Rheumatoid arthritis (RA) is a chronic autoimmune disease, which affects many organs and systems, but mainly attacks synovial joints and may lead to cartilage destruction and deformation, resulting in chronic pain, severe disability and increased mortality. Despite recent progress, our understanding of the etiology and pathophysiology of RA is still far from complete. Currently, there are numerous animal models of RA-like disease, including K/BxN arthritis, collagen-induced arthritis, antigen-induced arthritis, SKG mutant,
lpr, and IL-1Ra
−/− mice [
1], each of which mirror various aspects of RA. However, a common weakness of all models is the reliance on an entirely murine-based immune response to inflammation. As such, there have been instances where these models have led to contradictory results in therapeutic efficacy studies as compared to RA patients. For example, previous studies that examined the effect of biologic therapy in murine systems of RA-like disease have noted that inhibiting IL-1 provided suppression or complete amelioration of arthritis. However, anti-IL-1 therapy, although very successful in treating autoinflammatory syndromes and systemic juvenile idiopathic arthritis [
2], has limited efficacy in RA patients. One of the closest murine models to human RA is the transgenic mouse expressing the human HLA-DRβ1*0401 (DR4) gene, which develops an RA-like disease following stimulation with collagen or citrullinated peptides [
3]. While this model represents a tremendous discovery as the initiation of the disease is mediated by the expression of the share epitope, it still retains the limitations of all the previous models of RA-like disease, namely that the inflammation is driven by the murine immune system that ectopically express the shared epitope. The central reason for discrepancies between animal models and patients may be attributed to differences between human and murine immune systems. These differences affect both innate and adaptive immunity, including the balance of leukocyte subsets, defensins, toll-like receptors (TLR), inducible NO synthase, NK inhibitory receptor families Ly49 and KIR, FcR, Ig subsets, B cell (BLNK, Btk, and λ5) and T cell (ZAP70 and common γ-chain) signaling pathway components, Thy-1, γδT cells, cytokines and cytokine receptors, Th1/Th2 differentiation, costimulatory molecule expression and function, antigen presenting function of endothelial cells, and chemokine and chemokine receptor expression [
1]. Thus, development of an inflammatory arthritis model using human cells would be useful to understand how the human immune system responds during the course of inflammatory arthritis, and may direct the development of future therapies with improved efficacy as well as selectivity.
Until recently, many attempts to engraft human immune cells into various immunodeficient mice resulted in poor and short-term engraftment, which was mainly attributed to residual activity of the host’s immune system. To overcome these issues three major improvements were made over the last 15 years. First, was the generation of SCID (
Prkdc
Scid
) mice, which have a mutation in the protein kinase, DNA-activated, catalytic polypeptide (
Prkdc) gene and thus lack T- or B-cells but still have high NK-cell activity. These mice were able to sustain a limited and transient engraftment of the human immune system. A second improvement was the introduction of the
SCID mutation into the NOD background, which has substantially decreased activity of NK-cells, deficiency in C5, and inability of macrophages to produce IL-1β in response to stimulation with LPS, as well as other defects of the innate immune system [
4]. Both SCID and NOD-SCID mice have been widely used to study the engraftment of synovial tissue from RA patients [
5]. One study has even shown short-term reconstitution of human bone marrow stem cells in an arthritis model [
6]. However, these models either do not have a functional human immune system and/or support long-term engraftment of hematopoietic cells. A third generation of immunodeficient mice have the deletion of the
IL2rγ gene which is also known as the common cytokine-receptor γ-chain, and is required for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 signaling, and its absence significantly affects functioning of the innate immune system (such as monocytes and neutrophils) and completely prevents NK-cell development [
4]. The three immunodeficient mouse strains that employ this advantage are: BALB/c-
Rag2
−/−
IL2rγ
−/−
, NOD-
Rag1
−/−
IL2rγ
−/−
, and NOD-
scid IL2rγ
null
(the latter is commonly referred as NSG for
N OD
s cid
g amma). The inactivation of the gamma chain of the IL-2 receptor has dramatically improved the engraftment of human cells. While the only cell types that remain in these immunodeficient mice are neutrophils, monocytes/macrophages, and dendritic cells, they are hypofunctional [
7], which is evident by the lack the inflammatory immune response to bacterial and fungal pathogens [
8]. These characteristics allow not only transfer of human peripheral blood mononuclear cells (PBMC), but also support long-term engraftment of human hematopoietic stem cells (HSC). Over time, engrafted HSC undergo multilineage development, resulting in a fully functional human immune system, including T, B, NK and dendritic cells, as well as monocytes/macrophages and granulocytes. Human T cells undergo positive and negative selection in the thymus (which prevents development of the graft versus host disease), display a diverse repertoire of T cell receptors, exhibit human leukocyte dependent cytotoxicity, and produce a delayed type hypersensitivity response. Mature B-cells expressing functional B-cell receptors are readily detected as well as circulating IgM and IgG. Macrophage and dendritic cell production of cytokines and chemokines and presentation of antigens to T-cells have all been demonstrated in the humanized mouse [
4,
9]. This humanized mouse model helped the progression of studies on human-specific infectious diseases, such as HIV, Dengue virus and
Salmonella typhi for which animals are not susceptible [
4,
9]. Moreover, it also uncovered pathophysiological mechanisms involved in sepsis in humans [
10]. However, the tremendous potential of this model to study human autoimmunity has been minimally explored. Here, we developed a unique humanized mouse model for acute inflammatory arthritis. The major strength of this model is the ability to compare and contrast the activity of human immune cells prior to and during the course of inflamma-tory arthritis, which cannot readily be accomplished in patients.