Effective treatment of autoimmune disease and progressive renal disease by mixed bone-marrow transplantation that establishes a stable mixed chimerism in BXSB recipient mice

Abstract

Male BXSB mice spontaneously develop autoimmune disease with features similar to systemic lupus erythematosus. To determine whether this autoimmune disease can be treated as well as prevented by bone-marrow transplantation (BMT) and, at the same time, whether the immunity functions of lethally irradiated recipients can be reconstituted fully, male BXSB mice were engrafted with mixed T cell-depleted marrow (TCDM) both from fully allogeneic autoimmune-resistant BALB/c mice and from syngeneic autoimmune-prone BXSB mice, after the onset of autoimmune disease in the recipient mice. BMT with mixed TCDM from both resistant and susceptible strains of mice (mixed BMT) established stable mixed chimerism, prolonged the median life span, and arrested development of glomerulonephritis in BXSB mice. BMT with mixed TCDM also reduced the formation of anti-DNA antibodies that are observed typically in male mice of this strain. Furthermore, mixed BMT reconstituted the primary antibody production in BXSB recipients impressively. These findings indicate that transplantation of allogeneic autoimmune-resistant TCDM plus syngeneic autoimmune-prone TCDM into lethally irradiated BXSB mice can be used to treat autoimmune and renal disease in this strain of mice. In addition, this dual bone-marrow transplantation reconstitutes the immunity functions and avoids the immunodeficiencies that occur regularly in fully allogeneic chimeras after total body irradiation. This report describes an effective treatment of progressive renal disease and autoimmunity by establishing a stable mixed chimerism of TCDM transplantation from allogeneic autoimmune-resistant BALB/c mice plus syngeneic autoimmune-prone BXSB mice into BXSB mice.

Figure 1

Survival curves of male BXSB mice exposed to 9.5 Gy of TBI (¹³⁷Cs irradiation; 0.70 Gy/min) and given TCDM cells intravenously at 16 weeks of age, after the occurrence of autoimmune disease: BALB/c + BXSB → BXSB group (squares; group I; n = 18); BALB/c → BXSB group (triangles; group II, n = 8); and BXSB → BXSB group (circles; group III; n = 7). Untreated BXSB mice served as controls (diamonds; n = 8).

Figure 2

Histopathology of kidneys from BXSB recipients transplanted with mixed TCDM. Representative histological appearance of glomerular lesions of kidneys from 50-week-old untreated mice or chimeras, taken from biopsies of 16-week-old BXSB mice (A), untreated BXSB mice (B), BALB/c + BXSB → BXSB mice (C), BXSB → BXSB mice (D), BALB/c → BXSB mice (E), and C57BL/6 mice (F). The tissues were stained with periodic acid-Schiff reagent (×400).

Figure 3

Primary anti-SRBC antibody response in BXSB recipients transplanted with TCDM cells. Bars: BXSB (A), BALB/c + BXSB → BXSB (B), BALB/c → BXSB (C), BXSB → BXSB (D), C57BL/6 (E), C57BL/6 → C57BL/6 (F), and BALB/c → C57BL/6 (G). PFC data are given per 5 × 10⁵ spleen cells.

Figure 4

Serum levels of anti-dsDNA autoantibodies of TCDM-recipient male BXSB mice at 50 weeks of age. Untreated BXSB mice served as controls. BXSB, untreated BXSB mice; Group I, BALB/c + BXSB → BXSB chimeras; Group II, BALB/c → BXSB chimeras; Group III, BXSB → BXSB transplants.