Engraftment of human lymphocytes and thyroid tissue into scid and rag2- deficient mice: Absent progression of lymphocytic infiltration
To study human autoimmune thyroid disease in an animal model we have investigated the in vivo survival of human thyroid tissues and functionality of human lymphocytes in severe combined immunodeficient (scid) mice and recombination-activating gene (rag2) knockout mice. We found successful engraftment of human thyroid tissues in both scid and rag2-deficient mice. However, when peripheral blood mononuclear cells were transplanted ip, human immunoglobulin production was poor in rag2-deficient mice compared to that in scid mice (mean human immunoglobulin G levels at 6 weeks, 0.2 +/- 0.2 microgram/mL in two of eight rag2-deficient mice compared to 20.8 +/- 7.0 micrograms/mL in seven of nine scid mice; P < 0.05). We, therefore, only pursued the further use of scid mice and transplanted them with thyroid tissue from patients with either Graves' disease (four patients) or Hashimoto's thyroiditis (one patient). At the functional level, we observed transiently increased thyroid hormone levels (T4 peaking at 5.4 +/- 0.2 microgram/dL compared to a normal level of 2.6 +/- 0.2 microgram/dL); human autoantibodies to human thyroglobulin, human thyroid peroxidase, and the human TSH receptor were also detected in thyroid-transplanted mice. In contrast to recent reports, histological examination of the thyroid explants showed no increase in the lymphocytic infiltrate compared to the original donor tissue, nor was there any thyroid follicular destruction observed. In fact, many of the transplants demonstrated a marked diminution in the infiltrates over time, with an absence of HLA-DR antigen expression by both T-cells and thyrocytes. Cotransplanted allogeneic thyroid tissues were unremarkable in terms of lymphocytic infiltrates and showed intact morphology. Taken together, these data point to a relative degree of T-cell inactivity within the thyroid explants from the scid mouse. Hence, a factor(s) present in the patient with autoimmune thyroid disease that activates their thyroid-specific T-cells may be absent in this murine model as presently constructed.
Available from: Manon Huibers
- "Rag1 or Rag2 mutation in NOD-scid mice solved the leakiness-problem, but engraftment levels in these Ragmice remained low    and problems with development of lymphomas, as described in earlier models with NOD-scid, persisted  . Mice with a knockout of either Rag1 or Rag2 have a very similar phenotype to scid-knockout mice in the immune system (elimination of T and B cells), but they do not have the side effect of radiation sensitivity. "
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ABSTRACT: The interest in the use of humanized mouse models for research topics like Graft versus Host Disease (GvHD), allograft studies and other studies to the human immune system is growing. The design of these models is still improving and enables even more complicated studies to these topics. For researchers it can be difficult to choose the best option from the current pool of available models. The decision will depend on which hypothesis needs to be tested, in which field of interest, and therefore 'the best model' will differ from one to another. In this review, we provide a guide to the most common available humanized mouse models, with regards to different mouse strains, transplantation material, transplantation techniques, pre- and post-conditioning and references to advantages and disadvantages. Also, an evaluation of experiences with humanized mouse models in studies on GvHD and allograft rejection is provided.
- "Rag-2 knock-out mice have been successfully engrafted with human liver cells or thyroid tissue (Martin et al., 1994; Brown et al., 2000). However, engraftment of human lymphocytes, including human PBL, was limited in Rag-1-or Rag-2-deficient mice as judged by low production of human Ig in mouse sera and of human B and T cells in xenochimeric animals (Martin et al., 1994; Steinsvik et al., 1995; Berney et al., 2001b). Engraftment of human PBL can be optimized using Rag- 2-deficient mice in which the common cytokine receptor gamma chain has been knocked-out. "
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ABSTRACT: Laboratory models enabling to study in vivo human leukocyte functions have been developed. Most of the models consist of human immunocytes transferred to mice homozygous for the scid mutation. Mice with additional immunodeficient-prone genetic background or with immunodeficiency-induced conditioning have also been used. Human grafts mainly consisted of human immune cells in suspension injected intraperitoneally, or in pieces of human organs containing immunocytes implanted subcutaneously. Cells in suspension could be easily manipulated in vitro before transfer to the animal, but disseminated within the mouse body. In opposition, human cells mostly remained within implantation areas of animals given human organ pieces. This favorizes cell interactions and helps for cell recovery after their in vivo passage. Moreover, the diversity of antibodies in animals transplanted with human lymphoid organ pieces appeared broader than that of mice transferred with lymphocytes in suspension. Spontaneous recall antibody and autoantibody productions have been generally observed in animals transferred with cells from donors with such antibodies. In vivo boosting of recall antibody by antigen has been most successful, but such a manipulation inconstantly boosted autoantibodies. Primary human T and B cell responses were difficult to obtain in xenochimeric animals, and success has been generally obtained by optimizing human immune response parameters, such as antigen presentation.
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