Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice. A new model of myasthenia gravis.

Abstract

To study the role of the thymus in the cellular pathogenesis of myasthenia gravis (MG) we transplanted thymus tissue fragments from MG thymuses beneath the kidney capsule of severe combined immunodeficiency (SCID) mice. Immunocytochemical studies documented that the human thymus tissues are accepted as long-term grafts in the host SCID mice, with human lymphocytes, thymic stroma, and thymic myoid cells demonstrable in transplanted thymus for at least 15 weeks after transplantation. Human anti-acetylcholine receptor antibodies became detectable 1 to 2 weeks after transplantation, and in most chimeras the titers increased over at least 11 weeks to reach levels typically found in severe human MG. Human Ig deposits were detected at skeletal muscle end-plates, demonstrating that the human (auto)antibodies bound to murine acetylcholine receptor. In contrast, transfers of dissociated thymus cells only lead to a transient increase of anti-acetylcholine receptor antibodies. Our data prove that myasthenia gravis thymus is able to induce and maintain autoantibody production in immunodeprived host animals, and that this tissue contains all cellular components required for autoantibody production. Transplantation of solid thymus tissue seems to transfer an autoimmune microenvironment, which will allow direct studies ofthe mechanism of autosensitization inside the thymus. (J. Clin. Invest. 1992. 90:245-250.)

The severe combined immunodeficient (SCID) mouse as a model for the study of autoimmune diseases

“…Volpe et al [33] detected thyroid-stimulating anti-bodies more readily than anti-TG and anti-TPO. Crossreactivity between human anti-AChR and SCID mouse AChR has been reported [23]. It is conceivable that some mouse autoantigens, for example fragments of myelin-basic protein (MBP) or other CNS antigens, are more related to human autoantigens.…”

Animal Models of Myasthenia Gravis

“…MG-like disease could be induced (a) in rodents by passive transfer of serum from MG patients (15,16), (b) in mice by grafting MG thymus tissue or peripheral blood lymphocytes (17,18), and (c) by local production of IFN-␥ at the NMJ in ␥-IFN-⑀ transgenic mice (14).…”

Transplantation of Systemic Sclerosis (SSc) Skin Grafts into Severe Combined Immunodef icient Mice: Increased Presence of SSc Leukocytes in SSc Skin Grafts and Autoantibody Production following Autologous Leukocyte Transfer

“…26] and developed immunoglobulin deposition in their renal glomeruli [27]. Autoantibodies to thyroglobulin and thyroid peroxidase were expressed in Scid mice after PBMC transfer from patients with au toimmune thyroid disease [28][29][30] or following transplan tation of autoimmune thyroid tissue [31][32][33], Antibodies to the acetylcholine receptor and human IgG deposition at myocyte endplates were found in Scid mice after the transfer of PBMC from patients with myasthenia gravis [34], Antiacetylcholine antibodies were also found in Scid mice that were transplanted with thymus tissue from myasthenia gravis patients [35,36], In other studies, joint destruction mimicking that seen in patients with rheuma toid arthritis could be observed after transplantation of human rheumatoid arthritis synovial tissue into Scid mice [37,38]. Coinjection of allogeneic or autologous PBMC led to selective migration of human T cells to the synovial grafts [39].…”