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SP0162 “human scid chimeras: Models to dissect autoimmunity and inflammation”
  1. C. Pitzalis
  1. Musculoskeletal Clinical Academic Unit, Barts and the London NHS Trust, London, United Kingdom

Abstract

Human/SCID mouse chimeras have become a powerful tool to investigate immunological and inflammatory mechanisms involved in the pathogenesis of RA synovitis in leaving human synovial tissues and cells.

In this model, grafted human synovium or its cellular components have been shown to retain features of the diseased tissue with operational cellular and molecular systems, as well as vascularisation and lymphatic drainage that can be investigated by examining/targeting specific pathways within the grafts.

In particular, it has been shown that: a) grafts remain viable and become vascularized by mouse subdermal vessels as early as 7 days post-implantation; b) the graft vasculature forms chimeric anastomoses (human/mouse) at the edge of the transplants, while the transplanted tissue itself maintains expression of human adhesion molecules; c) the anastomoses are patent and functional allowing for the delivery of human cells, antibodies and pharmacological moieties; d) human adhesion molecules can be modulated by intra-graft injection of TNFα correlating with increased migration of human cells into the transplants; e) Chemokines e.g.SDF-1α are functional in this model and human cell migration into the graft can be inhibited by blocking the cognate CXCR4 receptor; f) VEGF induces a dose dependent blood vessel proliferation within synovial grafts; g) by TaqMan QT-PCR grafts can be examined for modulation of human pro-inflammatory cytokines in response to therapies such as biologics or conventional synthetic drugs.

Recently we have used this model to gain direct functional evidence that activation induced cytidine deaminase (AID) positive synovial germinal centre-like structures (GC-LS) support class switch recombination (CSR) and in situ manufacturing of class-switched IgG anti-CCP antibodies in the human grafts, which can be detected in mouse sera.

Thus, the functional information that this model provides in vivo is of great value to increase our understanding of disease pathogenesis and for drug development. This is of particular relevance for drugs in early phase of development when it might be important to obtain more supportive data before going into patients or target expression/modulation, tissue penetration as well as pharmacokinetics and pharmacodynamics. Currently, dose regimens are extrapolated to man from animal models and human cell in vitro systems, which may not be correct. Human-SCID chimeras permits a direct correlation between the dose regime and the degree of target tissue association, related to the effector response in the disease tissue, as well as validation of biomarkers/targets thus providing better understanding of pathobiology and some estimation of optimal dose regimen.

Several groups worldwide have used this model to dissect various immunological/inflammatory mechanisms. Thus, from the literature and our own work it is clear that the human/SCID mouse transplant model represents a robust platform to investigate disease pathogenesis, autoimmunity and facilitate drug development. This presentation will review and discuss current available evidence.

Disclosure of Interest None Declared

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