Abstract
BackgroundSubstantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA). Current murine models of RA-like disease have provided great insights into the molecular mechanism of inflammatory arthritis due to the use of genetically deficient or transgenic mice. However, these studies are limited by differences that exist between human and murine immune systems. Thus, the development of an animal model that utilizes human immune cells, will afford the opportunity to study their function in the initiation and propagation of inflammatory arthritis.MethodsOne to two-day old irradiated NOD-scid IL2rγnull (NSG) mice were reconstituted with human CD34+ cord blood stem cells. Leukocytes were analyzed by flow cytometry and circulating antibodies were determined by ELISA. Arthritis was induced by injecting complete Freund’s adjuvant into knee or ankle joints. Mice were also treated with the TNF inhibitor, Etanercept, or PBS and joints were analyzed histologically.ResultsHumanized mice were established with high reconstitution rates and were able to spontaneously produce human immunoglobulins as well as specific IgG in response to immunization. Intraperitoneal injection of thioglycolate or injection of complete Freund’s adjuvant into joints resulted in migration of human immune cells to the injected sites. Arthritic humanized mice treated with Etanercept had markedly less inflammation, which was associated with decreased total numbers of human CD45+ cells, including human lymphocytes and neutrophils.ConclusionsThe humanized mouse model is a new model to study inflammatory arthritis disease using human leukocytes without rejection of engrafted tissue. Future studies may adapt this system to incorporate RA patient cord blood and develop a chimeric animal model of inflammatory arthritis using genetically predisposed immune cells.
Highlights
Substantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA)
One-day old irradiated NOD-scid IL2rγnull (NSG) pups were reconstituted with human CD34+ cord blood stem cells, similar to prior studies [11]
In contrast to cord blood stem cells, CD34+ stem cells isolated from peripheral blood of healthy adult volunteers were unable to reconstitute the immune system of irradiated newborn NSG mice, consistent with a recent report [19]
Summary
Substantial advances have been generated in understanding the pathogenesis of rheumatoid arthritis (RA). Current murine models of RA-like disease have provided great insights into the molecular mechanism of inflammatory arthritis due to the use of genetically deficient or transgenic mice These studies are limited by differences that exist between human and murine immune systems. There are numerous animal models of RA-like disease, including K/ BxN arthritis, collagen-induced arthritis, antigen-induced is the transgenic mouse expressing the human HLADRβ1*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. 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
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