Severe combined immunodeficient (SCID) mice: a model for investigating human thyroid autoantibody synthesis

Abstract

SUMMARYWe have studied the ability of lymphocytes from the blood, thyroid and lymph nodcsof patients with autoimmune thyroid disease (AITD) to produce aiitoantibodies to thyroglobulin (Tg) and/or thyroid peroxidase (TPO) in SCID mice. Human IgG class Tg and/or TPO antibodies were delectable in plasma from SCiD mice 7 days after transfer of 15-25 x 10'' cells/moiise and ihc highest levels were recorded 2-3 weeks later. In contrast. Tg and/or TPO antibodies were undetcctable in recipients of lymphocytes from thyroid antibody negative controls. AITD thyroid lymphocytes produced the mosi antibody in recipient mice and lower levels were observed in recipients of AITD blood and lymph node lymphocytes. The amounls of Tg and/or TPO tmtibody detected were in accordance with the ability of Ihyroid and lymph node lymphocytes to secrete these autoanlibodies spontaneously in culture (indicating ihc presence of cells activated in the patient) and with the capacity of blood lymphocytes (probably B memory cells) to secrete Tgand/or TPO antibodies in ctilture in response to pokeweed mitogen. Tg antibodies in plasma from SCID recipients of thyroid lymphocytes were of subclasses IgGl. IgG2and !gG4and the proportions closely resembled those of the donor's serum Tg antibodies. Blood lymphocytes transferred to SCID recipients were also able to produce Tg antibodies of subclasses 1. 2 and 4 but the subclass distribution varied between mice and the reason for this is not clear at present. Since SCID mice provide an environment in which B lymphocytes from paiients with AITD can be activated without mitogen to secrete thyroid antibodies, this model will provide a powerful system for elucidating the mechanisms regulating the secretion of hutiian antibodies to Tg and TPO-

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

“…In almost all instances the duration of human autoantibodies in the circulation of SCID mice was relatively short, e.g. for TG antibodies with the earliest onset at 7 days and maximum level between 3 and 4 weeks posttransplant [19]. Some autoantibodies (e.g.…”

“…Macht et al [17] injected in SCID mice populations of PBL depleted of T or B lymphocytes, or depleted of either CD4+ or CD8+ lymphocytes. Reininger et al [18] transferred to SCID mice a line of pre-B lymphocytes, isolated from fetal liver cells of (NZB x NZW) Fi mice, whereas Macht et al [19] injected lymphocytes isolated from lymph nodes that drain the target organ (thyroid). These eells included memory B lymphocytes and activated lymphoblastoid B cells or plasma cells.…”

“…rheumatoid synovium) infiltrated with lymphocytes obtained from patients with autoimmune diseases was usually grafted into SCID mice under the kidney capsule [19,21,23], a common place for xenografts, but Moritae/a/. [22] and Akasu et al [24] successfully grafted thyroid tissue into each groin.…”

“…In several experiments, lymphocytes that infiltrate the human target organ, e.g. thyroid [19], were separated and engrafted to SCID mice, resulting in higher amounts of autoantibodies in these mice compared with transfer of hu-PBL from similar patients. Lymphocytes isolated from synovial fluid and synovial-infiltrating cells of patients with rheumatoid arthritis produced higher levels of rheumatoid factor (RF) in recipient SCID mice than PBL from the same patients [11,20,21].…”

“…With the exception of lymphocytes taken from cerebrospinal fluid (CSF) of patients with multiple sclerosis, which induced central nervous system (CNS) inflammation when transferred intracisternally to SCID mice, and lymphocytes from patients with primary biliary cirrhosis, lymphocytes from patients with other autoimmune diseases did not produce inflammation of the mouse organs. Inflammatory lesions in the corresponding mouse target organs were not observed even when lymphocytes infiltrating the human target organ [19] or tissue infiltrated with lymphocytes (e.g. thyroid) [22,24] were grafted to SCID mice.…”