge on most autoimmune diseases including RA. Currently the animal models are still the main link to understand how the immune system attacks its own components (cells or organs), as

Animal models, inducible (CIA models, passive antibody, or streptococcal wall transfer) or spontaneous (knockout mice), have been shown to be useful in understanding unknown processes. For spontaneous models, it is difficult to perceive the mechanism by which the disease in which the therapeutic compounds are evaluated is triggered. In the same way, no animal model shows all the characteristics of the disease and the route by which the therapeutic agent is introduced can generate variation in the results, so this information should be complementary with the evaluation of more routes of administration. It is envisaged that the generation of new molecular techniques will help to determine the complexity of the functioning of RA as well as to evaluate the different routes of administration of therapeutic compounds pending the attainment of low toxicity and wide benefit therapies that are determined and used for clinical phases.

This work was funded in part by CONACyT: INFR-2014-01-225520, INFR-2015-01-254106, SEP-CONACYT-CB-2015-258316, PDCPN-2015-01-63, and SS/IMSS/ISSSTE-CONACYT-2016-01-273144. The first author wants to thank the CONACyT doctorate scholarship, with

well as the evaluation of molecules with therapeutic objectives.

The transgenic T-cell receptor of the krn strain was originally generated to recognize a bovinetype antigen; its discovery was totally serendipity. Different authors have performed different series of studies to define the mechanism of action, the effector phases, as well as the evaluation of cells involved in this animal model of RA [99].

On the other hand, immunization with G6PI induces an inflammatory arthritis that is dependent on T cells in mice that have not been studied, generating clues about the knowledge and use of such a model [100].

In this model, arthritis is produced by transfer of serum antibodies from a previous arthritis model; mice are genetically modified to develop RA when it is induced. The targets in this model are cytokines and chemokines. The absence of these molecules is analyzed to verify if they generate protection or induction of RA and additional information such as the signaling pathway that it alters. The TRANCE/RANKL factor was one of the most used for evaluation of the NF-kB pathway with TNF [101]. The phenotypic characteristics of the major animal models are shown in **Figure 3**.

**Figure 3.** Phenotypic characteristics of animal models. There are different strains of mice and rats used as models for the evaluation of RA; among them the most representative strains are Lewis, DBA 1/J, C57BL/6, and K BxN, which respond to different genotypic and phenotypic characteristics.
